PROGRESS REPORT JUNE 2013

Transcription

PROGRESS REPORT
JUNE 2013
National Heart, Lung, and Blood Institute
Building 31, Room 5A52, 31 Center Drive MSC 2486, Bethesda, MD 20892 USA
Phone: (301) 592-8573 Fax: (240) 629-3246
National Cancer Institute
6116 Executive Boulevard, Suite 300, Bethesda, MD 20892-8322
Phone: (800) 422-6237
Center for International Blood and Marrow Transplant Research
9200 W. Wisconsin Avenue, Suite C5500, Milwaukee, WI 53226 USA
Phone: (414) 805-0700 Fax: (414) 805-0714
The EMMES Corporation
401 N. Washington Street, Suite 700, Rockville, MD 20850 USA
Phone: (301) 251-1161 Fax: (301) 251-1355
National Marrow Donor Program
3001 Broadway Street NE, Suite 100, Minneapolis, MN 55413 USA
Phone: (612) 627-5800 Fax: (612) 362-3415
This is a publication of the Blood and Marrow Transplant Clinical Trials Network Data and Coordinating Center
© 2013 All Rights Reserved
Blood and Marrow Transplant Clinical Trials Network Progress Report 2013
Table of Contents
Table of Contents
1.0 Overview and Significance .................................................................................................................................................. 1
1.1 The Value the BMT CTN Brings to the HCT Community ........................................................................................ 2
1.1.1 Extensive Areas of Study ......................................................................................................................................... 2
1.1.2 Accrual Leverage ....................................................................................................................................................... 2
1.1.3 Dissemination of Results .......................................................................................................................................... 3
1.1.3.1 Abstracts ................................................................................................................................................................ 3
1.1.3.2 Publications ........................................................................................................................................................... 3
1.1.4 Significant Findings and Impact ............................................................................................................................. 3
1.1.5 Biorepository Resource............................................................................................................................................. 7
1.1.6 Funding Leverage...................................................................................................................................................... 7
1.1.7 Key Collaborations .................................................................................................................................................... 8
1.1.8 Goals for Next Reporting Period ............................................................................................................................ 8
1.1.8.1 Anticipated Results .............................................................................................................................................. 8
1.1.8.2 Studies to be Activated........................................................................................................................................ 8
1.1.8.3 Future Study Concepts........................................................................................................................................ 8
2.0 BMT CTN Organizational Overview ............................................................................................................................... 10
2.1 Data and Coordinating Center (DCC) ........................................................................................................................ 10
2.2 Clinical Centers ............................................................................................................................................................... 11
2.2.1 Core Centers ............................................................................................................................................................. 11
2.2.2 Affiliate Centers ....................................................................................................................................................... 11
2.3 BMT CTN Committee Structure .................................................................................................................................. 11
2.3.1 Steering Committee................................................................................................................................................. 11
2.3.2 Protocol Teams......................................................................................................................................................... 11
2.3.3 Technical Committees ............................................................................................................................................ 12
2.3.3.1 Biomarkers Committee ..................................................................................................................................... 12
2.3.3.2 Clinical Research Associates Committee ....................................................................................................... 13
2.3.3.3 Pharmacy Committee ........................................................................................................................................ 13
2.3.3.4 Special Populations Committee....................................................................................................................... 13
2.3.3.5 Toxicity and Supportive Care Committee ..................................................................................................... 13
2.3.4 Administrative Committees .................................................................................................................................. 14
2.3.4.1 Executive Committees ....................................................................................................................................... 14
2.3.4.2 Publications, Abstracts, and Presentations Committee............................................................................... 14
2.3.5 Ad Hoc Committees................................................................................................................................................ 14
2.3.6 Scientific Advisory Committees ........................................................................................................................... 14
2.3.7 Review Committees ................................................................................................................................................ 15
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3.0 Administrative Functions of the DCC ............................................................................................................................. 16
3.1 DCC Partner Organizations .......................................................................................................................................... 16
3.2 Policies and Procedures ................................................................................................................................................. 19
3.3 Administrative Support ................................................................................................................................................. 19
3.4 Fiscal Planning and Contracting Support .................................................................................................................. 20
3.4.1 Cost-Saving Mechanisms ....................................................................................................................................... 20
3.5 Communication ............................................................................................................................................................... 21
3.5.1 Maintaining BMT CTN Websites ......................................................................................................................... 21
3.5.2 Developing Patient Support and Marketing Materials .................................................................................... 22
3.5.3 Communicating Trial Results ............................................................................................................................... 22
3.6 Training… ........................................................................................................................................................................ 22
3.7 Transplant Center Monitoring...................................................................................................................................... 23
3.8 Specimen Repository Support ...................................................................................................................................... 23
3.8.1 Specimen Collection................................................................................................................................................ 23
3.8.2 BMT CTN Research Sample Repository and Central Processing Lab ........................................................... 25
3.8.3 Maximizing Sample Handling .............................................................................................................................. 25
4.0 Concept to Publication: The Protocol Process ................................................................................................................ 27
4.1 Concept Evaluation and Approval .............................................................................................................................. 27
4.1.1 DCC Review ............................................................................................................................................................. 28
4.1.2 Executive Committee Review ............................................................................................................................... 28
4.1.3 Steering Committee Review .................................................................................................................................. 28
4.2 Protocol Development ................................................................................................................................................... 28
4.2.1 Establishment of a Protocol Team ........................................................................................................................ 28
4.2.2 Statistical Design...................................................................................................................................................... 29
4.2.3 Accrual Planning ..................................................................................................................................................... 29
4.2.4 Budget Preparation ................................................................................................................................................. 30
4.2.5 Federal Regulations................................................................................................................................................. 30
4.2.6 Final Draft Protocol ................................................................................................................................................. 30
4.3 Protocol Approval........................................................................................................................................................... 30
4.3.1 Steering Committee Review .................................................................................................................................. 31
4.3.2 Protocol Review Committee .................................................................................................................................. 31
4.3.3 Data and Safety Monitoring Board Review ........................................................................................................ 31
4.3.4 Final Review Prior to Release to Centers ............................................................................................................ 32
4.4 Protocol Pre-Activation.................................................................................................................................................. 32
4.4.1 Designing Case Report Forms............................................................................................................................... 32
4.4.2 Educational materials and other study documents .......................................................................................... 33
4.4.3 Release to Center Institutional Review Boards .................................................................................................. 33
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4.4.4 Site Initiation Training ............................................................................................................................................ 33
4.4.5 Medical Monitor Assignment ............................................................................................................................... 33
4.5 Protocol Activation ......................................................................................................................................................... 34
4.6 Protocol Maintenance..................................................................................................................................................... 34
4.6.1 Accrual Monitoring and Intervention ................................................................................................................. 34
4.6.2 High-Quality Clinical and Laboratory Data Collection ................................................................................... 34
4.6.2.1 AdvantageEDC................................................................................................................................................... 35
4.6.2.2 Specimen Tracking with GlobalTrace and Staff ........................................................................................... 35
4.6.2.3 CIBMTR Data Reports ....................................................................................................................................... 36
4.6.3 Data Audits............................................................................................................................................................... 36
4.6.4 Amendments ............................................................................................................................................................ 36
4.7 Study Completion ........................................................................................................................................................... 36
4.7.1 Notice to Cease Enrollment ................................................................................................................................... 36
4.7.2 Follow-up Data Collection after Closure ............................................................................................................ 37
4.7.3 Data Review and Analysis ..................................................................................................................................... 37
4.8 Dissemination of Results ............................................................................................................................................... 37
4.8.1 Authorship................................................................................................................................................................ 37
4.9 Ancillary and Correlative Studies................................................................................................................................ 38
5.0 Collaborations with other NIH-funded Research Networks ...................................................................................... 44
6.0 Future Directions ................................................................................................................................................................. 45
6.1 Planning for the Current Grant Cycle ......................................................................................................................... 45
6.2 Protocol Projections 2013-2014 ..................................................................................................................................... 45
6.2.1 Protocols Nearing Completion ............................................................................................................................. 45
6.2.2 Protocols Activated During the Reporting Period ............................................................................................ 46
6.2.3 Protocols Anticipated to be Activated ................................................................................................................. 46
6.3 Conclusions ...................................................................................................................................................................... 47
7.0 Protocol Descriptions .......................................................................................................................................................... 48
7.1 Protocols Open to Accrual............................................................................................................................................. 49
BMT CTN 0301 .................................................................................................................................................................. 50
BMT CTN 0601 .................................................................................................................................................................. 52
BMT CTN 0702 .................................................................................................................................................................. 54
BMT CTN 0801 .................................................................................................................................................................. 56
BMT CTN 0803 .................................................................................................................................................................. 58
BMT CTN 0804 / CALGB 100701 ................................................................................................................................... 60
BMT CTN 0805 / SWOG 0805......................................................................................................................................... 62
BMT CTN 0901 .................................................................................................................................................................. 64
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BMT CTN 0903 .................................................................................................................................................................. 66
BMT CTN 1101 .................................................................................................................................................................. 68
7.2 Protocols that Completed Accrual ............................................................................................................................... 71
BMT CTN 0101 .................................................................................................................................................................. 72
BMT CTN 0102 .................................................................................................................................................................. 74
BMT CTN 0201 .................................................................................................................................................................. 76
BMT CTN 0202 .................................................................................................................................................................. 78
BMT CTN 0302 .................................................................................................................................................................. 80
BMT CTN 0303 .................................................................................................................................................................. 82
BMT CTN 0401 .................................................................................................................................................................. 84
BMT CTN 0402 .................................................................................................................................................................. 86
BMT CTN 0403 .................................................................................................................................................................. 88
BMT CTN 0501 .................................................................................................................................................................. 90
BMT CTN 0502 / CALGB 100103 ................................................................................................................................... 92
BMT CTN 0603 .................................................................................................................................................................. 94
BMT CTN 0604 .................................................................................................................................................................. 96
BMT CTN 0701 .................................................................................................................................................................. 98
BMT CTN 0703 / SWOG 0410....................................................................................................................................... 100
BMT CTN 0704 / CALGB 100104 / ECOG 100104..................................................................................................... 102
BMT CTN 0802 ................................................................................................................................................................ 104
BMT CTN 0902 ................................................................................................................................................................ 106
7.3 Protocols Released to Centers ..................................................................................................................................... 109
BMT CTN 1202 ................................................................................................................................................................ 110
Attachment A: Data and Coordinating Center Organizational Structure .................................................................... 113
Attachment B: Core and Affiliation Centers ....................................................................................................................... 114
Attachment B1: Core Centers............................................................................................................................................ 114
Attachment B2: Affiliate Centers...................................................................................................................................... 117
Attachment C: Publications, Abstracts, and Presentations .............................................................................................. 120
Attachment C1: Publications............................................................................................................................................. 120
Attachment C2: Abstracts and Presentations................................................................................................................. 126
Attachment D: Committee Rosters ....................................................................................................................................... 132
Attachment D1: Steering Committee............................................................................................................................... 132
Attachment D2: Publications, Abstracts & Presentations Committee....................................................................... 134
Attachment D3: Biomarkers Committee......................................................................................................................... 135
Attachment D4: Clinical Research Associates Committee .......................................................................................... 136
Attachment D5: Pharmacy Committee ........................................................................................................................... 137
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Attachment D6: Special Populations (Pediatrics/Human Subjects) Committee ..................................................... 138
Attachment D7: Toxicity and Supportive Care Committee ........................................................................................ 139
Attachment E: Center Performance Report ........................................................................................................................ 140
Attachment F: Center Performance Rating ......................................................................................................................... 147
Attachment G: Total Accrual by Month .............................................................................................................................. 149
Attachment H: Accrual Plan Assessment ........................................................................................................................... 150
Attachment I: Review Checklist ............................................................................................................................................ 151
Attachment J: Terms and Abbreviations ............................................................................................................................. 155
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1.0 Overview and Significance
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN1 or the “Network”) was established in
October 2001 to conduct large, multi-institutional clinical trials to improve the outcomes of hematopoietic cell
transplantation (HCT) for patients facing life-threatening disorders. The BMT CTN allows the HCT community
to conduct prospective, collaborative, clinical research within an infrastructure expressly designed to:
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Facilitate effective communication and cooperation among transplant centers and collaborators at the
National Institutes of Health (NIH), particularly the National Heart, Lung, and Blood Institute (NHLBI)
and National Cancer Institute (NCI);
Implement and complete well-designed, multicenter trials of high scientific merit;
Offer participation in HCT clinical trials to patients in all regions of the United States.
Almost 18,000 HCTs are performed in the United States (US) annually, and the number increases by
approximately 5% per year. This increase reflects the utility of HCT in treating both malignant and nonmalignant diseases, higher donor availability, and treatment advances that allow HCT to be performed in older
and sicker patients.
While HCT is a rapidly evolving field, HCT clinical trials face unique challenges, including the relatively small
number of transplantations performed at any single center, the diverse indications for HCT, the complexities of
the procedure, and multiple post-transplant complications.
The BMT CTN was established to address these challenges and execute multicenter HCT trials with broad
national participation. The Network:
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Effectively fosters development of innovative and important concepts into well-designed trials that
answer questions in the most efficient manner;
 Supports timely implementation and completion of those trials;
 Ensures protection of subjects (both donors and recipients);
 Provides high-quality data and adherence to regulatory requirements in an increasingly complex
environment.
This Progress Report highlights the following:
 Accomplishments of the BMT CTN, including a detailed report of the Network’s progress for the period
of April 1, 2012, through March 31, 2013, (highlighted by bold font throughout the report) as well as plans
for the upcoming year;
 Organizational structure of the Network;
 Responsibilities and focus of the Network’s Data and Coordinating Center (DCC);
 Structure and collaborations of the Network;
 Protocol selection, development, and management processes;
 Status of past, current, and planned protocols.
1
A glossary of terms and abbreviations used in this report can be found in Attachment J.
1
1.1 The Value the BMT CTN Brings to the HCT Community
The BMT CTN and its network of Core and Affiliate Centers (Attachment B) play a critical role in improving
patient outcomes and advancing the science of hematopoietic cell transplantation. The BMT CTN’s many
scientific achievements include:
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Launching 28 trials, including two this reporting period;
Completing accrual to 18 trials, including two this reporting period;
Accruing almost 5,300 patients to its trials from more than 100 centers, including almost 600 patients this
reporting period;
Achieving an overall accrual rate of 104% of projections among trials that are currently open for
enrollment;
Engaging in 28 ancillary and correlative studies, including three that were completed this reporting
period.
1.1.1 Extensive Areas of Study
The BTM CTN studies various treatment options, including both allogeneic and autologous transplants. During
this reporting period, approximately 40% of the transplants performed on BMT CTN studies were allogeneic
transplants. Comparatively, 49% of the US transplants reported to the Center for International Blood and
Marrow Transplant Research (CIBMTR) were allogeneic transplants.
The BMT CTN has answered relevant research questions in both common and rare diseases. Its research
portfolio includes studies in leukemia, myelodysplasia, lymphoma, and multiple myeloma as well as rare
transplant indications, such as aplastic anemia, sickle cell disease, and human immunodeficiency virus (HIV)associated cancers. Additional areas of study include:
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Conditioning regimens;
Graft source (autologous, human leukocyte antigen [HLA]-identical and haploidentical related donors,
unrelated donors, and umbilical cord blood);
Graft manipulation;
Acute and chronic graft-versus-host disease (GVHD);
Post-transplant infection;
Treatment-related mortality;
Disease control;
Biomarkers;
Patient populations of various ages, including children and older adults;
Quality of life.
1.1.2 Accrual Leverage
Several BMT CTN studies have been designed for co-enrollment, including studies on quality of life (0902),
consent form evaluation (1205), and a biomarker repository protocol (1202). Over 100 patients have been coenrolled on BMT CTN studies.
2
1.1.3 Dissemination of Results
1.1.3.1 Abstracts
The Network has presented 37 abstracts from 15 trials and the DCC/Network at the following national and
international meetings:
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American Society of Clinical Oncology (ASCO);
American Society of Hematology (ASH), including the 2011 Plenary Session;
BMT Tandem Meetings;
European Group for Blood and Marrow Transplantation;
International Myeloma Workshop (April 2013);
International Society for Cellular Therapy;
NCI-American Society of Clinical Oncology Cancer Trial Accrual Symposium;
Public Responsibility in Medicine and Research;
Society for Clinical Trials.
Nine abstracts were presented during this reporting period at the meetings listed in bold above.
1.1.3.2 Publications
The Network has published 31 manuscripts, including nine primary study results papers, from 12 trials and the
DCC/Network in the following peer-reviewed journals:
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American Journal of Health-System Pharmacy;
Biology of Blood and Marrow Transplantation;
Blood;
Clinical Infectious Diseases;
Journal of Clinical Oncology;
Journal of the National Cancer Institute;
Journal of the Society for Clinical Trials;
Lancet Oncology;
New England Journal of Medicine.
Seven manuscripts were published or are in press during this reporting period in the journals listed in bold
above. Two of these manuscripts were primary results papers, and an additional seven manuscripts are in
preparation.
1.1.4 Significant Findings and Impact
The research findings of the BMT CTN provide information with effects on clinical practice. To date, BMT CTN
trials have provided important insights into several areas of HCT (Table 1).
3
Table 1. Significant findings and impact of BMT CTN studies
BMT CTN Study
Significant Findings and Impact of BMT CTN Studies
Results
Impact / Future Outlook
CONDITIONING REGIMENS
0301: Fludarabine-based
conditioning for allogeneic
marrow transplantation
from HLA-compatible
unrelated donors in severe
aplastic anemia
Identified high toxicity and high
graft failure rates after
unrelated donor transplantation
for aplastic anemia with
cyclophosphamide doses of 150
and 0 mg/kg, respectively, for
conditioning
Optimizing conditioning regimens for transplantation
for rare diseases is difficult and requires a
multicenter effort to determine the role of new
agents. This study determined that fludarabine is not
sufficiently immune suppressive to replace
cyclophosphamide in standard conditioning
regimens for unrelated donor transplantation for
aplastic anemia. Additionally, the finding of excess
toxicity with a commonly used dose of
cyclophosphamide when combined with fludarabine
was unexpected and will guide further exploration of
new agents as well as informing current practice.
Evaluation of 50 mg/kg and 100 mg/kg of
cyclophosphamide is ongoing.
0401: Phase III
Rituxan/BEAM versus
Bexxar/BEAM with
autologous hematopoietic
stem cell transplantation
for persistent or relapsed
chemotherapy-sensitive
diffuse large B cell nonHodgkin lymphoma (DLBL)
Determined the use of a
radiolabelled antibody in
addition to carmustine,
etoposide, cytarabine, and
melphalan (BEAM) increases
toxicity but does not decrease
relapse after autologous
transplantation for DLBL
Although several small Phase II studies suggested
that dose-intensification might decrease relapse, the
primary cause of treatment failure after autologous
HCT for DLBL, this study failed to show a benefit with
this approach. Future trials will focus on
maintenance strategies and/or immune therapies
after HCT to improve disease control.
0502: A Phase II study of
allogeneic transplant for
older patients with acute
myeloid leukemia (AML) in
first morphologic complete
remission using a
nonmyeloablative
preparative regimen
Demonstrated that allogeneic
transplantation with reducedintensity conditioning is feasible
and effective in elderly patients
with acute myelogenous
leukemia with acceptable rates
of regimen-related toxicity
Results of conventional chemotherapy in elderly
patients are dismal and have improved little over the
past two decades. This study demonstrates that,
with reduced intensity conditioning, patients older
than 60 can benefit from the graft-versus-leukemia
effects of allogeneic HCT with outcomes similar to
younger patients. These data should increase the
use of HCT in older AML patients and provides
justification to increase the age of inclusion for BMT
CTN allograft trials.
0601: Unrelated donor
hematopoietic cell
transplantation for children
with severe sickle cell
disease using a reducedintensity conditioning
regimen
Determined that a reducedintensity conditioning regimen
of alemtuzumab, fludarabine,
and melphalan prior to cord
blood transplantation was
associated with unacceptably
high levels of graft failure in
children with sickle cell anemia
This disappointing finding indicates the need for
novel transplant strategies for the large number of
patients with this disease who cannot find an HLAmatched adult donor. This trial continues for
patients with HLA-matched unrelated adult donors
to determine the success rate of a regimen that
potentially avoids some long term effects of
allogeneic transplantation, including infertility.
4
BMT CTN Study
Results
GRAFT SOURCES
0201: A Phase III
randomized, multicenter
trial comparing G-CSF
mobilized peripheral blood
stem cell with marrow
transplantation from HLA
compatible unrelated
donors
Determined there is no
difference in survival for
recipients of unrelated donor
peripheral blood versus bone
marrow grafts, though there is
increased risk of chronic GVHD
with peripheral blood grafts
0501: Multicenter, open
label, randomized trial
comparing single versus
double umbilical cord blood
transplantation in pediatric
patients with leukemia and
myelodysplasia
Demonstrated no survival
benefit for children with highrisk hematologic malignancies
receiving infusion of two
umbilical cord blood units versus
one umbilical cord blood unit
after myeloablative conditioning
for hematologic malignancies
0603/0604: Multicenter,
Phase II trials of nonmyeloablative conditioning
and transplantation of
partially HLA-mismatched
bone marrow / umbilical
cord blood from unrelated
donors in patients with
hematologic malignancies
Confirmed promising singlecenter results in a multicenter
setting using reduced-intensity
conditioning and either
haploidentical bone marrow
transplantation or double cord
blood transplantation in adults
with hematologic malignancies
Peripheral blood has largely replaced bone marrow
as a graft source for unrelated donor
transplantation. This study suggests that this may
not be appropriate in the myeloablative conditioning
setting since it offers no survival advantage but
produces higher rates of chronic GVHD requiring
prolonged immune suppression. Whether this will
substantially change current practice remains to be
determined, although requests to the National
Marrow Donor Program for bone marrow grafts
have increased since publication of these data. This
is the largest study of unrelated donor
transplantation ever performed and would not have
been possible without the infrastructure provided by
the BMT CTN.
This study indicates that increasing cell dose beyond
the accepted minimum by adding another cord
blood unit does not improve survival after cord
blood transplantation in children and increases the
risk of acute GVHD. This has important implications
for designing future strategies for improving
hematopoietic recovery and decreasing transplantrelated mortality after cord blood transplantation.
Acceptable outcomes of double cord and
haploidentical bone marrow transplantation suggest
that many more adults should be offered HCT, even
when an HLA-matched adult donor is not available.
These approaches are now being compared in a
randomized Phase III trial (BMT CTN 1101).
GVHD PREVENTION AND TREATMENT
0302: Initial systemic
treatment of acute GVHD: a
Phase II randomized trial
evaluating etanercept,
mycophenolate mofetil,
denileukin diftitox (Ontak),
and pentostatin
Determined that GVHD
biomarker panels can be used
for early identification of
patients at high or low risk for
treatment non-responsiveness
or death and that biomarker
panels may provide
opportunities for early
intervention and improved
survival following HCT
5
The wider use of biomarkers to identify patients at
high risk of GVHD will allow us to tailor our therapies
to better control this complication in these patients
and to reduce toxicity in patients who are unlikely to
benefit from intensive immune suppression. We will
use these biomarkers in designing future BMT CTN
trials of GVHD prevention.
BMT CTN Study
Results
0303: A single-arm,
multicenter Phase II trial of
transplants of HLA-matched,
CD34+ enriched, T cell
depleted peripheral blood
stem cells isolated by the
CliniMACS system in the
treatment of patients with
AML in first or second
morphologic complete
remission
Confirmed in a multicenter
setting the feasibility and
consistency of T cell depletion
by CD34 selection, with results
in AML that warranted
consideration of a phase III trial
versus non-T cell depleted
transplantation
These data are being used by the Food and Drug
Administration in its consideration of approving a
CD-34 selection column for clinical use in the US. A
Phase III trial comparing outcomes of CD34-selected
transplants using this approach with standard bone
marrow transplants followed by calcineurin-inhibitor
based GVHD prophylaxis is in development.
0402: A Phase III
randomized, multicenter
trial comparing sirolimus /
tacrolimus with tacrolimus /
methotrexate as GVHD
prophylaxis after HLAmatched, related peripheral
blood stem cell
transplantation
Identified a high risk of toxicity
when sirolimus is substituted for
standard methotrexate for
GVHD prophylaxis when the
conditioning regimen includes
busulfan and no advantage in
acute GVHD-free survival
Although the study showed a modest improvement
in grade III-IV acute GVHD, the findings do not
support substituting sirolimus for methotrexate
since it may increase toxicity in patients who receive
busulfan for conditioning, it was associated with
higher risks of chronic GVHD, and it did not improve
survival. Novel approaches to preventing GVHD are
needed and are being explored in a BMT CTN trial
(1203) now in development.
0802: A multicenter
randomized, double blind,
Phase III trial evaluating
corticosteroids with
mycophenolate mofetil
versus corticosteroids with
placebo as initial systemic
treatment of acute graftversus-host disease
Showed the addition of
mycophenolate mofetil to
steroids as a first line therapy
for patients with acute GVHD
does not result in improved
GVHD free survival compared to
treatment with steroids alone
This trial, closed early for futility, failed to show a
beneficial effect of adding mycophenolate mofetil to
steroids as initial treatment for acute GVHD.
Corticosteroids remain the standard approach.
Newer agents are being considered for evaluation by
the Network.
SUPPORTIVE CARE
0101: A randomized doubleblind trial of fluconazole
versus voriconazole for the
prevention of invasive
fungal infections in
allogeneic blood and
marrow transplant
recipients
Demonstrated that fluconazole,
a low-cost antifungal agent,
generally has similar efficacy as
and is generally more costeffective than the newer and
more expensive drug,
voriconazole, in preventing
serious fungal infections in the
first six months after HCT but
that voriconazole may be costeffective for those undergoing
an allogeneic HCT for AML
6
This ancillary study of a Phase III comparison of
fluconazole and voriconazole indicates that newer is
not always better and that, for most patients,
standard fluconazole is an effective fungal
prophylaxis agent. However, an ancillary study
suggested there is a subset of patients for whom
primary antifungal prophylaxis with voriconazole
may be cost-effective, allowing more informed
treatment planning by transplant centers.
BMT CTN Study
0102: A trial of tandem
autologous stem cell
transplants with or without
post-second autologous
transplant maintenance
therapy versus single
transplant followed by
matched sibling
nonmyeloablative allogeneic
stem cell transplant for
patients with multiple
myeloma
0704: A Phase III,
randomized, double-blind
study of maintenance
therapy with CC-5013 or
placebo following
transplantation for multiple
myeloma
Results
MULTIPLE MYELOMA TREATMENT
Determined, in the largest study
of HCT for multiple myeloma
ever conducted, that tandem
autologous HCT and autologous
HCT followed by allogeneic HCT
offer similar progression-free
survival rates in patients with
standard risk disease
This study highlights the need to reduce transplantrelated toxicity in the allogeneic HCT setting to allow
the graft-versus-tumor effect of allografts to
translate into survival benefits. It also indicated that
the graft-versus-tumor effect in standard risk
myeloma may not be as important as previously
thought. The use of tandem autologous-allogeneic
HCTs has decreased substantially over the past few
years, in part, because of the data from this trial.
Evaluation of the high-risk cohort is in progress and
will inform the Network's next allogeneic transplant
trial in this disease.
Determined lenalidomide
maintenance therapy prolongs
remission and survival after
autologous HCT for multiple
myeloma
The BMT CTN was an important contributor to this
study, which was led by CALGB. The data have led to
a major change in clinical practice, with most
myeloma patients now receiving lenalidomide
maintenance after transplantation.
1.1.5 Biorepository Resource
The Network’s Research Sample Repository is a valuable resource. To date, protocols have yielded a biological
research sample collection of more than 105,000 stored specimens. Over 18,314 specimens were added during
this reporting period. Additionally, an inventory of BMT CTN research samples collections has been added
to the Network’s public website as a resource for investigators planning correlative and ancillary studies.
This website section lists biological samples available for all BMT CTN studies by time point and sample
type, and it provides two summary tables: GVHD treatment trial samples and allogeneic transplant trial
samples.
1.1.6 Funding Leverage
The BMT CTN DCC encourages investigators to apply for supplemental funding to support ancillary or
correlative studies. During this reporting period, investigators sought and, in some cases, have been awarded the
following funding opportunities:




BMT CTN 1101 cost-effectiveness ancillary study (R01; awarded)
BMT CTN 1202 biomarkers ancillary study (R24; scored; funding determination unknown)
BMT CTN 1205 easy-to-read consent form (U10 supplement; awarded)
BMT CTN 0303 follow-on calcineurin inhibitor-free study proposal (R01 supplement; to be submitted in
June 2013)
7
1.1.7 Key Collaborations
The BMT CTN fosters successful collaborations with other networks and organizations, including:










AIDS Malignancy Consortium;
Canadian Blood and Marrow Transplant Group;
Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology;
Centers for Disease Control and Prevention Office of Minority Health & Health Disparities;
Children’s Oncology Group (COG);
Eastern Cooperative Oncology Group (ECOG);
NCI-sponsored Cancer Trials Support Unit;
NIH Sickle Cell Disease Clinical Research Network;
Pediatric Blood and Marrow Transplant Consortium (PBMTC);
SWOG.
1.1.8 Goals for Next Reporting Period
1.1.8.1 Anticipated Results
In the coming year, several trials will reach primary or secondary endpoints. The results will be analyzed to
address important questions:




Hodgkin’s Lymphoma. Is the approach of tandem HCT for patients with recurrent Hodgkin’s
lymphoma efficacious in a multicenter setting? (BMT CTN 0703/SWOG 0410 primary analysis)
Quality of Life. Does exercise and/or stress management improve patients’ functional status and
symptoms after HCT? (BMT CTN 0902 primary analysis)
Multiple Myeloma. Is there a difference in longer-term survival between the patient groups receiving
tandem autologous versus autologous/allogeneic HCT? (BMT CTN 0102 follow-up analysis)
Graft Sources. Is there a difference in longer-term survival between patients receiving haploidentical
HCT and double cord HCT? (BMT CTN 0603/0604 tandem studies follow-up analyses)
1.1.8.2 Studies to be Activated
Four protocols are in late stages of development and are anticipated to be activated in 2013:




BMT CTN 1102: A multi-center Phase III trial comparing reduced intensity allogeneic hematopoietic cell
transplant to hypomethylating therapy or best supportive care in patients aged 50-75 with intermediate-2
and high risk myelodysplastic syndrome;
BMT CTN 1203: A multi-center Phase II trial randomizing novel approaches for graft-versus-host disease
prevention compared to contemporary controls (the PROGRESS study: prevention and reduction of
GVHD and relapse enhancing survival after stem cell transplantation).
BMT CTN 1204: Reduced-intensity conditioning for children and adults with hemophagocytic
syndromes (the RICHeS study).
BMT CTN 1205: Easy-to-read informed consent (ETRIC) for hematopoietic cell transplantation clinical
trials.
1.1.8.3 Future Study Concepts
Two study concepts are in early development:


BMT CTN 1201 (in collaboration with the Alliance for Clinical Trials in Oncology): Phase II randomized
three arm study of maintenance therapy for diffuse large B-cell lymphoma
Calcineurin inhibitor-free proposal (BMT CTN number to be assigned): Phase III randomized three arm
8
study of calcineurin inhibitor-free interventions for prevention of graft-versus host-disease
In addition, the BMT CTN will host a State of the Science Symposium during the next reporting period to survey
the HCT landscape and identify areas with the greatest need for high-impact Phase II and III clinical trials.
Thirteen committees will present high-priority study concepts, which will be evaluated for potential
development.
9
2.0 BMT CTN Organizational Overview
The BMT CTN is comprised of a network of organizations that work together to achieve common goals. It
includes the following elements, each of which is described in this section:










Data and Coordinating Center;
Twenty Core Centers/Consortia;
Affiliate Centers;
Steering Committee;
Protocol Teams;
Technical Committees;
Administrative Committees;
Ad Hoc Committees;
Scientific Advisory Committees;
Review Committees.
2.1 Data and Coordinating Center (DCC)
The DCC is managed by three organizations with extensive HCT research expertise: the CIBMTR, the National
Marrow Donor Program (NMDP), and The EMMES Corporation (a contract research organization). Together
they are responsible for maintaining continuity of operations and effective communications, data management,
and statistical support for the Network. Figure 1 illustrates the DCC’s relationship to the organization as a whole,
which is explained more fully in Section 3.
Figure 1. BMT CTN Organizational Structure
10
2.2 Clinical Centers
2.2.1 Core Centers
The BMT CTN has 20 Core Clinical Centers (Attachment B1), some of which are consortia of two of more
centers. Each Core Center holds a cooperative agreement with the NHLBI to participate in the BMT CTN. These
centers were chosen by virtue of the scientific merit of their grant applications to the NIH, as well as evidence of
their ability to collaborate in carrying out the Network mission of developing and completing high-quality trials
as efficiently as possible.
2.2.2 Affiliate Centers
The BMT CTN has more than 100 Affiliate Centers (Attachment B2) that accrue patients to Network trials. About
23% of the BMT CTN’s overall accrual comes from Affiliate Centers; for this reporting period, the figure is 26%.
The Network encourages and facilitates broad participation of the HCT community through its Affiliate Center
system. Affiliate Centers participate in one or more BMT CTN trials through individual subcontracts with the
DCC. Applications for participation in Network trials can be found at www.bmtctn.net.
2.3 BMT CTN Committee Structure
The BMT CTN committee structure ensures the Network works toward common goals. Each committee is
described in this section.
2.3.1 Steering Committee
The Steering Committee consists of the Principal Investigator of each Core Center or Consortium, the DCC
Principal Investigator and Co-Principal Investigators, the NHLBI Project Officer, the NCI Project Officer, a
representative of each of the NCI-funded Cancer Cooperative Groups, and representatives of Affiliate Centers
that meet standards for exemplary accrual and participation in BMT CTN trials. Other members of the DCC,
Core Centers, and NIH regularly participate in Steering Committee meetings. The Steering Committee roster is
listed in Attachment D1.
The Steering Committee sets the scientific agenda and oversees the selection, design, execution, and analysis of
all BMT CTN studies. The Committee ensures the most relevant studies are chosen, they are appropriately
designed and executed, and data analyses are properly conducted. Additionally, the Steering Committee works
in collaboration with the DCC to ensure participating transplant centers adhere to BMT CTN policies and
procedures. The Committee also resolves any operational issues raised by investigators, Clinical Research
Associates, laboratory and repository staff, DCC members, or others.
The Steering Committee selects a Committee Chair who first serves a one-year term as Vice-Chair, then a oneyear term as Chair-Elect, followed by a two-year term as Chair, and finally a one-year term as Immediate PastChair. During this reporting period, the Steering Committee also approved appointment of the Vice-Chair role,
which consists of a one year term preceding the Chair-Elect position. Ginna Laport, MD, (Stanford Medical
Center) began a two-year term as Chair on January 1, 2012. Frederick Appelbaum, MD, (Fred Hutchinson Cancer
Research Center) is the Chair-Elect, and Steven Devine, MD, (Ohio State University Medical Center) is the ViceChair.
2.3.2 Protocol Teams
Each Protocol Team consists of one to three Chairs; three to five co-investigators from Core and Affiliate Centers;
an NHLBI and/or NCI representative; an NHLBI Statistician; and a DCC Protocol Officer, Coordinator,
Statistician, and Contracts Representative. A Protocol Team is formed when a proposal is accepted by the
11
Network. This team develops the study concept into a working study design and provides scientific oversight for
the trial throughout its life cycle. The Protocol Team also:






Reviews applications for participation from Affiliate Centers;
Develops patient and physician educational materials;
Monitors accrual and compliance with protocol requirements;
Prepares amendments as necessary;
Analyzes and interprets study data;
Prepares manuscripts.
2.3.3 Technical Committees
Standing and ad hoc Technical Committees generally consist of a maximum of nine members who are not
associated with the DCC or NIH. Each Technical and Administrative committee is also assigned one or more
NHLBI and NCI representatives and one or more DCC staff members. These committees conduct specified
functions of Network activity, advise the Steering Committee on certain Network policies and procedures, and
provide technical expertise to protocol design. Most Technical and Administrative Committee meetings are
conducted by conference call.
Committee members are appointed by the Executive Committee to three-year terms. Several Technical and
Administrative Committee members completed their terms of service as of December 31, 2012. Nominations
were open to participating Core and Affiliate centers. A Nominating Committee reviewed the nominations and
proposed a slate of candidates. These candidates were approved by the Executive and Steering Committees. The
current Technical Committee rosters are listed in Attachment D.
2.3.3.1 Biomarkers Committee
The Biomarkers Committee, which is made up of Core and Affiliate Center transplant physicians, was formed to:



Inform the Network’s scientific agenda with a focus on questions involving analysis of biologic
specimens for genomic and proteomic markers;
Review new and existing studies for opportunities to collect blood and tissue samples for analysis of
potential prognostic markers;
Advise the Network protocol teams in their review of ancillary study proposals that request the use of
BMT CTN-related research samples.
This committee participated in the review of two ancillary study concepts that were originally presented to BMT
CTN protocol teams. Recommendations and comments regarding the potential impact of the proposed study
concepts and the use of the research biospecimen collections were submitted to the protocol teams for
consideration as they made final decisions regarding study approvals. The proposed research sample collection
strategy incorporated into the BMT CTN 1102 study was reviewed by the committee and guidance provided to
the protocol team for consideration as they finalized the study and obtained necessary NHLBI approvals.
The Biomarker Committee-initiated proposal, “Prospective multi-center cohort for the evaluation of biomarkers
predicting risk of complications and mortality following allogeneic HCT,” was recently released to core BMT
CTN centers as protocol 1202, which will be opened soon. The primary aim of this proposal is to establish a
national, multi-center cohort of biologic samples to be collected prospectively from patients treated in US
transplant centers. This biospecimen collection and high-quality clinical data resource is designed to serve as a
national resource supporting future genomic, proteomic, functional, and transcriptional BMT-related research.
The design of the resource will support important future analyses aimed at identifying risk factors for
12
development and severity of acute GVHD, chronic GVHD, organ toxicity, relapse, mortality, and other clinically
significant complications occurring after allogeneic HCT.
This committee played a significant role in the development of a CIBMTR-lead R24 application for funding
opportunity PAR-11-090, “NHLBI investigator-initiated resource-related research projects.” The national effort
proposed in this application extends the research scope of the BMT CTN 1202 study, furthering the potential
impact of this national resource. A final NHLBI determination of funding is expected within the next two or
three months.
2.3.3.2 Clinical Research Associates Committee
The Clinical Research Associate Committee consists of Clinical Research Associates and Data Managers from
Core and Affiliate Centers. This committee:




Reviews each BMT CTN protocol before it is distributed to centers, focusing on reviewing and resolving
logistical issues (e.g., shipping and receipt of specimens or drugs);
Assists in developing and reviewing Case Report Forms;
Reviews educational materials for use at participating clinical centers;
Provides input for the BMT CTN Coordinators’ meeting held during the BMT Tandem Meetings.
2.3.3.3 Pharmacy Committee
The Pharmacy Committee consists of transplant physicians and pharmacists from Core and Affiliate Centers. It
reviews BMT CTN protocols for appropriate use and administration of pharmaceuticals. It also advises Protocol
Teams about possible pharmacokinetic or other ancillary studies. The Pharmacy Committee must review each
protocol before it is distributed to centers for implementation.
2.3.3.4 Special Populations Committee
The Special Populations Committee consists of pediatric and adult transplant physicians from Core and Affiliate
Centers as well as an ethicist. It ensures that children, women, and minority study participants are considered for
inclusion in all appropriate investigational protocols developed by the Network. It also ensures that, for studies
involving pediatric participants, appropriate modifications are addressed in informed consent, patient care, and
monitoring documents. The Special Populations Committee reviews each protocol before it is distributed to
centers for implementation.
Evaluation of HCT in the pediatric population presents some unique challenges. The Network is committed to
developing strategies to address these challenges and increase the participation of children in HCT clinical trials.
Thirteen Network trials have enrolled or are enrolling children (BMT CTN 0101, 0201, 0301, 0302, 0402, 0501,
0601, 0603, 0604, 0801, 0802, 0803 and 0903); two of them focus specifically on pediatric issues (BMT CTN 0501
and 0601). There is a protocol in development for children with hemophagocytic syndromes or primary immune
deficiencies (BMT CTN 1204) that is anticipated to be opened during the next reporting period. In addition,
children are eligible to participate in the soon-to-be open biomarkers study (BMT CTN 1202). The proportion of
BMT CTN trial participants under age 16 is only slightly lower than the overall proportion in the US transplant
population. Since many US pediatric HCT recipients also have access to HCT trials through the COG, Network
leadership feels these enrollment figures are appropriate.
2.3.3.5 Toxicity and Supportive Care Committee
The Toxicity and Supportive Care Committee consists of Core and Affiliate Center transplant physicians. It
works with the DCC to define methods for evaluating adverse events and toxicities after transplantation; reviews
the evaluation and monitoring requirements for toxicities on BMT CTN protocols; and designs and approves
forms and procedures for collecting toxicity data, including standards for expedited reporting of certain adverse
13
events. The Toxicity and Supportive Care Committee must review each protocol before it is distributed to centers
for implementation.
2.3.4 Administrative Committees
2.3.4.1 Executive Committees
The Executive Committee consists of the Steering Committee Chair, Chair-Elect or Immediate Past Chair, ViceChair, NHLBI and NCI Project Officers, and DCC Principal Investigator and Co-Principal Investigators.
Executive Committee members are indicated by an asterisk (*) in Attachment D1. The Executive Committee is a
subcommittee of the Steering Committee and works in collaboration with the DCC.
The Executive Committee ensures participating transplant centers adhere to BMT CTN policies and procedures,
and it works together with the Steering Committee to resolve operational issues raised by investigators, Clinical
Research Associates, laboratory and repository staff, members of the DCC, and others. It appoints Technical and
Administrative Committee members. The Executive Committee also:






Addresses policy making issues;
Reviews contractual arrangements and financial matters affecting the Network as a whole;
Makes recommendations to the Steering Committee;
Reviews and approves Transplant Center Performance Reports, audits, and corrective action plans;
Provides initial review of research proposals submitted to the BMT CTN for new trials and ancillary
studies;
Assists in developing Steering Committee meeting agendas.
2.3.4.2 Publications, Abstracts, and Presentations Committee
The Publications, Abstracts, and Presentations Committee consists of Core and Affiliate Center transplant
physicians. This committee develops publication and presentation policies. It also reviews publications and
presentations to ensure confidentiality of study participants and proprietary information as well as to ensure
appropriate acknowledgements of contributions, sponsorship, and authorship.
2.3.5 Ad Hoc Committees
Additional administrative and technical committees are convened as needed. For example, a Nominating
Committee is formed to propose candidates for open committee positions. Several technical committees are also
convened as needed to discuss new study concepts, provide an update to the Steering Committee on recent
advances in the field, or provide input into the Network’s Technical Manual of Procedures. These committees
include GVHD, Graft Characterization, Cellular Therapy, and Infectious Disease.
2.3.6 Scientific Advisory Committees
As a result of the Network’s 2007 State of the Science Symposium, twelve Scientific Advisory Committees were
formed to address specific areas pertinent to HCT trials. Additionally, the symposium resulted in a publication
that provided a road map of high-priority studies recommended for implementation by the US transplant
community using the resources of the BMT CTN, NCI Cooperative Groups, and other programs (Ferrara J,
Anasetti C, Stadtmauer E, Antin J, Wingard J, Lee SJ, Levine J, Schultz K, Appelbaum F, Negrin R, Giralt S,
Bredeson C, Heslop H and Horowitz M. BMT CTN State of the Science Symposium 2007. Biology of Blood and
Marrow Transplantation. 2007;13:1268-128. Also listed in Attachment C1.)
These Scientific Advisory Committees continued to operate and meet on an ad hoc basis to review and prioritize
the Network’s scientific agenda. In summer 2011, the committees reviewed and summarized protocol concepts
14
submitted by Core Center applicants, for discussion at the July Steering Committee Meeting, the first meeting
with new Core Center representatives.
During this reporting period, the Committees were redesigned and reconvened to start planning for a State of
the Science Symposium in 2014. (See Section 6 for more information about this symposium.)
2.3.7 Review Committees
Two independent Review Committees provide additional oversight for BMT CTN trials:


Protocol Review Committee. The Protocol Review Committee is appointed by the NHLBI and consists of
a Chairperson and Members whose experience reflect areas of expertise necessary to evaluate the
scientific merit and design of BMT CTN protocols. Consultants may be added on an ad hoc basis if
needed. The Protocol Chair (or designee), Protocol Officer, Statistician, and senior members of the DCC
represent the Protocol Team at Protocol Review Committee meetings.
Data and Safety Monitoring Board. The Data and Safety Monitoring Board, an independent board
appointed by the NHLBI and/or NCI, is composed of a Chair and Members with expertise in biostatistics,
clinical trials, bioethics, and the specific research area(s) of the Network studies. Consultants may be
added on an ad hoc basis if needed. The Network currently employs two Data and Safety Monitoring
Boards for its large number of active studies.
15
3.0 Administrative Functions of the DCC
The DCC is a collaborative partnership of three organizations with extensive experience in multicenter, HCTrelated clinical research. The DCC is led by Mary Horowitz, MD, MS, (CIBMTR), Shelly Carter, ScD, (The
EMMES Corporation), and Dennis Confer, MD, (NMDP). The DCC supports and manages the efficient
development, implementation, and completion of high-quality Phase II and III clinical trials for the Network,
including:






Evaluating and prioritizing study concepts;
Developing protocols with appropriate statistical designs;
Activating studies and developing plans to accrue patients in a timely manner;
Monitoring for safety, regulatory, and protocol compliance as well as data accuracy;
Collecting complete clinical and laboratory data;
Analyzing and sharing research results.
The DCC also coordinates and supports overall BMT CTN activities to enhance Network effectiveness,
including:








Maintaining the Administrative and Technical Manuals of Procedures;
Facilitating communication and maintaining public and private websites;
Maintaining a state-of-the-art research database;
Maintaining systems for acquisition and storage of biologic specimens;
Managing contractual arrangements and fiscal activities;
Monitoring and improving overall center performance;
Supporting all Network committees and activities with meeting planning and other logistical support;
Collaborating with government organizations to avoid competing studies, facilitate study completion,
and publish results in a timely manner.
3.1 DCC Partner Organizations
The DCC consists of three partners:



CIBMTR (Milwaukee, Wisconsin, and Minneapolis, Minnesota) is a research organization formed in 2004
from the affiliation of the International Bone Marrow Transplant Registry at the Medical College of
Wisconsin (MCW) and the Research Department of NMDP. The CIBMTR has a proven history of clinical
research and publication in both HCT and statistical methodology. It has fostered effective collaborations
with a large network of transplant centers. It also maintains an extensive observational research database
of virtually all allogeneic transplantations and most autologous transplantations performed in the United
States.
EMMES Corporation (Rockville, Maryland) is a contract research organization established in 1978 that
has managed more than 350 Phase I-III trials and registries for over 15 years. EMMES provides
experience in planning, implementing, and managing multicenter clinical trials in a variety of areas,
including HCT; statistical design and analysis; clinical trial design and management; complex data
collection system design and implementation; site monitoring; and regulatory support.
NMDP (Minneapolis, Minnesota) was established in 1987. It is the world leader in HCT donor registry
and graft procurement management, and it operates the world’s largest HCT-related Research Sample
Repository. NMDP has a large network of donor, collection, transplant centers, and cord blood banks; a
skilled Contracts and Procurement Department that manages contracts with 176 US and international
transplant centers and maintains contractual relationships with specimen repositories and contract
16
laboratories; an experienced Patient Services department that provides educational and counseling
services to patients in need of a transplant; and a Case Management department that facilitates most of
the unrelated donor transplantations performed in the United States.
Figure 2 illustrates the relationship among DCC organizations and its distribution of responsibilities, and Table 2
describes the specific responsibilities of each DCC member. Appendix A displays the organizational structure of
the DCC.
Figure 2. DCC Organization
EMMES
CIBMTR
Overall coordination
Statistical
design
& analysis
Data management
Real-time electronic
data collection
Scientific leadership
Protocol
development &
implementation
Medical
monitoring
Trial oversight &
monitoring
Research Sample
Repository
management
Patient advocacy
Contracting
NMDP
17
Table 2. Responsibilities of DCC members
DCC Member Responsibilities
CIBMTR
NMDP
EMMES
Lead
Support
Support
Support
Support
Lead
Support
Lead
Support
Support
Support
Lead
Manage electronic communications (general and study-specific)
Support
Support
Lead
Maintain roster of participants
Support
Support
Lead
Prepare budget and track financials
Support
Lead
Support
Lead
Support
Support
Shared
Shared
Shared
Serve as Protocol Officer
Shared
Shared
-----
Serve as Protocol Statistician
Shared
-----
Shared
Serve as Patient Services Representative
-----
Lead
-----
Serve as Protocol Coordinator
-----
-----
Lead
Support
Support
Lead
Shared
Shared
Shared
Lead
Support
Support
Support
Support
Lead
Contract with centers
Support
Lead
Support
Identify laboratories/repositories
Support
Lead
Support
Contract with laboratories
Support
Lead
Support
Support
-----
Lead
Support
Support
Lead
Develop Case Report Forms
Support
Support
Lead
Coordinate laboratory & repository functions
Support
Lead
Support
Ensure quality of therapeutic & diagnostic modalities
Support
Support
Lead
-----
-----
Lead
Train site personnel
Support
Support
Lead
Develop patient materials
Support
Lead
Support
Monitor Adverse Events
Support
Support
Lead
Develop and implement accrual plan
Shared
Shared
Shared
Provide Data and Safety Monitoring Board support
Support
Support
Lead
Review performance of centers
Shared
Shared
Shared
Monitor accrual
Shared
Support
Shared
Administrative Functions
Provide overall scientific /administrative leadership
Develop Manuals of Procedures/Standard Operating Procedures
Facilitate meeting logistics
a
Coordinate meeting materials
b
Trials Development & Management
Develop/review concepts
Develop protocols
Protocol Team
Manage Protocol Document
Provide Protocol Review Committee support
c
Protocol Implementation
Identify centers
Certify centers
d
Maintain roster of study participants
Manage data management system
e
Manage site activation process, including monitoring regulatory compliance
18
DCC Member Responsibilities
CIBMTR
NMDP
EMMES
Monitor data accuracy and conduct data review sessions
Support
-----
Lead
Prepare reports/manuscripts
Shared
Shared
Shared
Coordinate dissemination of results
Shared
Shared
Shared
Develop Statistical Methodology
Shared
-----
Shared
a Schedule site location, travel arrangements, conference calling, travel reimbursements
b Develop agendas, supporting materials and reports, minutes
c Support Steering and Protocol Review Committees during review process, identify and address reasons for delay
d Certify ability of centers to execute special requirements of protocol
e Including systems for registration, Web-based data entry, database design, study archive backup, contingency plans
3.2 Policies and Procedures
The BMT CTN has two Manuals of Procedures: Administrative and Technical. The Administrative Manual
includes policies and procedures related to:








Participation in Network protocols including detailed steps for proposing, drafting and executing
studies;
Roles and duties of Core and Affiliate Centers and Network committees;
Roles of CIBMTR, NMDP, and EMMES within the DCC;
Transplant center site monitoring;
Adverse event reporting;
Human subject protection and regulatory procedures;
Publications, abstracts, and presentations;
Ancillary studies.
The Technical Manual of Procedures is a composite of policies and procedures pertinent to practice guidelines
and laboratory evaluations unique to HCT. The Technical Manual includes detailed policies and procedures
regarding:




Acute and chronic GVHD;
Characterization and processing for hematopoietic cellular products;
Diagnosing and grading infectious diseases;
Technical Committees’ policies.
Several updated chapters of the Technical Manual were released to the Steering Committee in March 2013.
The remaining chapters, and the Administrative Manual, will be revised and distributed within the next
reporting period. These and other procedural documents are available at http://www.bmtctn.net (public website)
and http://www.bmtctnsp.net (password-protected, secure website for Network members).
3.3 Administrative Support
The DCC coordinates and schedules meetings and conference calls for the Steering, Executive, Scientific
Advisory, Administrative, and Technical Committees as well as for Protocol Teams. From April 1, 2012, through
March 31, 2013, the DCC managed 302 conference calls. DCC representatives attend and participate in all
Network meetings, providing logistical support to ensure the meetings are conducted efficiently and effectively.
Two or more DCC staff members participate on all Technical Committee and Protocol Team calls, preparing and
19
circulating agendas and minutes for these committees. The DCC also maintains version control of protocols
during development and after their approval, including all amendments.
3.4 Fiscal Planning and Contracting Support
NMDP manages fiscal planning and contract support for the BMT CTN. Personnel from the NMDP Contracts
and Procurement Department participate in DCC conference calls, protocol development calls, Executive and
Steering Committee calls, and in-person Steering Committee meetings. NMDP develops and executes Requests
for Proposals, service agreements, and agreements for laboratory and pharmacy services to support specific
protocols.

Throughout the history of the BMT CTN, and in collaboration with both NHLBI and NCI, NMDP has
negotiated a number of Memoranda of Agreement to sponsor contributions that offset the cost of
individual protocols or provide pharmaceutical products.

Master Agreements and corresponding Clinical Study Protocol Riders for each protocol facilitate
participation of Affiliate and Core Centers in BMT CTN protocols.

Due to a change in management of the COG and the PBMTC, the NMDP Contracts Department
collaboratively negotiated a new Master Agreement and Clinical Study Protocol Riders with the
Children’s Hospital of Philadelphia.

NMDP also manages and distributes Core Center budgets for protocol-specific funds.

Pharmacy agreements with Eminent Pharmacy Services on BMT CTN Protocols 0402, 0701, 0702, and
0802 were managed in the past year. NMDP coordinates with Eminent to ensure accurate and timely
drug distribution for such studies. The agreement for 0702 remains open; the other protocols are
complete.
In order to assist with financial planning, NMDP also coordinates and manages the protocol budget
development process, generates financial reports on protocol spending, and provides forecasts of future
spending based on observed patterns, when requested.
BMT CTN leadership understands that optimizing external funding is critical at any time but particularly in the
current economic environment. The Network works hard to leverage NIH support as well as direct and in-kind
contributions to further its scientific agenda. The DCC develops relationships and contracts with pharmaceutical
companies and laboratory vendors for additional budgetary support and for drugs used in studies, always with
proper attention to avoiding potential conflicts of interest. All contributions are made through NHLBI-approved
Memoranda of Agreement. On behalf of the BMT CTN and in collaboration with both NHLBI and NCI, NMDP
negotiated several Memoranda of Agreement to sponsor contributions that offset the cost of individual protocols
or provide pharmaceutical products.
3.4.1 Cost-Saving Mechanisms
The DCC carefully manages the resources of the Network. It established a uniform budgeting model to project
trial costs accurately and uses a competitive bid process to procure laboratory, pharmacy, and other services,
ensuring that NIH funds are used wisely. To minimize delays associated with contracting with private
companies, the DCC established a policy of face-to-face meetings with potential contributors early in the protocol
development process. These meetings familiarize potential contributors with the Network, its membership, and
its research activities, and they allow the DCC to identify specific corporate contract liaisons. Additionally, the
Steering Committee encourages Protocol Teams to consider cost-saving mechanisms such as:

Restricting study requirements, such as research repository samples, to those that are essential to
20


answering the primary and secondary questions;
Limiting the number of secondary questions to the most scientifically important;
Reducing the length of follow-up periods and using the established CIBMTR Research Database for longterm follow-up of enrolled patients beyond the primary endpoint.
3.5 Communication
Managing the large Network and its protocol activity requires excellent communication. Information must flow
among DCC members, Network committees, transplant centers, laboratory and repository facilities, the medical
community, and the lay public. Weekly teleconferences for leadership and DCC members and monthly
teleconferences for the Executive Committee are conducted. Steering Committee meetings are scheduled either
in-person or by teleconference each month. Additional communication efforts are described in this section.
3.5.1 Maintaining BMT CTN Websites
The DCC maintains a public website (www.bmtctn.net) and a secure, password-protected website
(www.bmtctnsp.net). The Network’s public website features:

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A BMT CTN organizational overview and contact information;
A current BMT CTN Progress Report;
Current versions of open protocols;
Educational materials for all open protocols;
Applications to participate in BMT CTN protocols as an Affiliate Center;
Administrative and Technical Manuals of Operations;
A new section of BMT CTN research samples collections listing biological samples available for all
studies, by time point and sample type, and two summary tables: GVHD treatment trial samples and
allogeneic transplant trial samples;
A password-protected page for BMT CTN Coordinators that includes:
o Data and Safety Monitoring Board reviews and data reports;
o Links to private BMT CTN, AdvantageEDC data collection, and GlobalTrace specimen tracking
websites;
o Links to AdvantageEDC and GlobalTrace training modules;
o Presentations from the BMT CTN Coordinators' Meeting;
o Quarterly BMT CTN Coordinator newsletters;
o Links to related DCC and government partner websites;
o Panels featuring BMT CTN news, health news, and links to related medical articles.
The Network’s secure, password-protected website uses Microsoft SharePoint Server™ software to allow
Network participants to share confidential information. It features:
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Meeting materials, including agendas, minutes, and conference call materials;
Protocol Team materials including the current version of each protocol;
Rosters of personnel at participating centers;
Rosters for the Steering, Administrative, and Technical Committees as well as Protocol Teams;
Study accrual reports;
Monthly recruitment reports.
The DCC uses a separate password-protected area of the secure site to post Data and Safety Monitoring Board
meeting materials, share confidential information, and distribute monthly safety monitoring reports. All
necessary meeting materials are posted two weeks before scheduled meetings. Adverse events reports and
21
stopping guideline (safety) tables and graphs are posted monthly. Data and Safety Monitoring Board members
can access the accrual, monthly recruitment, data quality, and site activation status reports, which are updated
nightly or monthly depending on the report.
The CIBMTR’s public website, www.cibmtr.org, has a page dedicated to the Network, including an overview of
its functions, a list of all BMT CTN protocols, and a link to the BMT CTN public website. Additionally, the
CIBMTR displays information about the Network and its protocols at national and international meetings.
NMDP’s public website, www.bethematch.org, also has a page dedicated to the BMT CTN, including an
overview of the Network and links to the BMT CTN and government partner websites.
3.5.2 Developing Patient Support and Marketing Materials
NMDP’s Patient Services Department assists the Network in developing patient-friendly study materials. This
department managed an extensive project to reformat the Network’s patient consent and assent forms for easier
readability and comprehension. This resulted in a 2011 manuscript that summarized recommendations of the
review team for the development and formatting of accessible consent forms for multicenter clinical trials
(Denzen et al., Biology of Blood and Marrow Transplantation, full citation listed in Attachment C1.) The intent of
these recommendations is to guide the informed consent form writing process, simplify local Institutional
Review Board review of consent forms, enhance patient comprehension, and improve patient satisfaction. The
recommendations will be tested in a randomized study of the updated consent vs. the standard format in the
upcoming Easy-to-Read Informed Consent study (BMT CTN 1205) to be released to centers this year. Several
members of the original Patient Services team who revised the consent form format are on the BMT CTN 1205
protocol team.
The Patient Services Department and NMDP Marketing and Communications Department also support
communications for accrual enhancement, help develop patient education materials, and help design Network
publicity materials such as protocol flyers and posters used for national meetings and emailed accrual updates.
3.5.3 Communicating Trial Results
Communicating trial results rapidly and accurately is a fundamental activity of the DCC. Efficient and accurate
data collection, processing, and analysis — each stage of which is supported by the DCC — ensure the integrity
of Network trials and provide the foundation for publication and dissemination of study results.
The DCC helps Protocol Teams disseminate study results and publish as quickly as possible, assisting
investigators in developing study slide sets and poster presentations for national and international meetings. The
DCC also provides administrative support to the Publications Committee in its oversight of the publication
process and assures proper acknowledgement of trial contributors. DCC staff members coordinate, compile, and
distribute the annual BMT CTN Progress Report to the research community and the public to provide them with
updated information on protocol activity including published findings. These reports are available in print and
digital format, and they are posted on the Network’s public website (www.bmtctn.net).
3.6 Training
Ongoing education is imperative for ensuring protocol compliance and data quality. DCC staff members conduct
site visits and calls to transplant centers to initiate protocols and educate center personnel on Network policies
and procedures. Research staff members at the center receive an initiation report.
Clinical Research Associate training sessions are held annually in conjunction with the BMT Tandem Meetings.
These sessions cover data entry, quality control issues, and reviews of procedures and protocol requirements.
They also provide the DCC with useful feedback from centers. General Clinical Research Associate calls are held
22
at least quarterly, and protocol-specific calls are held as necessary with minutes distributed to research staff.
Additionally, the Network provides online training in its AdvantageEDC and GlobalTrace software packages
that includes training modules with a training practicum (AdvantageEDC) and competency assessments
(GlobalTrace). The Network also prepares a quarterly electronic newsletter for research staff and provides a
variety of materials to assist centers in understanding and implementing protocol requirements.
3.7 Transplant Center Monitoring
The DCC regularly monitors the performance of BMT CTN Core Centers and their contributions to the Network.
Daily or monthly reports include each center’s accrual rate, number of eligible patients, reasons for nonenrollment, number of ineligible patients, and reasons for ineligibility, for most protocols. The DCC also tracks
each center’s form delinquency, number of data queries, and major and minor protocol violations. The Data and
Safety Monitoring Board routinely reviews these data.
Center Performance Reports (Attachment E) are prepared annually (most recently in January 2013).
Overall scores on Center Performance Rating (Attachment F) are based on five categories:

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

Scientific/administrative contributions (10 points);
Patient accrual (60 points);
Activation and enrollment (10 points);
Data quality (10 points);
Laboratory compliance (10 points).
Final scoring is a composite of category-specific metrics associated with each of these measures of commitment
and involvement. The few centers that receive a “needs improvement” score in any area must submit an action
plan for resolving problems within six weeks of receiving the report. Additionally, Center Performance
“snapshots” of actual-versus-projected accrual and laboratory compliance reports are distributed to Core Centers
quarterly.
3.8 Specimen Repository Support
3.8.1 Specimen Collection
Each BMT CTN protocol creates an important new opportunity for the scientific community to collect baseline
and post-transplant/post-treatment biologic specimens for clinical research. For most protocols, biologic samples
are collected for use in protocol-defined research aimed at answering specific questions for that patient
population and its transplantation outcomes. Collection of supplementary samples was incorporated into most
protocols for use in future research. These samples and the associated clinical data will be made available as a
valuable resource for investigators at large. During this reporting period, a new section of BMT CTN research
samples inventory has been added to the Network’s public website to help investigators better utilize this
resource. The section lists biological samples available for all studies by time point and sample type, and it
provides two summary tables: GVHD treatment trial samples and allogeneic transplant trial samples.
The DCC receives requests for the use of its research samples for transplantation or post-transplantation
treatment-related ancillary studies. The procedures for judging the scientific merit of such studies, including
evaluations by the parent study Protocol Team, Biomarkers Committee, DCC and Steering Committee, are
defined in the BMT CTN Administrative Manual of Procedures.
Samples for early Network studies (BMT CTN 0101 to 0402) were processed at the clinical sites and shipped to
the NHLBI Repository for storage and future distribution for protocol-defined correlative studies and additional
ancillary studies. In 2009, the storage and management of all future BMT CTN protocol-related research sample
23
collections was moved to the NMDP Research Sample Repository.
As of March 27, 2013, a total of 105,875 specimens were stored by the BMT CTN Repository Network: NHLBI
Repository, BMT CTN Sample Repository operated by NMDP, and the AIDS and Cancer Specimen Resource
Repository. A total of 18,314 specimens were added during this reporting period. A summary of currently
available research samples is shown in the following tables.
Table 3a. BMT CTN center processed samples received and stored at the NHLBI Repository
BMT CTN
Protocol
Total Biospecimens
Received
Currently Available
Biospecimens
Subjects with Available
Biospecimens
0101
24,354
NHLBI Managed Open
Collection (data unavailable)
NHLBI Managed Open
Collection (data unavailable)
0102
13,070
10,507
615 patients
85 donors
0201
15,282
7,235
437 patients
0302
1,554
1,033
137 patients
0401
233
221
116 patients
0402
20,048
19,395
312 patients
178 donors
Table 3b. Samples processed and stored at the BMT CTN Repository
BMT CTN
Protocol
Total Biospecimens
Stored
Currently Available
Biospecimens
Biospecimens
0701
99
94
57 patients
0702
21,265
19,380
581 patients
0801
2,449
2,198
81 patients
0802
5,833
4,559
207 patients
0901
744
665
136 patients
1101
298
298
7 patients
4 donors
Table 3c. Samples processed and stored at the AIDS and Cancer Specimen Resource Repository
BMT CTN
Protocol
Total Biospecimens
Received
Currently Available
Biospecimens
Biospecimens
0803
566
566
31 patients
0903
80
80
4 patients
During this reporting period, 24,345 frozen sample aliquots were shipped to project laboratories for the
following protocol-defined correlative studies:



BMT CTN 0101: 713 samples – Voriconazole & fluconazole pharmacokinetics
BMT CTN 0101: 21,875 samples – Investigational fungal diagnostic assays
BMT CTN 0201: 1,359 samples – Immune reconstitution assays
24



BMT CTN 0801: 60 samples – Plasma B cell activating factor testing
BMT CTN 0802: 338 samples – Plasma biomarker panel testing
BMT CTN 0802: 361 samples reserved – Expanded plasma biomarker panel testing (funding pending)
3.8.2 BMT CTN Research Sample Repository and Central Processing Lab
The central processing laboratory at the BMT CTN Research Sample Repository plays an important role in
standardizing complex specimen processing procedures and expanding the collection of quality sample types for
correlative studies. The availability of these services, which will be applicable to many future studies, helps
reduce the research sample processing burden for clinical sites. The laboratory is currently processing peripheral
blood samples into serum, plasma, viable peripheral blood mononuclear cell (PBMC) and granulocyte sample
types. Bone marrow aspirates, buccal swabs, and viable marrow product mononuclear cell sample types are also
being processed and stored at the BMT CTN Research Sample Repository.
3.8.3 Maximizing Sample Handling
The DCC invested substantial efforts throughout this reporting period to improve Network procedures for
research sample collection, associated data accuracy, sample storage, and research sample testing. Highlights of
these efforts and benefits include:
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
Continued integration of standardized sample acquisition forms and sample tracking (AdvantageEDC
and GlobalTrace). Systematic sample data collection and specimen tracking provides additional realtime center assessment opportunities to increase the accuracy and compliance of sample collection
information at each critical time point. The availability of sample acquisition forms in AdvantageEDC
forms grid provides centers an additional reminder of future sample collection target dates, facilitating
patient appointment scheduling.
Continued development of a network of research and clinical laboratories that support current and
future studies. There are currently 16 active laboratory agreements, some of which were established
through competitive Requests for Proposals. Announcements of future laboratory support opportunities
are communicated on the BMT CTN Public website and via email to current and past Core and Affiliate
Center PIs at pre-screened clinical and research laboratories. Additionally, the American Society for
Blood and Marrow Transplantation and the American Society for Clinical Pharmacology and
Therapeutics send notification emails to their members regarding Request for Proposal opportunities for
laboratory support of BMT CTN ancillary studies.
Continued review of all pending sample shipments to the NHLBI Repository for older protocols. This
process continues to provide an opportunity to review key procedures with center staff and to discuss
effective sample management strategies, build relationships with research staff, and receive feedback on
transplant center needs. The DCC continues to work with Network Centers and NHLBI BioLINCC staff
to proactively review sample manifest inventory data to ensure accurate linkage of clinical data
associated with research samples being submitted for inclusion in BMT CTN biospecimen collections.
Review of comprehensive center-specific sample collection and required laboratory testing
compliance reports. Clinical centers receive the information they need to assess their achievements and
areas of deficiencies and to facilitate discussions with DCC staff. These reports are periodically reviewed
by DCC staff members who contact centers to discuss opportunities for improvement and process
optimization.
Focus on more complete instructional materials, training, and educational opportunities for research
staff. Education efforts have improved understanding of the purpose and importance of the research
sample collections by transplant center staff. Staff members are encouraged to discuss and develop best
25
practices for tracking upcoming research sample collections and improving accuracy of patient
information associated with biologic research samples. Dedicated DCC personnel and Research Sample
Repository staff are always available to answer questions and support transplant center staff.
26
4.0 Concept to Publication: The Protocol Process
Since its establishment in 2001, the Network has refined its processes for supporting selection, development, and
implementation of studies. Current procedures reflect the Network’s commitment to efficient use of its resources
to implement well-designed studies that accrue sufficient numbers of patients as rapidly as possible. This section
describes the typical sequence of events. There is substantial overlap in the timeframes of these steps, as the
Network seeks to implement tasks in parallel rather than sequentially whenever possible.
Transplant center investigators, Protocol Team members, DCC staff members, external oversight bodies
(Protocol Review Committee and Data and Safety Monitoring Board), NCI Cooperative Group collaborators, and
funding partners (NHLBI and NCI) are all involved in developing, implementing, and completing studies. The
Steering Committee is responsible for:



Reviewing and prioritizing all concepts proposed for Network consideration;
Approving final draft protocols prior to Protocol Review Committee and Data and Safety Monitoring
Board review;
Overseeing execution and analysis of approved Network trials.
Figure 3 displays the protocol development and implementation processes described in this section.
Figure 3. Schema for protocol development and implementation
Protocol Development
Proposal
Concept
Evaluation /
Approval
Protocol Approval
Protocol
Development
Steering
Committee
PRC
DSMB
IRBs
Technical Committees
Protocol Implementation / Completion
Activation
Case Report Forms* / Study
documents and procedures* / Data
systems* / Contracts / Accrual plan* /
Educational materials* / Site training
Maintenance
Accrual / Compliance /
Data quality / Safety /
Amendments /
Continued site training
Closure
Data review / Data
files / Analysis /
Abstracts /
Publications
*Work on these documents / tasks begins during the protocol development phase and is generally close to
complete by the time the first IRB approvals are available.
4.1 Concept Evaluation and Approval
Any investigator may submit study concepts for consideration. Study proposal requirements are posted on the
Network’s public website (www.bmtctn.net).
27
4.1.1 DCC Review
Study concepts are submitted first to the DCC, which performs a preliminary review to ensure the proposed
study does not conflict with an active study and the proposal is complete. The DCC then distributes the study
concept to the Executive Committee for discussion at a regularly scheduled monthly meeting.
4.1.2 Executive Committee Review
The Executive Committee reviews the study concept to ensure that it is consistent with the Network’s mission,
does not compete with active BMT CTN protocols or BMT CTN protocols in development, and poses no major
conflicts of interest. Eligible proposals are scheduled for review by the Steering Committee.
4.1.3 Steering Committee Review
Study concepts are scheduled for discussion at the monthly Steering Committee conference calls or in-person
meetings, which are held three times per year. The Steering Committee evaluates concepts for scientific merit,
feasibility, and Network members’ willingness to participate. The Steering Committee may accept, reject, or
recommend changes to the study concept.
The DCC assists in the review process, using CIBMTR data to assess feasibility based on study population and
eligibility requirements. The DCC supports the Steering Committee in its deliberations by providing the
following information whenever possible:
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Numbers of patients currently undergoing transplantation at Core and Affiliate Centers who might meet
eligibility criteria;
Outcomes of interest in the specified population;
Evaluation of sample size requirements;
Suggestions for alternate study designs;
Special requirements for research samples and/or necessary agents;
Potential competing protocols.
4.2 Protocol Development
4.2.1 Establishment of a Protocol Team
When the Steering Committee approves a study concept, the DCC assigns it a protocol number, and a Protocol
Team is formed. The Protocol Team meets weekly by teleconference during the development process, and the
Steering Committee reviews team progress as needed. The Protocol Team includes:
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Protocol Chairs (Study Principal Investigators). The Protocol Chairs, generally the investigators who
submitted the original concept, have primary responsibility for the protocol’s development and progress.
Most Network protocols have two Chairs.
Core and Affiliate Centers representatives. Most Protocol Teams have four to six representatives (coinvestigators) from Core and Affiliate centers.
Protocol Officer. The Protocol Officer (physician DCC member) helps address scientific and medical
issues.
Protocol Coordinator. A DCC Protocol Coordinator manages logistical and practical issues such as
coordinating meetings, preparing minutes, and maintaining protocol version control.
Protocol Statisticians. DCC and NHLBI statisticians create and coordinate the Statistical Analysis Plan
(Section 4.2.2).
Contracts Representative. A DCC Contracts Representative manages laboratory and supply
28
procurements and contributor agreements.
4.2.2 Statistical Design
Statistical analyses of study data are prepared and documented in a Statistical Analysis Plan within the protocol
document. This plan includes a synopsis of the study design; endpoints; hypotheses; randomization and
stratification procedures; sample size and power calculations; stopping rules for efficacy, futility and/or toxicity;
planned analyses of primary and secondary endpoints; adjustment for multiple testing; and control of type I
error and subgroup analyses. Since the potential pool of patients for HCT trials is limited, statistical designs must
make optimal use of available patients.
Additionally, HCT trials face some unique challenges:
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
When donors and recipients are consented and randomized separately, delays in this process can lead to
dropout, as seen in BMT CTN 0201.
There is the potential for multiple complications (infection, organ toxicity, GVHD, relapse, etc.) during
the early post-transplantation period. Therefore, competing risks must be considered with all study
endpoints. Competing risks are commonly addressed using composite endpoints as the primary outcome
measure, as in BMT CTN 0101 and 0402. The CIBMTR Research Database helps identify patient
candidates for study exclusion due to high risks of competing events. Cumulative incidence estimators
are used to approximate probabilities of individual events occurring in the presence of competing risks.
Non-proportional hazards and crossing survival curves occur when treatments under investigation have
different timing of events, as with allogeneic versus autologous HCT (BMT CTN 0102), or with different
regimen intensities (BMT CTN 0901). If this occurs, the usual log-rank test is inappropriate, and a
pointwise comparison of survival probabilities is often performed instead. CIBMTR data are again useful
in identifying an appropriate follow-up time point, a time when most events of interest have occurred.
More efficient methods for comparing groups with non-proportional hazards were recently proposed for
the analysis of BMT CTN 0901.
Analysis of quality-of-life data must consider non-ignorable missing data due to early mortality,
particularly when quality of life is the primary endpoint, as in BMT CTN 0902.
EMMES and CIBMTR statisticians are experts in analysis of HCT data, with many methodological publications
to their credit. This expertise is an invaluable resource for addressing statistical challenges. DCC statisticians hold
conference calls that include PhD and Master’s-level statisticians to discuss current analyses and approaches to
statistical issues. These discussions help ensure consistent, high quality, and appropriate statistical analyses for
BMT CTN studies.
4.2.3 Accrual Planning
Accrual planning is an important step in the protocol development process. The BMT CTN Project Manager
works with Protocol Team members to develop a customized accrual plan for each study, including an Accrual
Plan Assessment (Attachment H). When eligibility criteria are established, the Protocol Coordinator invites Core
Centers to participate and provide projected accruals. Using the CIBMTR Research Database, accrual projections
are checked against each center’s reported activity, and discrepancies are resolved. If there are not enough
potentially eligible patients from participating Core Centers, the DCC contacts Affiliate Centers that have both
the potential for contributing substantively to accrual and the necessary expertise to execute the study.
The accrual plan for each study includes projected accrual rates from Core and Affiliate Centers, a list of
advocacy and other groups that should receive information about the trial, and materials for referring physicians
and study participants.
29
4.2.4 Budget Preparation
When a draft protocol is available, the NMDP-based Financial Analyst arranges a teleconference with the
Protocol Chair(s), Officer, and Coordinator as well as other key parties to initiate budget preparation. The
Financial Analyst drafts a budget based on the final draft protocol as well as laboratory and services
requirements. Costs of labor for center and DCC personnel, medications, other therapies, shipping, and supplies
are also considered.
The Protocol Chair(s) and Protocol Officer review the draft budget, which is included in the materials that are
distributed to the Protocol Review Committee. Before submission to NHLBI and NCI for approval, the NMDP
Chief Financial Officer (or appropriate designee), Steering Committee Chair, and DCC Principal Investigator
review and sign the final draft budget.
4.2.5 Federal Regulations
The DCC maintains regulatory files for the Network, including Food and Drug Administration (FDA) 1572
forms, investigator curriculum vitae, Institutional Review Board approvals and approved consent forms,
financial disclosures, medical licenses, pharmacy licenses (if applicable), and evidence of Human Subjects
Research Training staff certification for each Core and Affiliate Center.
The DCC prepared and submitted three Investigational Device Exemption applications, which were required for
BMT CTN protocols 0101, 0303, and 0801. The DCC also submitted eight Investigational New Drug applications
to the FDA for BMT CTN protocols 0102, 0201, 0302, 0401, 0403, 0701, 0702, 0801, and 1101. The FDA
subsequently deemed Investigational New Drug applications unnecessary for BMT CTN protocols 0701, 0801,
and 1101.
4.2.6 Final Draft Protocol
The development process results in a final draft protocol document that provides the necessary details to
perform a clinical trial. This document includes:
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








An outline of the study design;
Study background, scientific rationale, and objectives;
Detailed description of treatments;
Detailed description of experimental design, including the Statistical Analysis Plan;
Definition of primary and secondary endpoints;
Eligibility requirements;
Follow-up schedules and requirements for patient exams;
Specimen submission schedules;
Safety measurements and adverse event reporting procedures;
Registration and randomization procedures;
Procedures for blinding study treatments;
Protocol-specific technical guidelines (e.g., donor selection criteria and graft processing techniques);
Informed consent template;
References;
Appendices.
The final draft protocol then undergoes a multi-step review process, as follows.
4.3 Protocol Approval
The final draft protocol requires approval by the Steering Committee, several BMT CTN Technical Committees,
30
the Protocol Review Committee, the Data and Safety Monitoring Board, and, finally, local Institutional Review
Boards.
4.3.1 Steering Committee Review
Two weeks in advance of Steering Committee review of a final draft protocol, the Steering Committee Chair
assigns two or three members as primary reviewers. These reviewers study the final draft protocol in detail.
They complete a BMT CTN Review Checklist (Attachment I) and evaluate the study’s background and rationale,
design, endpoints, clinical and laboratory tests, statistical considerations, informed consent, and ancillary studies.
They also provide an overall assessment of the protocol. The final draft of the protocol is then presented at a
Steering Committee meeting.
If approved by the Steering Committee, a Protocol Review Committee presentation is scheduled.
Simultaneously, the final draft protocol is distributed to the four Technical Committees responsible for final draft
protocol review.
4.3.2 Protocol Review Committee
The Protocol Review Committee assessment is scheduled through NHLBI. This group performs scientific review
of each study. The DCC submits review materials (final draft protocol, a Frequently Asked Questions document,
accrual plan, and budget) to the Protocol Review Committee several weeks in advance. The Protocol Review
Committee conducts a preliminary evaluation of the documents and returns comments to the Protocol Team.
The Protocol Team sends its written responses back to the Protocol Review Committee prior to the scheduled
presentation. This approach makes deliberations more efficient and usually avoids the need for follow-up
meetings and potential delays in implementation of the protocol. Once it receives Protocol Review Committee
approval, the protocol is scheduled for Data and Safety Monitoring Board review.
4.3.3 Data and Safety Monitoring Board Review
Each BMT CTN trial is approved and monitored by one of two NHLBI-appointed Data and Safety Monitoring
Boards. Boards have scheduled Webcasts in March, May, October, and December as well as in-person meetings
in April and November to review the safety and efficacy endpoints outlined in the statistical sections of each
protocol being presented. The DCC is responsible for providing the Boards with the information necessary for
them to make their determinations.
The Data and Safety Monitoring Boards must approve all new protocols or protocol amendments before
implementation. When protocols or amendments are scheduled for review, the Data and Safety Monitoring
Board provides written comments to the Protocol Team for response prior to the Data and Safety Monitoring
Board meeting, similar to the Protocol Review Committee process.
The BMT CTN’s Data Safety Monitoring Plan has been reviewed by the Data and Safety Monitoring Boards and
approved by NHLBI. All clinical sites enrolling patients on BMT CTN trials must adhere to the reporting
requirements in the Data Safety Monitoring Plan, approved by NHLBI. The DCC prepares all materials for Data
and Safety Monitoring Board meetings and posts them for the Board on a password-protected area of the
website: http:www.bmtctnsp.net. The DCC also posts monthly safety monitoring reports, including adverse
event reports and stopping guideline safety tables and graphs. These reports, in addition to accrual, monthly
recruitment data quality, and site activation status reports, are available to the Data and Safety Monitoring Board
members and to NIH program staff.
After all Data and Safety Monitoring Board reviews, the DCC disseminates the Board’s recommendations (after
approval by NHLBI) to the Protocol Chairs; Protocol Officer; additional protocol team members; and
31
Investigators, Coordinators and other key personnel at the participating centers. These memos are also posted on
the appropriate protocol-specific pages of the Network website (www.bmtctnsp.net). The DCC ensures center
compliance with the recommendations, including center Institutional Review Board review and approval,
training, accrual closure, and additional data review, as needed.
4.3.4 Final Review Prior to Release to Centers
After the Data and Safety Monitoring Board approves the protocol, the two Protocol Chairs and the Protocol
Officer review the protocol a final time, using a review checklist. Starting in 2011, a final sign-off process was
implemented: After the review is complete, at least two of the three reviewers must sign the first page of the
protocol before it is distributed to centers.
4.4 Protocol Pre-Activation
To expedite study implementation and facilitate timely activation and successful accrual, the following activities
occur concomitantly with protocol development:





Creating Case Report Forms;
Preparing and distributing other protocol-specific materials, including a Laboratory Research Sample
Information Guide, Data Management Handbook and User’s Guide, and guides for pharmacy
procedures;
Modifying data systems to receive and monitor protocol-specific data;
Developing systems to acquire, store, distribute, and analyze protocol-specific biospecimens;
Contracting with centers, laboratories, pharmacies, and contributors.
The Protocol Team also forms an Endpoint Review Committee, with a charter, before the study opens to accrual.
The Protocol Coordinator and Statistician are responsible for preparing review materials for the Endpoint
Review Committee, which:





Outlines the primary and secondary endpoints to be evaluated;
Identifies the endpoints to be adjudicated and the process for adjudication;
Defines procedures for resolving discrepancies and recording results;
Outlines the mechanisms for assessing subject eligibility and protocol compliance;
Conducts final reviews of the study data in a blinded manner whenever possible.
4.4.1 Designing Case Report Forms
Designing data collection forms is a collaborative venture involving each study’s scientific and clinical
leadership, statisticians, laboratory collaborators, and the DCC. Standard processes ensure the study will have
clear, easy-to-use forms that provide data to support its objectives without overwhelming study resources.
The DCC is responsible for developing Case Report Forms and, to date, has developed 14 core Case Report
Forms for use in all protocols. Another 311 protocol-specific forms were developed and are in use. Protocolspecific forms capture data on particular endpoints, important covariates, protocol-specified treatments, severe
adverse events, and protocol compliance. Draft forms are distributed to the Protocol Team for review and input,
and the revised forms are then reviewed by the Clinical Research Associate Committee, which evaluates them
from a practical use perspective. Each data element is explicitly defined in a User’s Guide to minimize variability
in responses. DCC staff members test each form prior to release.
32
4.4.2 Educational materials and other study documents
The NMDP’s Patient Services department works with the Network to develop patient education materials to
support new clinical trials. These materials help educate potential patients about the basics of clinical trials and
provide a patient-friendly summary of the specific clinical trial. Educational materials are created for each new
study and are available with the protocol when it is released for initial Institutional Review Board submission.
Patient Services staff members also help design Informed Consent documents so that they are patient-friendly
and readable at an eighth-grade reading level. The Network is evaluating a new two-column template for
Informed Consent documents via the upcoming randomized Easy-to-Read Informed Consent study (BMT CTN
1205).
4.4.3 Release to Center Institutional Review Boards
Once approved by the Data and Safety Monitoring Board, the DCC releases the protocol materials to centers that
agreed to participate so that they can submit the materials to their local Institutional Review Boards. Each
Protocol includes a template for documenting Informed Consent that can be modified by participating sites to
meet their local Institutional Review Board requirements.
4.4.4 Site Initiation Training
Prior to protocol implementation, the Protocol Coordinator arranges either an initiation site visit or activation call
with key center personnel to review materials and processes. The purpose of these contacts is to make certain the
responsibilities and communication lines within the center are clear. Study procedures are discussed, including
procedures for data and sample collection. If local pharmacies or laboratories are involved in a study,
representatives from those departments participate in the site initiation meetings, as well. A site initiation visit
report is issued to all site personnel involved in the protocol within 60 days.
The Network’s Sample Repository Research Administrator plays an important role in preparing centers for their
biospecimen submissions by:



Creating a protocol-specific Research Sample Information Guide that is distributed to sites;
Providing telephone and email support for site-specific questions regarding the Institutional Review
Board, project laboratories, repositories, or information in the Research Sample Information Guide;
Providing training and ongoing technical and contractual support for all project laboratory staff on the
protocol.
Customized initiation training is provided when needed, as in BMT CTN 0901 and BMT CTN 1101. BMT CTN
0901 has complex sample data and sample collection/processing requirements that differ from previous studies.
In a new initiative related to this trial, the Sample Repository Research Administrator holds additional research
sample-specific training calls for the clinical centers that activate this trial. The Research Administrator will also
review sample submission for compliance for the first few patients enrolled by each center. BMT CTN 1101 also
has cord blood training requirements that differ from other trials, requiring additional training calls for clinical
centers activating this trial.
4.4.5 Medical Monitor Assignment
The DCC assigns a Medical Monitor to each study when it is activated. Medical Monitors are transplant
physicians familiar with the conduct of clinical research and regulatory requirements for safety monitoring and
reporting. When applicable, Medical Monitors with disease-specific expertise are also recruited to monitor the
study (e.g. sickle cell disease, HIV). The Network’s Medical Monitors hold teleconferences quarterly to ensure
uniformity in assessing adverse events and to share updates on regulatory requirements. As a matter of policy
33
and to avoid bias, these physicians may not enroll patients or care for patients enrolled in a study on which they
serve as Medical Monitor.
4.5 Protocol Activation
A protocol is activated when a sufficient number of committed centers receive Institutional Review Board
approval and provide all necessary documents to the DCC. Each center must provide proof of approval from its
Institutional Review Board and submit required regulatory documents. Centers must also demonstrate
proficiency in data submission by reviewing an online training module and completing a post-module
practicum.
4.6 Protocol Maintenance
4.6.1 Accrual Monitoring and Intervention
The success of a clinical trial depends on timely accrual, which is influenced by many factors. To ensure that
problems relating to accrual are minimized, and promptly identified and addressed if they occur, the Protocol
Team develops an accrual plan that includes monitoring accrual milestones, planning and holding trial
promotion events, and assessing off-protocol transplantation activity through data obtained from the CIBMTR
Research Database.
Centers receive a quarterly report that compares their actual versus projected accrual to each protocol, and
centers submit monthly recruitment reports detailing the numbers of patients screened versus enrolled for each
protocol, with reasons for non-enrollment. The CIBMTR Research Database provides the denominator of total
transplantations performed in patients potentially fulfilling clinical trial eligibility, and these data are used to
interpret accrual by transplant centers.
When accrual to a study lags, the Protocol Team intervenes quickly to identify and resolve delays. These actions
may include:




Holding calls with investigators to discuss accrual challenges and strategies;
Resending accrual surveys to participating centers to obtain new or revised accrual projections;
Amending the protocol to address unanticipated accrual barriers;
Submitting regular study update emails to participating center investigators and coordinators to
highlight current and target accrual;
 Contacting investigators from participating centers that have not enrolled patients to encourage them to
enroll;
 Preparing protocol-specific educational materials to facilitate accrual;
 Recruiting additional centers.
Among the eight Network-led protocols currently open, the overall accrual rate is at 104% of target projections.
See Attachment G for a graph of BMT CTN total accrual by month.
4.6.2 High-Quality Clinical and Laboratory Data Collection
One measure of the Network’s success is its efficient and accurate collection, processing, and retrieval of clinical
and laboratory data. The Network uses several tools, described in this section, to ensure the integrity of each trial.
In doing so, the Network provides the foundation for study results that can be analyzed properly and
disseminated for use by physicians caring for patients.
34
4.6.2.1 AdvantageEDC
The EMMES AdvantageEDC system is a Web-based, interactive data entry system,which serves as the
Network’s primary data collection tool. To ensure high-quality data collection, the system performs field-level
checks during data entry to ensure accuracy, consistency, and completeness of data. If an entry does not pass the
validation check or the data do not meet the specified requirements, the system requires the user to resolve the
inconsistency.
As data are entered, they are maintained in data entry transaction master files, which are periodically processed
into master files for analysis. Data entry transaction files are stored separately from the master analysis
databases. This procedure provides the statisticians with a stable, fixed data set for a predetermined period that
can be used for multiple or frequently repeated analyses without the need for making private copies. It also preprocesses data for anomalies.
Master files are updated nightly and typically stored in SAS® format. These files are the basis for all project
reports and analyses. A dynamic forms grid provides an online list of currently submitted, due, and delinquent
forms. During the past year, 39,698 forms were submitted in the AdvantageEDC system for BMT CTN.
Accrual reports stratified by center, gender, and ethnicity are updated nightly. Reports summarizing each trial’s
progress are updated either weekly or monthly, depending on the report.
The DCC developed an integrated, Web-based Severe Adverse Events module. Notification of severe adverse
events is provided to Medical Monitors and other key personnel through an automated email system, allowing
rapid dissemination of critical information. Source data regarding severe adverse events is available to the
Medical Monitors, and review of severe adverse events is incorporated into the data system. Integration of
Medical Monitoring functionality in the data entry system has facilitated rapid review and reporting of events to
study sponsors and regulatory bodies.
4.6.2.2 Specimen Tracking with GlobalTrace and Staff
GlobalTrace is a proprietary EMMES product that the Network uses for all studies. This product is a unique,
Web-based application for specimen tracking, inventory, and shipping. It uses bar-coded specimen labels to
improve the reliability of specimen inventories by tracking individual samples shipped to either project
laboratories or a repository. Individual centers and the NMDP Repository can use GlobalTrace to generate
electronic manifests and trace/track each individual specimen. The application allows the study management
team to know in real-time which specimens have been collected, where they are, and when they were received
by the NMDP Repository. This system has been used by the BMT CTN for more than 10 years for several clinical
trials.
An online training and competency assessment module for the GlobalTrace application is available on the
secured BMT CTN website for all new clinical site staff. A GlobalTrace user guide can be easily accessed from the
AdvantageEDC website to review functionality of specific elements of procedures related to this system.
The HCT-knowledgeable staff at the NMDP Research Sample Repository and Central Processing Laboratory is a
unique asset of the DCC. The Research Sample Repository maintains a local database of processed and stored
Network inventory that supports DCC queries.
In addition to GlobalTrace, the DCC also has a unique asset in the HCT-knowledgeable staff at the NMDP
Research Sample Repository and Central Processing Laboratory. The Repository staff maintains a local database
of processed and stored Network inventory that supports DCC queries.
35
4.6.2.3 CIBMTR Data Reports
All transplant centers in the United States, including Network centers, are required by law to report pre-and
post-transplantation clinical data on allogeneic HCT recipients to the Stem Cell Transplant Outcomes Database,
which is a component of the C.W. Bill Young Cell Transplantation Program and is managed by CIBMTR. The
Network stipulates that Core and Affiliate Centers must also report similar data for autologous transplant
recipients.
Some pre-and post-HCT information collected by CIBMTR is deliberately not captured by AdvantageEDC, but
rather is transferred from the CIBMTR database to the EMMES database for incorporation into study files. All
long-term follow-up for Network studies (beyond the primary and secondary endpoints) is captured through
CIBMTR report forms to avoid a duplicative long-term follow-up program. The Network is committed to
maximizing two-way data sharing between the two databases, AdvantageEDC (EMMES) and FormsNet™
(CIBMTR), as a means of minimizing transplant center reporting burden. A detailed description of CIBMTR data
collection procedures can be found at http://www.cibmtr.org/DataManagement.
4.6.3 Data Audits
Data quality is critical to the BMT CTN’s success and is an important element for assessing transplant center
performance. Data audits are performed at each center at least every three years and as often as biannually for
centers with high enrollment. The target error rate for Network studies is less than 2%. Centers exceeding 2%, or
with other deficiencies, must submit a corrective action plan for improving performance. These visits provide an
opportunity for information exchange between the centers and the DCC as well as an opportunity to provide
continuing education on protocol adherence and case report forms completion to help maximize data and overall
study quality.
During the past year, the DCC conducted data audit site visits at 49 BMT CTN centers. The Auditors/Protocol
Monitors evaluated data submission compliance (missing forms/missing values completion), laboratory sample
compliance (collection and shipment of protocol-defined research samples), regulatory compliance, protocol
compliance, and data quality.
Reports are issued to the participating transplant centers after each visit, detailing what was reviewed during the
visit, such as regulatory files, pharmacy procedures, laboratory compliance, forms completion, and data
accuracy. Findings from the visit, as well as an action items list, are included in the report, and center staff
members are expected to successfully address all action items before the site visit is considered complete. Reports
are reviewed by the NHLBI and DCC and referred to the Executive Committee if results are below expectations
or other issues of concern are identified.
4.6.4 Amendments
Protocol amendments are necessary for a variety of reasons, including clarifying study procedures, addressing
unexpected toxicities, and improving accrual. The Protocol Coordinator, in consultation with the Protocol Team,
drafts amendments and coordinates the Data and Safety Monitoring Board approval process. The DCC ensures
that centers have the most current amendments and provides training, if necessary, for changes in study
procedures.
4.7 Study Completion
4.7.1 Notice to Cease Enrollment
As a trial nears its accrual goal, a memo is sent to each participating center notifying them of the closing date,
after which no patient may be enrolled. Centers are required to maintain Institutional Review Board approval for
36
each study that has completed accrual until follow-up is finished, endpoint data review is complete, the first
manuscript is published, and the BMT CTN DCC protocol coordinator has notified the site that it is appropriate
to permanently close the study with their Institutional Review Board.
4.7.2 Follow-up Data Collection after Closure
Once the protocol has closed to accrual, centers may be queried by the Endpoint Review Committee to submit
outstanding report forms, follow-up data, or source documentation.
4.7.3 Data Review and Analysis
The Endpoint Review Committee reviews and adjudicates complex primary and secondary study endpoints. The
process involves central review of Case Report Forms and source documents, clarification of discrepant
information, and review of complex grading or staging of clinical conditions, such as GVHD and myeloma
disease status. When centers have provided all required data and data review is complete, the dataset is locked
for analysis.
The DCC completes data analysis and prepares reports in accordance with the Statistical Analysis Plan (Section
4.2.2). Upon completion of the statistical analysis, the DCC issues an analysis report (technical data report) for the
study. In general, the analysis report is available within two months of locking the trial dataset. Study results are
available for presentation after final analyses are reviewed by the Protocol Team, Endpoint Review Committee,
and Steering Committee.
4.8 Dissemination of Results
Substantial effort is made by Protocol Teams to move forward quickly with manuscript preparation. When
completed, the Publications Committee reviews proposed publications and presentations to ensure scientific
validity and appropriate authorship and acknowledgements.
To date, 31 papers are published or are in press for 13 studies. Additionally, 37 abstracts and presentations,
representing 16 studies, have been accepted or presented. See Attachment C for a complete list of manuscripts,
abstracts, and presentations from Network activities, including study results and methodology reports.
4.8.1 Authorship
Network authorship guidelines are outlined in the Administrative Manual of Procedures, available on the public
website (www.bmtctn.net). Authorship status is based on intellectual input and effort throughout the lifecycle of
the trial. The Publications Committee maintains authorship policy guidelines, which are ratified by the Steering
Committee and consistent with American Medical Association guidelines.
Authorship credit on BMT CTN publications is a privilege commensurate with both personal and center
contribution to the research, including:




Membership and active participation on the Protocol Team;
Active accrual to the protocol;
Timely and accurate reporting of data;
Active participation in data review and analysis.
These activities may involve participation in hypothesis generation, concept development, protocol
development, study implementation, subject enrollment, data collection, data analysis, and manuscript
preparation.
37
4.9 Ancillary and Correlative Studies
BMT CTN ancillary studies use data, biospecimens, and/or analyses that are outside the specific objectives of the
primary study. Within the BMT CTN, most ancillary studies are protocol-defined, but some are independent (not
included in the primary objective of any specific protocol). Independent ancillary studies must be reviewed and
approved by the BMT CTN Steering and Biomarkers Committee before the Network can endorse them. Figure 4
illustrates this process.
Figure 4. Ancillary study proposal approval process
Ancillary
Proposal
Proposals utilizing
samples or data from
a specific protocol
Primary Review
DCC
Proposals utilizing samples or
data from multiple trials
BMT CTN
Steering/Exec
Committees
Protocol
Team
Secondary
Review
Biomarkers
Committee
External
Reviewers
Expert review of methodologies
Oversight of all biospecimen-related ancillary studies
During this funding period, a new section of BMT CTN research samples collections has been added to the
Network’s public website as a resource for investigators planning correlative and ancillary studies. This website
section lists biological samples available for all BMT CTN studies by time point and sample type, and it provides
two summary tables: GVHD treatment trial samples and allogeneic transplant trial samples.
Correlative studies are defined in the protocol and are secondary analyses performed after the primary analysis
is complete. Funding for ancillary and correlative studies may come from Network resources or non-Network
public or private funding agencies. For lists of ongoing, completed, and discontinued ancillary and correlative
studies, see Tables 4a, 4b, and 4c, respectively.
During this reporting period, there were 20 protocol-defined correlative or approved ancillary studies
proposed or ongoing. The Network’s protocol-defined correlative and ancillary studies in progress are described
in Table 4a.
38
Table 4a. BMT CTN correlative and ancillary studies in progress
BMT CTN Correlative and Ancillary Studies in Progress
Protocol
Project
Status
Laboratory/Location
Antimicrobial
Pharmacodynamics and
Therapeutics Laboratory
Department of Molecular
and Clinical
Pharmacology
University of Liverpool
Pharmacokinetic studies of
voriconazole and fluconazole
BMT CTN administered for prevention of
0101
invasive fungal infections in
allogeneic blood and marrow
transplant recipients
 BMT CTN approved protocol-defined
correlative study
 Testing of research samples completed
 Initiation of data analysis and
pharmacokinetic data modeling is in
progress
Investigational fungal diagnostic
BMT CTN
assays to diagnose aspergillus and
0101
other infections
correlative study
University of Florida
 Research samples have been shipped
College of Medicine
 Clinical data file being transferred
 Initiation of various projects to begin soon
Free light chain analysis in patients  BMT CTN approved ancillary study
undergoing autologous or allogeneic
BMT CTN
 Results presented at ASH in 2011 by
hematopoietic stem cell
0102
P Hari, et al.
transplantation for multiple
 Manuscript in progress
myeloma
The Binding Site
correlative study
BMT CTN Immune reconstitution studies
 Results presented at ASH in 2011 by
0201
 Donor HCT graft characterization
EK Waller, et al.
 Manuscript in progress
Emory University
Winship Cancer Institute
Immune reconstitution studies
 Immunophenotype assays of
lymphoid subsets and dendritic
correlative study
BMT CTN
cells
0201
 Final review of data and data analysis in
 Assays for antigen-specific T cells
progress
 TREC assay for de novo T cell
generation
Emory University
Winship Cancer Institute
BMT CTN Immune reconstitution studies
0201
 Antibody and cytokine levels
correlative studies
 Testing of stored samples in last phases
Esoterix Clinical Trials
Services (Division of
LabCorp)
Pharmacogenetics of steroid
BMT CTN
responsive acute graft-versus-host
0302
disease
 BMT CTN approved revised protocoldefined correlative study
 Sample testing completed
 Data analysis in progress
University of Minnesota
39
Protocol
Project
Status
Laboratory/Location
BMT CTN Immune reconstitution studies 0402
immunophenotyping
correlative study
 In progress – final patient samples to be
collected by the end of 2013
Esoterix Clinical Trials
Services (Division of
LabCorp)
BMT CTN
Immune reconstitution studies
0501
correlative study
 In progress
Duke University
BMT CTN Obesity and multiple myeloma
0702
ancillary study
 BMT CTN approved ancillary study
 In progress
Participating clinical sites
PRIMeR study: minimal residual
BMT CTN
disease in multiple myeloma by flow
0702
 In progress
cytometry
Roswell Park Cancer
Institute
Participating Centers
Regulatory T cell / B-cell
BMT CTN Immunophenotyping and B cell
correlative study
0801
activating factor biomarker levels by
 In progress
ELISA
Dana-Farber Cancer
Institute
Analysis of acute GVHD biomarkers
BMT CTN
measured before and during
0802
treatment
correlative study
 All testing completed
 Data analysis pending
American Red Cross,
Penn-Jersey
Histocompatibility/
Molecular Biology
Laboratory
BMT CTN Microbial translocation marker
0803
measurements
correlative study
 In progress
University of North
Carolina
Characterization of HIV infection in
BMT CTN AIDS-related malignancies: HIV
0803
single-copy HIV viral titer
measurements
correlative study
 In progress
Johns Hopkins University
BMT CTN
Plasma DNA tumor monitoring
0803
correlative study
 In progress
Immunophenotypic and functional
BMT CTN
characterization of immune
0803
reconstitution
correlative study
 In progress
Ohio State University
40
Protocol
Project
Status
Laboratory/Location
BMT CTN
Busulfan pharmacokinetics study
0901
correlative study
 In progress
Seattle Cancer Care
Alliance
Pharmacokinetics
Laboratory
Immunophenotypic and functional
BMT CTN
characterization of immune
0903
reconstitution
correlative study
 In progress
Ohio State University
BMT CTN Microbial translocation marker
0903
measurements
correlative study
 In progress
University of North
Carolina
BMT CTN Characterization of HIV Infection and
0903
latent HIV Reservoirs
correlative study
 In progress
Characterization of HIV infection in
BMT CTN AIDS-related malignancies: HIV
0903
single-copy HIV viral titer
measurements (PBMC & plasma)
correlative study
 In progress
University of Pittsburgh
Seven protocol-defined correlative or approved ancillary studies have been completed. These studies are
described in Table 4b.
Table 4b. BMT CTN correlative and ancillary studies completed
BMT CTN Correlative and Ancillary Studies Completed
Protocol
Project
Status
BMT CTN
0101
Cost-effectiveness analysis of
voriconazole compared with
fluconazole for prevention of
invasive fungal infection after
allogeneic hematopoietic cell
transplantation
BMT CTN
0302
correlative study
 Study completed
Analysis of serum biomarkers
during treatment of acute GVHD  Results presented at EBMT in 2011 by
JE Levine, et al.
 Manuscript published in Blood in 2012 by
JE Levine, et al.
 Study completed
 Practice report in press with American
Journal of Health System-Pharmacy in
2013 by J Mauskopf
41
Laboratory/Location
RTI Health Solutions
University of Michigan
BMT CTN Correlative and Ancillary Studies Completed
Protocol
Project
Status
Laboratory/Location
BMT CTN
0302
Mycophenolate pharmacokinetics correlative study
and association with response to  Study completed
acute GVHD treatment from the  Manuscript published in Biology and Blood
BMT CTN
and Marrow Transplantation in 2010 by PA
Jacobson, et al.
BMT CTN
0302
 BMT CTN approved correlative study
 Study completed
Graft-versus-host disease
N/A
treatment: predictors of survival  Manuscript published in Biology and Blood
and Marrow Transplantation in 2010 by JE
Levine, et al.
BMT CTN
0302
Lymphocyte phenotype during
therapy for acute graft versus
host disease: a brief report from
BMT-CTN 0302
BMT CTN
0303
Characteristics of CliniMACS(®)
system CD34-enriched T cell Study completed
depleted grafts in a multicenter  Manuscript published in Biology and Blood N/A
trial for acute myeloid leukemiaand Marrow Transplantation in 2011 by C
BMT CTN protocol 0303
Keever-Taylor, et al.
BMT CTN
0303
Comparative outcomes of donor
graft CD34+ selection and
immune suppressive therapy as  BMT CTN approved correlative study
graft-vs-host disease prophylaxis  Study completed
for patients with acute myeloid  Manuscript published in Journal of
leukemia in complete remission
Clinical Oncology in 2012 by M Pasquini,
undergoing HLA-matched sibling
et al.
allogeneic hematopoietic cell
transplantation
 Study completed
 Manuscript published in Biology and
Blood and Marrow Transplantation in
2012 by J Bolanos-Meade, et al.
42
N/A
N/A
One approved ancillary study was discontinued during this reporting period. This study is described in Table
4c.
Table 4c. BMT CTN ancillary study discontinued
BMT CTN Ancillary Study Discontinued
Protocol
BMT CTN
0102
Project
Status
Laboratory/Location
 Baseline samples shipped and testing
Detection of t(4;14) in circulating
started
peripheral blood nucleated cells  Project discontinued due to determination
Mayo-Arizona
of multiple myeloma patients
that overall sample quality was not
using a RT-PCR approach
consistently sufficient to support the
recovery of high quality RNA (a suspected
concern that needed to be evaluated)
43
5.0 Collaborations with other NIH-funded Research Networks
5.0 Collaborations with other NIH-funded Research Networks
The mission of the BMT CTN overlaps with the mission of NCI-sponsored Cancer Clinical Trials Cooperative
Groups and other NIH-sponsored networks. A major responsibility of DCC leadership is to enhance
communication among these groups to minimize the number of competing trials and to foster collaboration to
decrease the time required to complete studies. To that end, the Network has:





Shared accrual on 12 protocols:
o BMT CTN-led studies:
 BMT CTN 0102 – SWOG
 BMT CTN 0501 – COG
 BMT CTN 0601 – COG, Sickle Cell Disease Clinical Research Network
 BMT CTN 0701 – CALGB, ECOG, SWOG
 BMT CTN 0702 – CALGB, ECOG, SWOG
 BMT CTN 0803 and 0903 – AIDS Malignancy Consortium
o Cooperative group-led studies:
 CALGB 100103 – BMT CTN 0502
 SWOG 0410 – BMT CTN 0703
 CALGB 100104 – BMT CTN 0704
 CALGB 100701 – BMT CTN 0804
 SWOG 0805 – BMT CTN 0805
Implemented a shared national agenda for myeloma transplantation trials that is represented by CALGB
100104/BMT CTN 0704 and BMT CTN 0702 and was led by the BMT CTN-initiated Multiple Myeloma
Intergroup, including representatives from CALGB/Alliance for Clinical Trials in Oncology, ECOG, and
SWOG;
Participated in the NCI Lymphoma, Myeloma, and Leukemia Steering Committees;
Included cooperative group representation on the Network Steering Committee to promote
communication and collaborative partnerships with these groups;
Partnered with the AIDS Malignancy Consortium to support innovative trials for AIDS-associated
malignancies (BMT CTN 0803 and 0903).
44
6.0 Future Directions
6.1 Planning for the Current Grant Cycle
In October 2010, a leadership group of current and past BMT CTN Steering Committee Chairs and DCC
Principal Investigators met to lay out short-, mid-, and long-term goals for the DCC and the Network. The
primary goals of this meeting were to enhance the BMT CTN’s proficiency and efficiency, identify optimal uses
of funds, and refine processes to promote success and scientific productivity of the Network. This early work laid
the foundation for the activities that the Steering Committee and DCC took on when new funding was
authorized. Due to these initial efforts, both were poised to move forward quickly into planning and
implementing new trial ideas using guidelines established during the previous year.
Continuing these efforts for the remainder of the grant cycle, the DCC and Executive Committee proposed
hosting another State of the Science Symposium in 2014 to survey the HCT landscape and identify greatest areas
of need. The Steering Committee agreed with this plan. Frederick Appelbaum, Steering Committee Chair-Elect,
was selected to Chair the State of the Science Symposium. Twelve of the 2007 State of the Science Committees
have been reestablished with the addition of a second pediatric committee. The committees are:













Clinical Trial Design
Comorbidity and Regimen Related Toxicity
Gene & Cell Therapy
GVHD
Infection / Immune Reconstitution
Late Effects / Quality of Life
Leukemia
Lymphoma
Multiple Myeloma
Non-Malignant Diseases
Optimal Donor & Graft Source
Pediatric Transplant—Indications / Approaches
Pediatric Transplant—Outcomes / Late Effects
The State of the Science Symposium will be held in February 2014. External reviewers will be invited to review
trial concepts and lead the discussions. Prioritized concepts will be brought to the Executive and Steering
Committees for consideration.
6.2 Protocol Projections 2013-2014
In addition to developing new protocols chosen by the Steering Committee, the Network will continue working
toward completion of protocols already in progress, in particular:
6.2.1 Protocols Nearing Completion


BMT CTN 0601: Unrelated donor reduced intensity bone marrow transplant for children with severe
sickle cell disease (The SCURT study: sickle cell unrelated transplant)
The Data and Safety Monitoring Board approved reducing the target accrual to 30 marrow HCT patients.
There are 22 patients enrolled. Accrual in anticipated to be completed by the end of the next reporting
period.
BMT CTN 0702: A trial of single autologous transplant with or without consolidation therapy versus
tandem autologous transplant with lenalidomide maintenance for patients with multiple myeloma (The
45


STaMINA study: stem cell transplantation for multiple myeloma incorporating novel agents)
The study was opened in July 2010. Accrual is several months ahead of projected and is anticipated to be
completed in early fall 2013. To date, there are 600 of 750 patients enrolled.
BMT CTN 0803: High dose chemotherapy with autologous stem cell rescue for aggressive B cell
lymphoma and Hodgkin lymphoma in HIV-infected patients
The study was activated in July 2010. Like its sister study, BMT CTN 0903, this trial is a partnership with
the NCI-supported AIDS Malignancy Consortium. The NCI Cancer Therapy Evaluation Program for
Non-AIDS-Defining Cancers provides additional funding for this protocol. To date, 38 of 42 patients have
been enrolled.
BMT CTN 0805/SWOG 0805: A Phase II study of combination of hyper-CVAD and dasatinib with or
without allogeneic stem cell transplant in patients with Philadelphia chromosome positive and/or BCRABL positive acute lymphoblastic leukemia (a BMT study)
This collaborative study is being led by SWOG, with active involvement of BMT CTN and ECOG. It
opened to accrual in SWOG centers in September 2009 and through the CTSU in August 2010. Several
BMT CTN centers have either activated or are in the process of activating the study. Total target accrual is
85 patients, of which 74 patients have been enrolled.
6.2.2 Protocols Activated During the Reporting Period


BMT CTN 0903: Allogeneic hematopoietic cell transplant for hematological cancers and myelodysplastic
syndromes in HIV-infected individuals. This protocol received Data and Safety Monitoring Board
approval in March 2011 and was released to centers in April. There were delays as an amendment was
released prior to study activation. The trial was opened to accrual in May 2012. Like its sister study, BMT
CTN 0803, this trial is a partnership with the NCI-supported AIDS Malignancy Consortium. The NCI
Cancer Therapy Evaluation Program for Non-AIDS-Defining Cancers provides additional funding for
this protocol. Target accrual is 15 patients.
BMT CTN 1101: A multi-center, Phase III, randomized trial of reduced intensity conditioning and
transplantation of double unrelated umbilical cord blood versus HLA-haploidentical related bone
marrow for patients with hematologic malignancies. This Phase III randomized trial is a follow-on study
to the BMT CTN 0603 and BMT CTN 0604 Phase II studies that completed accrual in spring 2010. The
Data and Safety Monitoring Board approved the protocol in January 2012, and it was released to sites in
February. The trial was activated in June 2012. Target accrual is 410 patients.
6.2.3 Protocols Anticipated to be Activated
Four protocols are in late stages of development and are anticipated to be activated in 2013:


BMT CTN 1102: A multi-center Phase III trial comparing reduced intensity allogeneic hematopoietic cell
transplant to hypomethylating therapy or best supportive care in patients aged 50-75 with intermediate-2
and high risk myelodysplastic syndrome. This protocol received Protocol Review Committee approval in
early 2013 and is undergoing Data and Safety Monitoring Board review. Target accrual is 338 patients to be
enrolled over a three year accrual period.
BMT CTN 1203: A multi-center Phase II trial randomizing novel approaches for graft-versus-host disease
prevention compared to contemporary controls (The PROGRESS study: prevention and reduction of
GVHD and relapse enhancing survival after stem cell transplantation)
This protocol received Protocol Review Committee approval in early 2013 and is undergoing Data and
Safety Monitoring Board review. Target accrual is 270 patients (90 per arm) to be enrolled over a two and a
half year accrual period. Patients will be compared to a minimum of 270 controls from the CIBMTR.
46


BMT CTN 1204: Reduced-intensity conditioning for children and adults with hemophagocytic syndromes
(The RICHeS study)
The protocol was presented to the Steering Committee in early 2013 and will be re-presented after
incorporating the Committee’s study design recommendations. The trial is slated to accrue 35 patients over
a three year period.
BMT CTN 1205: Easy-to-read informed consent (ETRIC) for hematopoietic cell transplantation clinical
trials
The protocol was approved by the Protocol Review Committee and Data and Safety Monitoring Board. It is
anticipated to be released to centers in the spring of 2013 and activated in early fall. Target accrual is 160
patients (80 per arm) over an 18 month accrual period.
6.3 Conclusions
The Blood and Marrow Transplant Clinical Trials Network has created a successful and efficient infrastructure
for conducting important HCT trials. Network trials address critical issues in optimal graft sources, conditioning
intensity, regimen-related toxicity, engraftment, GVHD, infection, disease control, and quality of life. Because of
this comprehensive portfolio, the Network is recognized as the leading group to facilitate and complete HCT
clinical trials. This is clearly evidenced by successful collaborations with affiliate transplant centers, NIH
cooperative groups, the CTSU, other consortia and research networks, and pharmaceutical and device
companies.
These trials have accrued almost 5,300 patients in a timely manner through the involvement of more than 100
transplant centers. Of the eight studies opened since 2010, two are already complete, in large part due to fast
accrual. BMT CTN 0902 finished 17 months ahead of projections, and 0802 was four months ahead of projected
accrual before being closed to futility. Five studies, which are currently open to accrual, are also ahead of accrual
projections.
More than 65 publications/presentations have been published and shared since 2004, including seven
publications (two of primary study results) and nine presentations during this reporting period. These results,
as well as results from pending trials, will help define future transplant practice. BMT CTN is committed to
sharing these results in HCT, hematology, oncology, and medical peer-reviewed journals as well as at scientific
meetings. The BMT CTN plays a crucial role in advancing the field of HCT and is dedicated to its original
mission: to improve the outcomes of HCT for patients with life-threatening disorders.
While multicenter trials pose logistical and scientific challenges beyond those of a single-center study, these trials
address questions that are unanswerable in single institutions. Well-designed studies offer answers for future
patients. Even non-randomized Phase II approaches bring the strength of broader multi-institutional enrollment
to confirm, amplify, or simply clarify conclusions from prior, more limited experience. The HCT community
must remember that innovative and multi- institutional trials can address the hardest questions facing patients
with life-threatening hematopoietic diseases.
The DCC and the Network’s Core and Affiliate Centers represent the highest level of commitment and
participation by patients, researchers, transplant center staff, and support personnel—all working together in this
valuable endeavor.
47
7.0 Protocol Descriptions
7.0 Protocol Descriptions
The following section describes each BMT CTN research study. Accrual graphs, included as appropriate, are
based on the period from study inception through March 31, 2013. Protocols are grouped by study development
stage:



Open to accrual and actively accruing patients (10)
Completed accrual (18)
Released to centers (1)
48
7.1 Protocols Open to Accrual
BMT CTN Protocols Open to Accrual (as of March 31, 2013)
BMT CTN
Protocol #
0301
Protocol Title
Fludarabine-based conditioning for allogeneic marrow transplantation from
HLA-compatible unrelated donors in severe aplastic anemia
0601
Unrelated donor HCT for children with severe sickle cell disease using a
reduced-intensity conditioning regimen
0702
A trial of single autologous HCT with or without consolidation therapy versus
tandem autologous HCT with lenalidomide maintenance
0801
A Phase II/III randomized, multicenter trial comparing sirolimus plus
prednisone and sirolimus/calcineurin inhibitor plus prednisone for the
treatment of chronic GVHD
0803
High-dose chemotherapy with autologous stem cell rescue for aggressive B cell
lymphoma and Hodgkin lymphoma in HIV-infected patients
0804 /
Phase II study of reduced-intensity allogeneic HCT for high-risk chronic
CALGB 100701 lymphocytic leukemia
0805 /
A Phase II study of combination of hyper-CVAD and dasatinib with or without
SWOG 0805
allogeneic HCT in patients with Philadelphia chromosome positive and/or
BCR-ABL positive acute lymphoblastic leukemia (ALL) (a BMT study)
0901
A randomized, multicenter, Phase III study of allogeneic HCT comparing
regimen intensity in patients with myelodysplastic syndrome or acute myeloid
leukemia
0903
Allogeneic HCT for hematological cancers and myelodysplastic syndromes in
HIV-infected individuals
1101
A multi-center, Phase III, randomized trial of reduced-intensity conditioning
and transplantation of double unrelated umbilical cord blood versus HLAhaploidentical related bone marrow for patients with hematologic
malignancies
49
BMT CTN 0301
Protocol Number:
BMT CTN 0301
Status:
Open to Accrual
Title:
Fludarabine-based conditioning for allogeneic marrow transplantation from HLA-compatible unrelated
donors in severe aplastic anemia
Rationale:
Allogeneic HCT is an effective treatment for severe aplastic anemia; however, only about 25% of patients
have a suitable HLA-matched sibling donor. Those who lack such a donor could benefit from a matched
unrelated donor transplant, but transplant-related mortality (TRM) and graft rejection jeopardize the
successful outcomes of these transplants. The optimal conditioning regimen for unrelated donor
transplantation for aplastic anemia remains to be determined. Efforts to minimize graft rejection with
more intensive preparative regimens generally lead to more TRM; whereas, attempts to reduce TRM
often lead to graft failure. Purine analogs, such as fludarabine, have profound immunosuppressive activity
with low rates of systemic toxicities. Introduction of fludarabine led to development of a new class of
conditioning known as reduced-intensity preparative regimens, now commonly employed in a variety of
hematologic malignancies. This study was designed to determine the feasibility and toxicity of employing a
fludarabine-based conditioning regimen to reduce TRM while maintaining (or ideally, improving)
engraftment after marrow transplantation from unrelated donors in patients with severe aplastic anemia.
The study will determine the degree of cyclophosphamide dose reduction achievable with the
introduction of fludarabine, with a goal of maintaining (or improving) engraftment, reducing major
transplant-related toxicity and early deaths, and thereby, ultimately improving long-term survival.
Primary Objective:
To select the optimal cyclophosphamide dose in a regimen of fludarabine, cyclophosphamide, total body
irradiation and antithymocyte globulin, based on day 100 assessments of graft failure (primary and
secondary), regimen-related toxicity, and early death.
Second. Objectives:
Team Principals:
To evaluate post-transplant survival, graft failure, TRM, and acute and chronic GVHD.
Name:
Email:
PRC Approval Date:
03/31/2005
Paolo Anderlini
[email protected]
DSMB Approval Date:
07/15/2005
Chairs:
Joachim Deeg
[email protected]
Opened to Accrual:
01/24/2006
Officer:
Mary Eapen
[email protected]
Closed to Enrollment:
N/A
Coordinator:
Iris Gersten
[email protected]
Target Accrual:
78-81
Medical Monitor:
Christopher Bredeson [email protected]
Total Accrual as of 3/31/13:
81
Statistician:
Shelly Carter
[email protected]
Reporting Period Accrual
16
Contract Rep:
Pamela Budnick
[email protected]
IND Number:
N/A
Additional Members: Email:
Recent Version Released:
02/03/2010
Joseph Antin
[email protected]
Additional Members:
Email:
Nancy DiFronzo
[email protected]
Elizabeth Murphy
[email protected]
Mary Horowitz
[email protected]
Ryotaro Nakamura
[email protected]
Mitchell Horwitz
[email protected]
Michael Pulsipher
[email protected]
Eric Leifer
[email protected]
Jakub Tolar
[email protected]
Key Highlights:
This study was activated January 24, 2006. Twenty centers have enrolled patients. The accrual rate was
slower than projected, primarily due to the study design, which requires review of day 100 outcomes data
to ensure that stopping boundaries will not be crossed. Another factor is the lack of severe aplastic
anemia patients referred for unrelated donor transplantation (about 85/ year in the US). Accrual on the
trial was temporarily suspended in May 2008 for DSMB review of toxicities. An amendment was released
to centers in August 2008 to address the findings of the 150 mg/kg (excess toxicity) and 0 mg/kg
cyclophosphamide (excess graft failure) cohorts. The stopping rules were also revised to reflect a
combined day 100 endpoint of graft failure and TRM. Accrual resumed in December 2008. An amendment
50
Protocol Number:
BMT CTN 0301
was released to centers in February 2010 to allow accrual on parallel tracks using cyclophosphamide at the
100 mg/kg and 50 mg/kg levels, with the proviso that if a stopping threshold is reached on 100 mg/kg for
graft failure, the DCC will notify the DSMB before enrolling to the 50 mg/kg dose. As a result, the protocol
temporarily closed less often while patients were followed to the day 100 safety point. This amendment
enhanced accrual, and the DSMB recommendation in fall 2011 to preferentially enroll on the 50mg/kg
dose level to until a minimum of 20 patients with 8/8 HLA match were accrued has been met.
Reporting Period
Update:
This year, the DSMB recommended accrual continue beyond the accrual goal of 78-81 patients while the
protocol team develops a plan to extend accrual, a possible modification in primary endpoints, and the
future direction of the study. The plan will be reviewed by the DSMB in April 2013.
Results of the lowest and highest cyclophosphamide dose levels were presented at EBMT and
subsequently published.
Publications:
1. Optimization of therapy for severe aplastic anemia based on clinical, biological and treatment response
parameters: conclusions of an international working group on severe aplastic anemia convened by the
BMT CTN, March 2010. Biology of Blood and Marrow Transplantation. 2011 Mar;17(3)291-299. Epub
2010 Oct 27.
2. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic
anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse
events at predefined cyclophosphamide dose levels. Biology of Blood and Marrow Transplantation.
2012 July 18(7):1007-1011. Epub 2012 Apr 30.
Presentations:
1. Fludarabine-based conditioning for allogeneic marrow transplantations from unrelated donors in
severe aplastic anemia (SAA): serious and unexpected adverse events in pre-defined cyclophosphamide
(CY) done levels: results from BMT CTN Protocol # 0301. Presented at 53rd Annual ASH Meeting, San
Diego, CA, December 2011.
2. Fludarabine-based conditioning for allogeneic marrow transplantation from unrelated donors in
severe aplastic anemia: serious and unexpected adverse events in pre-defined cyclophosphamide
dose levels. Poster presented at EBMT, Geneva, Switzerland, April 2012.
Target Accrual = 81 patients
Accrual per Month
5
BMT CTN #0301
Monthly Actual Accrual
Projected Steady State Monthly Accrual
Cumulative Accrual
90
80
70
4
60
50
3
40
2
30
20
1
10
0
0
51
Cumulative Accrual
6
BMT CTN 0601
Protocol Number:
BMT CTN 0601
Status:
Open to Accrual
Unrelated donor hematopoietic cell transplantation for children with severe sickle cell disease using a
Title:
reduced-intensity conditioning regimen
Patients with severe sickle cell disease (SCD) have progressive perfusion-related vascular complications
like stroke, acute chest syndrome, and vaso-occlusion-related pain. Both disease and therapy can cause
morbidity and early mortality, especially when complications persist or progress despite supportive care
measures. Allogeneic HCT can correct the hemoglobinopathy associated with SCD by engraftment of
donor cells and is best performed in the pediatric population before irreversible organ damage has
developed. Although excellent outcomes are reported in children with SCD following matched sibling
donor HCT, this approach is rarely used because of (1) excess toxicities from standard myeloablative
conditioning regimens; (2) absence of HLA-matched family donors; and (3) transplant-related morbidity
and mortality, such as infection and GVHD. The rationale for this study derives from previous transplant
Rationale:
experience in patients with nonmalignant disorders, including hemoglobinopathies, with use of a
reduced-intensity conditioning regimen comprised of alemtuzumab, fludarabine, and melphalan to
support donor cell engraftment. The regimen was well tolerated, supported donor cell engraftment, and
produced acceptable rates of graft rejection, transplant-related mortality, and GVHD. This Phase II trial
will test the efficacy of bone marrow transplantation using this preparative regimen in children with
severe complications of SCD without matched family donors. The protocol was developed in conjunction
with sickle cell hematologists and incorporates detailed guidelines for prevention and treatment of SCD
and transplant-related complications.
To determine one-year event-free survival after unrelated donor bone marrow transplantation in
Primary Objective:
patients with SCD (death, disease recurrence, or graft rejection rates at one year will be used to measure
this endpoint)
To determine the effect of HCT on clinical and laboratory manifestations of SCD, including stroke; the
incidence of other transplant-related outcomes, including overall survival, neutrophil and platelet
recovery, grades II-IV and grades III-IV acute GVHD, chronic GVHD, hepatic veno-occlusive disease,
Secondary Objectives: idiopathic pneumonia syndrome, central nervous system toxicity (reversible posterior leukoencephalopathy syndrome, hemorrhage, and seizures), neurocognitive dysfunction, cytomegalovirus infection,
adenovirus infection, Epstein-Barr virus after transplant, lymphoproliferative disease, invasive fungal
infection, donor chimerism, immune reconstitution, and health-related quality of life.
Team Principals:
Name:
Email:
Naynesh Kamani
[email protected]
Chairs:
Shalini Shenoy
[email protected]
Officer:
Mary Eapen
[email protected]
Coordinator:
Iris Gersten
[email protected]
Medical Monitor:
Angie Smith
[email protected]
Statistician:
Brent Logan
[email protected]
Contract Rep:
Nancy Poland
[email protected]
Additional Members:
Email:
Joel Brochstein
[email protected]
Kirk Schultz
[email protected]
Shelly Carter
[email protected]
Paul Scott
[email protected]
Dennis Confer
[email protected]
Elliot Vichinsky
[email protected]
Michael DeBaun
[email protected]
Mark Walters
[email protected]
Nancy DiFronzo
[email protected]
Lolie Yu
[email protected]
Rebecca Drexler
[email protected]
PRC Approval Date:
08/13/2007
Allison King
[email protected]
DSMB Approval Date:
11/19/2007
Janet Kwiatkowski
[email protected]
Opened to Accrual:
06/27/2008
52
Protocol Number:
BMT CTN 0601
Richard Labotka
John Levine
Julie Panepinto
Suhag Parikh
Michael Pulsipher
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Key Highlights:
This study, known as the “SCURT” study (sickle cell unrelated transplantation), was activated on June 27,
2008. The trial was delayed because centers were not activated until enrollment of a first patient, to
minimize activating too many centers for a study that targets only 45 patients. Currently, 2 Core and 16
PBMTC Centers are activated.
In June 2010, the DSMB recommended an amendment to exclude cord blood grafts, due to an observed
high graft failure rate after cord blood transplantation. Cord blood as a graft source was removed from
Protocol Version 6. In addition, eligibility criteria were modified to increase the age limit to 19.75 years
and include increased transcranial Doppler findings as a clinically significant neurological event. The
amendment excluding cord blood grafts required centers to submit a revised protocol to their IRBs
before continuing enrollment. Before this revision, 8 of 15 transplants used cord blood as the graft
source. Not unexpectedly, accrual significantly slowed. The original accrual projections and completion
were revised in April 2011 to address both the pause in enrollment required by these events and the
anticipated decrease in the rate of future accrual since fewer patients would have an available graft
source. In May 2011, the glomerular filtration rate requirement in the protocol was adjusted to include
patients 16 years of age and older. In October 2011, the protocol was modified to ensure consistent
HLA-matching criteria language.
Reporting Period
Update:
The protocol was further amended in June 2012 (version 9.0) to reduce the targeted sample size to 30
bone marrow recipients and again in December 2012 to change the liver biopsy requirements from 30
days prior to initiation of alemtuzumab to 90 days prior.
Publication:
1. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one
cohort from the Phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT
CTN). Biology of Blood and Marrow Transplantation. Epub 2012 Feb 16.
Revised Target Accrual:
Reporting Period Accrual:
IND Number:
N/A
30 BM recipients/ 8 CB
22 BM recipients/ 8 CB
6
N/A
12/19/2012
Accrual per Month
4
BMT CTN #0601
Cumulative Accrual
40
30
3
20
2
10
1
0
0
53
Cumulative Accrual
5
BMT CTN 0702
Protocol Number:
BMT CTN 0702
Status:
Open to Accrual
Title:
A trial of single autologous transplant with or without consolidation therapy versus tandem autologous
transplant with lenalidomide maintenance
Rationale:
The study compares three different treatment strategies that combine high-dose therapy and
autologous stem cell rescue with novel anti-myeloma therapies. The hypothesis is that addition of novel
agents will provide long-term disease control and survival equivalent to the effect of a second
autologous transplant. The three strategies to be tested are autologous transplantation with high-dose
melphalan followed by (1) second autologous transplantation with high-dose melphalan (followed by
lenalidomide maintenance); (2) four cycles of bortezomib, lenalidomide and dexamethasone
consolidation (followed by lenalidomide maintenance); or (3) lenalidomide maintenance alone.
Primary Objective:
To compare three-year progression-free survival among the three treatment arms.
To compare response rates of very good partial remission or better; rates of complete remission
conversion for patients not in complete remission at initiation of maintenance; overall survival; rates of
Secondary Objectives: Grade  3 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE); incidences
of infections; treatment-related mortality rates; and rates of discontinuation of therapy.
The study will also describe and compare quality-of-life in the three arms.
Team Principals:
Name
Amrita Krishnan
Chairs:
George Somlo
Edward Stadtmauer
Officer:
Marcelo Pasquini
Courtney Nelson
Coordinators:
Connie Weaver
Medical Monitor:
Shannon Smiley
Statistician:
Shelly Carter
Contract Rep:
Nancy Poland
Additional Members: Email
Kenneth Anderson
[email protected]
Robert Schlossman
[email protected]
Angela Dispenzieri
[email protected]
[email protected]
Rafael Fonseca
[email protected]
Nancy Geller
Sergio Giralt
[email protected]
Phillip Greipp
[email protected]
Parameswaran Hari
[email protected]
John Koreth
[email protected]
Mary Horowitz
[email protected]
[email protected]
Muzaffer Qazilbash
Philip McCarthy
[email protected]
Key Highlights:
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Target Accrual:
IND Number:
Current Version Released:
Additional Members:
William Merritt
Heather Landau
David Vesole
10/31/2008
03/18/2009
06/01/2010
N/A
750
600
243
104912
01/16/2013
Email
[email protected]
[email protected]
[email protected]
This trial is the follow-on study to BMT CTN 0102 and BMT CTN 0704/CALGB 100104 and is known as the
STaMINA (Stem Cell Transplantation for Multiple Myeloma Incorporating Novel Agents) study. It was
developed by a Multiple Myeloma Inter-Group Committee that included representatives from SWOG,
CALGB, ECOG, and BMT CTN. The protocol was placed on the CTSU roster in March 2010. This is one of
54
Protocol Number:
BMT CTN 0702
the high-priority trials recommended during the 2007 State of the Science Symposium. It was identified
as important to assess the role of post-transplantation treatment for myeloma in the era of novel agents.
Reporting Period
Update:
Protocol Version 6 was released to centers on January 22, 2013, and requires lenalidomide to be
mailed to patients through the RevAssist® for Study Participants Program. Version 6 of the protocol
also allows for bortezomib to be administered subcutaneously and includes updated language and
figures to provide clarity.
As of March 2013, 22 Core Centers and 37 Affiliate Centers (23 through the CTSU) are activated for
enrollment. 600 patients are enrolled on the trial, which is more than 3 months ahead of the projected
accrual.
BMT CTN #0702
Accrual per Month
30
800
Cumulative Accrual
700
600
25
500
20
400
15
300
10
200
5
100
0
0
55
Cumulative Accrual
35
BMT CTN 0801
Protocol Number: BMT CTN 0801
Status:
Open to Accrual
Title:
A Phase II/III randomized, multicenter trial comparing sirolimus plus prednisone and sirolimus/calcineurin inhibitor
plus prednisone for the treatment of chronic GVHD
Rationale:
Standard immunosuppressive therapy for chronic GVHD using glucocorticoids ± calcineurin inhibitor has not
changed for three decades, yet most patients respond inadequately and require at least 2 years of
immunosuppressive therapy to achieve clinical tolerance. Protean and sometimes irreversible organ manifestations
of chronic GVHD create a burden of symptoms that may negatively impact quality of life even after tolerance is
achieved. New approaches are needed to improve early control of chronic GVHD and facilitate tolerance. The NIH
Consensus Development Project for trials in chronic GVHD has primed the field for more rigorous evaluation of
short-term clinical response endpoints.
In parallel, a renewed understanding of regulatory T cells (Tregs) and their role in facilitating graft tolerance has
generated enthusiasm for testing tolerance-induction strategies that do not impede the expansion of Tregs.
Relevant to this, traditional calcineurin inhibitor-based therapy impedes Tregs. In contrast, therapies that facilitate
Tregs, such as sirolimus have shown activity in steroid-refractory GVHD. This study compares early response rates to
sirolimus plus prednisone against sirolimus plus calcineurin inhibitor plus prednisone. The intent is to enroll subjects
either at the start of their initial therapy for chronic GVHD, or before their chronic GVHD is steroid refractory or
chronically dependent on steroids and multiple immunosuppression therapy.
Phase II study: To compare a treatment regimen that contains sirolimus without a calcineurin inhibitor, to a
comparator regimen of sirolimus with a calcineurin inhibitor, with the goal of determining if sirolimus plus
prednisone is a sufficiently promising treatment regimen for further comparison in the Phase III trial.
Primary Objective: The primary hypothesis is that avoidance of a calcineurin inhibitor in the treatment of chronic GVHD might facilitate
the development of tolerance and improve the GVHD response rates at 6 months and, ultimately, the 24 month
complete response rates compared to immunosuppressive therapy regimens that contain a calcineurin inhibitor
(the comparator arm, sirolimus plus calcineurin inhibitor plus prednisone).
Secondary
Objectives:
Phase II study: To compare percent reductions in average daily dose of prednisone by 6 and 12 months; cumulative
incidences of treatment failure at 1 year; prevalence of active symptomatic chronic GVHD at 1 and 2 years;
cumulative incidences of discontinuation of all systemic immunosuppressive therapy at 1 and 2 years; overall and
cancer progression-free survival at 1 and 2 years; candidate serum biomarkers of chronic GVHD at baseline, 2
months and 6 months.
Phase III study: To compare percent reduction in average daily dose of prednisone at 6, 12, and 24 months;
cumulative incidences of treatment failure at 1 and 2 years; prevalence of active symptomatic chronic GVHD at 1
and 2 years; cumulative incidence of discontinuation of all systemic immunosuppressive therapy at 1 and 2 years;
overall and cancer progression-free survival at 1 and 2 years; candidate serum and urine biomarkers of chronic
GVHD at baseline, 2 months and 6 months.
The Phase II and Phase III studies will both evaluate NIH and other new response instruments in chronic GVHD.
Team Principals:
Name:
Email:
Mukta Arora
[email protected]
Chairs:
Paul Carpenter
[email protected]
Officer:
Marcelo Pasquini
[email protected]
Coordinator:
Moira Lewis
[email protected]
Medical Monitor: Bipin Savani
[email protected]
Statistician:
Brent Logan
[email protected]
Contract Reps:
Pamela Budnick
[email protected]
Additional Members:
Email:
Amin Alousi
[email protected]
Javier Bolanos-Meade
[email protected]
Corey Cutler
[email protected]
56
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Target Accrual:
IND Number:
Additional Members:
Carrie Kitko
Stephanie Lee
05/18/2009
09/17/2009
04/15/2010
N/A
110 (Phase II)
110
63
N/A
07/09/2012
Email:
[email protected]
[email protected]
Nancy DiFronzo
Mary Horowitz
David Jacobsohn
Laura Johnston
[email protected]
[email protected]
[email protected]
[email protected]
Pablo Parker
Steven Pavletic
Daniel Weisdorf
[email protected]
[email protected]
[email protected]
This study was rated as “high priority” at the 2007 State of the Science Symposium. The protocol was approved by the
PRC in May 2009 and by the DSMB in September 2009. The study was activated April 15, 2010, after several centers
received IRB approval.
The BMT CTN 0801 trial was originally designed as two parallel but stand-alone studies of Sirolimus plus Prednisone,
Sirolimus/Extracorporeal Photopheresis (ECP) plus Prednisone, and Sirolimus/Calcineurin Inhibitor. Key personnel
from the Protocol Team met in June 2011 to address slow accrual (total of 31), particularly on the ECP study (n=6) of
the Phase II component of the trial. Accrual initiatives included one-on-one calls with center’s PIs and development of
an accrual thermometer and congratulatory emails to enrolling sites.
Key Highlights:
The team also discussed changes in the protocol, resulting in Protocol Version 5, which was released in September
2011. Eligibility criteria were broadened to allow standard risk patients at diagnosis, patients with 16 weeks of prior
therapy, and patients of any weight. In addition, the ECP component of the trial was closed; centers that had been
participating on the ECP study were encouraged to join the non-ECP study so that subjects across all centers will
participate in just one Phase II study and be randomized to one experimental arm, Sirolimus + Prednisone, or the
comparator arm, Sirolimus + Calcineurin Inhibitor + Prednisone. Since the BMT CTN 0801 trial was originally designed
as two parallel but stand-alone studies, the DSMB determined that discontinuation of the ECP study would not
compromise the scientific integrity of the trial. The Phase II study will proceed into the Phase III component if the
experimental arm is more efficacious than the comparator arm.
The study continues to address the important question regarding the removal of a calcineurin inhibitor for treatment
of chronic GVHD. Target enrollment for the combined Phase II/III trial is 300 patients, 100 less than the original target.
Twenty-eight Core Centers and 21 Affiliate Centers have been activated for enrollment. Fifteen additional centers are
anticipated to participate in this trial. Accrual is close to projections.
Accrual to the Phase II component of the study was completed at the end of this reporting period, and accrual to
Phase III has commenced.
Reporting Period The protocol was also amended (current version) with broadended eligibility criteria to allow newly diagnosed
Update:
patients to receive prednisone (or equivalent) for up to two weeks prior to enrollment/randomization, while the
functional test (two minute walk, the grip test and Schirmer’s eye exam) became optional. The transition process
from the Phase II portion to the Phase III portion was also clarified.
Target Accrual = 110 patients (Phase II)
BMT CTN #0801
10
120
Accrual per Month
8
100
Cumulative Accrual
80
6
60
4
40
2
20
0
0
57
Cumulative Accrual
BMT CTN 0803
Protocol Number:
BMT CTN 0803
Status:
Open to Accrual
Title:
High-dose chemotherapy with autologous stem cell rescue for aggressive B cell lymphoma and
Hodgkin lymphoma in HIV-infected patients
Rationale:
Before effective anti-retroviral therapy, advances in and appreciation of the importance of antifungal
and pneumocystis prophylaxis, and the availability of hematopoietic growth factors, high-dose
chemotherapy with stem cell rescue was associated with fatal opportunistic infection in HIV patients.
Several small studies suggest that high-dose chemotherapy with stem cell rescue is appropriate for
patients with HIV and lymphoma and is often associated with long-term disease-free survival.
However, many transplant guidelines exclude patients with HIV. As transplant studies to date have
mainly been carried out in institutions with special expertise in HIV and transplant, there is some
uncertainty as to whether the encouraging results in these smaller studies could be reproduced or
improved upon in a multicenter setting.
As with lymphoma patients without HIV, lymphoma relapse is the major cause of mortality in recent
small studies of high-dose therapy with stem cell rescue. PET/CT imaging is emerging as an important
tool for assessing disease responsiveness. If PET/CT were applied to lymphoma in HIV patients, it
might be useful for identifying those patients most likely to benefit from high-dose therapy. PET/CT
has not been systematically studied in HIV patients. However, there is literature characterizing
fluorodeoxyglucose uptake in patients with HIV infection that raises concerns about extrapolating
PET/CT findings in other populations to this population.
Fluorodeoxyglucose uptake seems to be associated with the cellular response to the virus following
initial infection, viral replication in lymphoid tissue, and immune reconstitution following the
initiation of effective antiretroviral therapy. A second aim of the study is to systematically and
prospectively assess the utility of PET/CT responses in identifying patients who would benefit from
high-dose therapy.
Primary Objective:
To assess overall survival after autologous HCT for chemotherapy-sensitive aggressive B cell
lymphoma or Hodgkin lymphoma in patients with HIV, using BEAM for pre-transplant conditioning.
Secondary Objectives:
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician
Contract Rep:
Additional Members:
Gorgun Akpek
Robert Baiocchi
Shelly Carter
Steven Devine
To evaluate time-to-progression, progression-free survival, complete remission (CR), and CR+PR
(partial remission) proportion at day 100, time to progression after CR, lymphoma disease-free
survival, time to hematopoietic recovery, hematologic function at day 100, toxicities, incidence of
infections, treatment-related mortality, immunologic reconstitution, assessment of microbial gut
translocation and assessment of DNA in blood (clonal Ig DNA in plasma, Epstein-Barr virus DNA in
plasma and peripheral blood mononuclear cells) as tumor markers.
Name:
Email:
Joseph Alvarnas
[email protected]
Richard Ambinder
[email protected]
Willis Navarro
[email protected]
Jason Thompson
[email protected]
Bipin Savani
[email protected]
Brent Logan
[email protected]
Pamela Budnick
[email protected]
Email:
PRC Approval Date:
11/13/2009
[email protected]
DSMB Approval Date:
01/05/2010
[email protected]
Opened to Accrual:
07/12/2010
[email protected]
N/A
[email protected]
Target Accrual:
40
58
Protocol Number:
Charles Flexner
Stephen Forman
Mary Horowitz
Richard Jones
Lawrence Kaplan
Amrita Krishnan
Richard Little
Jennifer Le-Rademacher
Alexandra Levine
John Mellors
38
15
N/A
04/30/2010
Email:
[email protected]
[email protected]
[email protected]
[email protected]
BMT CTN 0803
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
IND Number:
Additional Members:
Ariela Noy
Uday Popat
Aruna Subramanian
John Zaia
The BMT CTN 0803 Protocol Team was formed in November 2008. In November 2009, the protocol
received PRC approval, followed by DSMB approval in January 2010. It was released to centers for
IRB submission in January 2010. On April 30, 2010, Protocol Version 2 was released to centers for IRB
submission. The amendment removed the HIV reservoir ancillary study from the protocol.
Key Highlights:
Eleven Core, four affiliate and four AIDS Malignancy Consortium Centers are participating in the
study, which opened to accrual in July 2010. Sixteen centers have enrolled 38 patients, and accrual is
ahead of projections.
The study is conducted in partnership with the AIDS Malignancy Consortium, an NCI-supported
clinical trials group. Additional funding is provided by the NCI program for Non-AIDS-Defining
Cancers.
Reporting Period Update:
Accrual has been steady throughout the year and is anticipated to close on time during the next
reporting period.
BMT CTN #0803
Accrual per Month
6
45
Cumulative Accraul
40
35
5
30
4
25
3
20
15
2
10
1
5
0
0
59
Cumulative Accrual
7
BMT CTN 0804 / CALGB 100701
Protocol Number:
Status:
Open to Accrual
Title:
Phase II study of reduced-intensity allogeneic stem cell transplant for high-risk chronic lymphocytic
leukemia
Rationale:
Despite recent therapeutic advances that include monoclonal antibody therapy with alemtuzumab
and rituximab in combination with chemotherapy, chronic lymphocytic leukemia (CLL) remains
incurable with standard therapy. Although both autologous and allogeneic HCT have been
attempted as definitive therapy, the role and optimal timing of transplantation in the treatment of
CLL remain unclear. Recent attention has focused on allogeneic transplantation, given the
demonstration of a robust graft-versus-leukemia effect in CLL. In an effort to expand the role of
allogeneic transplantation to the age group affected by CLL, reduced-intensity conditioning
allogeneic transplantation has been explored.
Recent advances in understanding the biology of CLL include identifying prognostic factors that
strongly predict outcomes, including overall survival. These factors include the gene mutation status
of the IgVH gene, expression of CD38 and ZAP-70, and genetic abnormalities as assessed by
fluorescence in situ hybridization. Among these genetic abnormalities, deletions of 17p and 11q
account for 25% of presenting cases of CLL and are associated with median times to progression of
only two years. These genetically-defined subsets are currently the subgroup of CLL patients with
the poorest prognosis. Furthermore, patients with these genetic abnormalities respond to
fludarabine-based regimens less well than others and manifest short response durations. Patients
with these findings represent an excellent population in which to test the efficacy of upfront
reduced-intensity allogeneic transplant, to determine whether this early intervention can favorably
impact the natural history of the disease.
Primary Objective:
To determine if this treatment improves the current two-year rate of progression-free survival (PFS)
in the early-disease cohort compared to historical controls, specifically assessing whether 2-year PFS
≥ 70% is achievable and whether two-year PFS ≤ 50% can be excluded.
To evaluate whether two-year current PFS ≥ 50% is achievable and two-year PFS ≤ 30% can be
excluded in the advanced disease cohort; objective response rate; incidences of grades 2-4 and 3-4
acute GVHD; incidence of extensive chronic GVHD; incidences of transplant-related mortality at 100
days and one year; overall survival; donor chimerism for CD3+ cells at one and two years after
transplantation; presence of donor antigen-specific T cell clones before and after withdrawal of
immune suppression; relapse profiles of patients with T cell responses against CLL to those whose
CLL cells that are not reactive; and to prospectively examine the impact of high-risk genomic
features and immune-based single nucleotide polymorphisms on response, toxicity, and two-year
PFS to reduced-intensity allogeneic HCT.
Team Principals:
Chair:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Statistician:
Contract Rep:
Name:
Richard Maziarz
Mary Horowitz
Jason Thompson
CALGB
CALGB
CALGB
Nancy Poland
Email:
[email protected]
[email protected]
[email protected]
[email protected]
60
Protocol Number:
Additional Members:
Edwin Alyea
Allison Booth
Michael Caligiuri
Steven M. Devine
John Gribben
Vera Hars
Michael Kelly
Richard Larson
Kouros Owzar
Morgen Alexander-Young
Email:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Key Highlights:
This study was rated as a “very high priority” at the 2007 State of the Science Symposium, and this
protocol is a collaborative effort between CALGB and BMT CTN. CALGB patient accrual began
February 15, 2010. BMT CTN opened the trial to enrollment on March 16, 2011.
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Target Accrual:
IND Number:
CALGB
CALGB
03/16/2011
N/A
86
52 Total, 12 BMT CTN
23 Total, 7 BMT CTN
N/A
1/15/2012
As of January 15, 2013, all registrations for CALGB and BMT CTN centers have moved to the CTSU
Reporting Period Update: OPEN registration system. BMT CTN centers have enrolled 12 of the 52 patients on this trial, seven
during this past reporting period.
Target Accrual = 86
Accrual per Month
8
6
BMT CTN #0804/CALGB 100701 (BMT CTN accrual N = 12)
Cumulative Accrual
60
50
CALGB opened this protocol
in February 2010; enrollment
started in January 2011.
BMT CTN opened the trial to
enrollment in March 2011.
40
30
4
20
2
10
0
0
61
Cumulative Accrual
10
BMT CTN 0805 / SWOG 0805
Protocol Number: BMT CTN 0805 / SWOG 0805
Status:
Open to Accrual
Title:
A Phase II study of combination of hyper-CVAD and dasatinib with or without allogeneic stem cell transplant
in patients with Philadelphia chromosome positive and/or BCR-ABL positive acute lymphoblastic leukemia
(ALL) (a BMT study).
Rationale:
The availability of targeted therapies of Philadelphia+ leukemia has improved outcomes of patients with
these diseases. However, Philadelphia+ ALL still has a high risk of relapse. This study addresses the efficacy of
two approaches; chemotherapy with the tyrosine kinase inhibitor dasatinib and allogeneic HCT, in achieving
leukemia-free survival in patients with this disease.
Primary
Objective:
To test whether the relapse-free survival after allogeneic HCT among Philadelphia+ and/or BCR-ABL gene+
ALL patients given an intensive short-term chemotherapy regimen of hyper-CVAD (cyclophosphamide,
vincristine, adriamycin and dexamethasone) in combination with the tyrosine kinase inhibitor dasatinib is
sufficiently high to warrant further investigation, and to test whether the continuous complete remission
rate for previously untreated Philadelphia+ and/or BCR-ABL+ ALL patients given an intensive short-term
chemotherapy regimen of hyper-CVAD in combination with the tyrosine kinase inhibitor dasatinib is
sufficiently high to warrant Phase III investigation.
To investigate, in a preliminary manner, the relative effectiveness of minimum residual disease detection
using real-time quantitative polymerase chain reaction for BCR/ABL versus flow cytometry to predict the
Secondary
outcome of patients treated by the hyper-CVAD + dasatinib regimen and/or allogeneic stem cell transplant;
Objectives:
estimate the frequency and severity of toxicities of the intensive short-term chemotherapy regimen in these
patients; and estimate the overall survival of all patients on the study.
Team Principals: Name:
Email:
David Porter (BMT CTN)
[email protected]
Chairs:
Farhad Ravandi (SWOG)
[email protected]
Officer:
SWOG
Amy Foley (BMT CTN)
[email protected]
Coordinators:
Sandi Jo McMillan (SWOG)
[email protected]
Medical Monitor: SWOG
Statistician(s):
SWOG
Contract Rep:
Pamela Budnick
[email protected]
PRC Approval Date:
SWOG
Additional
Email:
Members:
DSMB Approval Date:
SWOG
Stephen Forman [email protected]
SWOG: 09/1/09
Opened to Accrual:
CTSU: 8/9/10
Chul S Ha
[email protected]
Susan O’Brien
[email protected]
Closed to Accrual:
N/A
Jerald P Radich
[email protected]
Target Accrual:
85
Jeffrey YC Wong [email protected]
Total Accrual as of 3/31/13: 74
46
IND Application Number:
Held by SWOG
This study was rated as a “very high priority” trial during the 2007 State of the Science Symposium; the
collaborative study is led by SWOG with active involvement of BMT CTN and ECOG representatives on the
Protocol Team. This protocol opened to accrual to SWOG centers in September 2009 and through the CTSU
Key Highlights:
in August 2010, where the study can be accessed by all BMT CTN centers. Several centers affiliated with both
SWOG and BMT CTN are already participating on the study. The BMT CTN contributes to patient
reimbursement for all patients on the transplant arm.
62
Protocol Number: BMT CTN 0805 / SWOG 0805
One BMT CTN Core center was activated to participate on the study through the BMT CTN and enrolled
Reporting Period
one patient. Twelve other BMT CTN Core/Consortia centers are activated through SWOG or the CTSU and
Update:
have enrolled 38 total patients. Accrual is anticipated to be completed during the next reporting period.
An accrual graph is not included because participation through the BMT CTN is limited.
63
BMT CTN 0901
Protocol Number:
BMT CTN 0901
Status:
Open to Accrual
Title:
A randomized, multicenter Phase III study of allogeneic stem cell transplantation comparing regimen
intensity in patients with myelodysplastic syndrome or acute myeloid leukemia
Myelodysplastic syndrome (MDS) and AML are predominantly diseases of older patients. For patients
with advanced or chemotherapy refractory disease, allogeneic HCT is currently the only strategy that
offers a cure. Unfortunately, this modality is currently available only to a small proportion of patients.
Many patients do not undergo HCT either because of advanced age, because no suitable donor is
available, or because of unacceptable risks currently associated with HCT.
Rationale:
One major cause of mortality after HCT is toxicity from pre-transplant conditioning, which historically
has included high, myeloablative doses of cytotoxic chemotherapy with or without radiation. In recent
years, reduced-intensity conditioning regimens were introduced in an attempt to reduce non-relapse
mortality so that HCT could be offered to patients who otherwise would not be considered candidates.
The encouraging results of initial studies with these regimens are of particular interest for patients with
MDS or AML diseases that increase in frequency with age, since older patients are at highest risk of
severe complications from intensive conditioning.
This study proposes a Phase III multicenter trial to compare outcomes with myeloablative and reducedintensity conditioning regimens in patients undergoing allogeneic HCT for MDS and AML.
To compare 18-month overall survival between the two groups. The hypothesis to be tested is that
reducing the intensity of the conditioning regimen will decrease treatment-related mortality without
increasing relapse, so that overall survival will be improved.
To compare disease-free survival rate after transplantation, rate of transplant-related mortality,
hematologic recovery, kinetics of donor cell engraftment, incidence of graft failure, incidence and
severity of acute and chronic GVHD, immune reconstitution, quality of life, rates of infectious
complications, rates of ≥ grade 3 toxicities according to CTCAE criteria, and quality of life.
Team Principals:
Name
Email
Mitchell Horwitz
[email protected]
Chairs:
Bart Scott
[email protected]
Officer:
Marcelo Pasquini
[email protected]
Coordinator:
Iris Gersten
[email protected]
Medical Monitor:
Bipin Savani
[email protected]
Statistician:
[email protected]
Contract Rep:
Renee Carby
[email protected]
Additional Members: Email
PRC Approval Date:
07/23/2010
Shelly Carter
[email protected]
DSMB Approval Date:
09/15/2010
Joachim Deeg
[email protected]
Opened to Accrual:
06/2/2011
Steve Devine
[email protected]
N/A
Nancy DiFronzo
[email protected]
Target Accrual:
356
Sergio Giralt
[email protected]
147
Mary Horowitz
[email protected]
101
Eric Leifer
[email protected]
IND Number:
N/A
Brent Logan
[email protected]
03/06/2012
Richard Maziarz
[email protected]
Willis Navarro
[email protected]
Nancy Poland
[email protected]
Primary Objective:
64
Protocol Number:
BMT CTN 0901
David Porter
Erica Warlick
[email protected]
[email protected]
Key Highlights:
The concept for this protocol was approved by the Steering Committee in October 2008 after being
rated as a “high” priority at the 2007 State of the Science Symposium. The Protocol Team was formed
in December 2008 and held its first meeting in March 2009. The protocol was approved by the PRC on
June 23, 2010, and by the DSMB on September 15, 2010. It was activated on June 2, 2011, after several
centers received IRB approval and identified potential patients. Eighteen Core and 15 Affiliate Centers
have been activated, and 28 centers have enrolled patients to date.
Version 3.0 of the protocol was released in March 2012; clarifications were added to patient eligibility
criteria and donor age restriction was removed.
Reporting Period
Update:
Accrual has remained above projections throughout the year. A protocol amendment (Version 4) will
be submitted to the DSMB for review in April 2013. Changes will include allowance of serological
typing on Class I alleles for related donors, drug dosage instruction clarification, and other minor
updates.
Target accrual = 356 patients
BMT CTN #0901
12
200
Cumulative Accrual
150
10
8
100
6
4
50
2
0
0
65
Cumulative Accrual
Accrual per Month
14
BMT CTN 0903
Protocol Number:
BMT CTN 0903
Status:
Open to Accrual
Title:
Allogeneic hematopoietic cell transplant for hematological cancers and myelodysplastic syndromes in
HIV-infected individuals
Rationale:
Survival in patients with HIV has improved dramatically with the advent of highly active antiretroviral
therapy (HAART). Despite improvements in HIV infection-related survival, the risk of malignancies
remains significant in patients with HIV infection. While non-Hodgkin lymphoma is an acquired
immune deficiency (AIDS)-defining diagnosis, a comparison of a large cohort of HIV-infected patients to
Surveillance, Epidemiology and End Results data demonstrates a significantly higher incidence of
vaginal, Hodgkin lymphoma, liver, lung, melanoma, oropharyngeal, colorectal, renal cancers and
leukemia in patients with HIV infection.
Prior to the advent of HAART, the treatment of patients with malignancy in the setting of HIV infection
was hamstrung by limited chemotherapy tolerance and complications due to opportunistic infection.
Since the widespread availability of HAART, there have been significant improvements in the capacity
to treat these patients in a fashion comparable to that of patients without HIV infection. This in turn
has led to marked improvements in the outcomes of patients with malignancies in the setting of HIV
infection.
The prognosis for patients with AIDS-related lymphoma is dramatically different in the era of HAART
therapy. In a comparison of treatment outcomes for patients treated before and after the advent of
HAART, there is a statistically significant improvement in the overall survival of patients treated with
HAART (p=0.002). While the International Prognostic Index remains a useful tool for estimating the
prognosis of patients with AIDS-related non-Hodgkin lymphoma, the CD4 count of less than 100 per
microliter has independent prognostic value for this group of patients. The impact of HAART therapy
upon the immunological and functional status of patients with HIV infection has permitted the
extension of aggressive therapeutic regimens to this patient population. HAART allows a significant
portion of patients to reduce their viral load to undetectable levels and, therefore, tolerate far more
aggressive therapeutic interventions than would have been possible previously.
Primary Objective:
To assess non-relapse morality at 100 days after allogeneic HCT.
To analyze disease status at day 100 post HCT, time to hematopoietic recovery, chimerism at 30, 100,
and 180 days, hematologic function at 100 and 180 days, infections, six-month overall survival, acute
and chronic GVHD, immunologic reconstitution at 8 weeks, 180 and 365 days and the impact of HCT on
the HIV reservoir at day 100, 6 months, 1 year and 2 years post HCT.
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Gorgun Akpek
Robert Baiocchi
Shelly Carter
Steven Devine
Charles Flexner
Name:
Joseph Alvarnas
Richard Ambinder
Willis Navarro
Jason Thompson
Tammy Kindwall-Keller (P)
Jennifer Le Rademacher
Pamela Budnick
Email:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Email:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
09/15/2010
DSMB Approval Date:
03/29/2011
Opened to Accrual:
5/11/2012
N/A
Target Accrual:
15
5
66
Protocol Number:
Stephen Forman
Mary Horowitz
Rick Jones
Amrita Krishnan
Richard Little
Alexandra Levine
Brent Logan
John Mellors
BMT CTN 0903
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Key Highlights:
The protocol was approved by the PRC in September 2010 and by the DSMB in March 2011. Protocol
Version 1 was released to centers in April 2011; however, due to the need for immediate protocol
amendments, study activation was delayed. Protocol Version 2 was released on January 20, 2012, and
the protocol opened to accrual on May 11, 2012.
Like its sister study BMT CTN 0803, this trial is a partnership with the NCI-supported AIDS Malignancy
Consortium. Additional funding will be provided by the NCI Cancer Therapy Evaluation Program for
Non-AIDS-Defining Cancers.
Reporting Period
Update:
IND Number:
Additional Members:
Ariela Noy
Uday Popat
Aruna Subramanian
John Zaia
5
N/A
1/20/2012
Email:
[email protected]
[email protected]
[email protected]
[email protected]
The study was opened this year. Accrual has been steady and continues ahead of schedule.
BMT CTN #0903
4
15
Cumulative Accrual
10
3
2
5
1
0
0
67
Cumulative Accrual
Accrual per Month
5
BMT CTN 1101
Protocol Number:
BMT CTN 1101
Status:
Open to Accrual
Title:
A multi-center Phase III randomized trial of reduced intensity conditioning and transplantation of
double unrelated umbilical cord blood versus HLA-haploidentical related bone marrow for patients
with hematologic malignancies
Rationale:
Reduced intensity conditioning (RIC) BMT has allowed older and less clinically fit patients to receive
potentially curative treatment with allogeneic BMT for high risk or advanced hematological
malignancies. Patients lacking an HLA-matched sibling may receive a graft from a suitably HLAmatched unrelated donor. However, up to a third of patients will not have an HLA-matched sibling or
a suitably matched adult unrelated donor (i.e., no more than a mismatch at a single locus). Even
when a suitably matched unrelated donor is identified, data from the NMDP indicate that a median
of four months is required to complete searches that result in transplantation; thus some number of
patients succumb to their disease while awaiting identification and evaluation of a suitably matched
adult unrelated donor.
Single or dual center studies have shown that partially HLA-mismatched related bone marrow and
unrelated double umbilical cord blood are valuable sources of donor cells for RIC BMT, extending this
treatment modality to patients who lack other donors. In order to study the reproducibility, and thus
the wider applicability of these two alternative donor strategies, BMT CTN conducted two parallel
multicenter prospective Phase II clinical trials. These two studies evaluated the safety and efficacy of
related haplo-bone marrow (BMT CTN 0603) and double umbilical cord blood (BMT CTN 0604)
transplantation after RIC. Both of these alternative donor approaches produced early results similar
to that reported with unrelated donor, and even HLA-matched sibling, BMT. These data demonstrate
not only the efficacy of both of these approaches but also that both can be safely exported from the
single center setting. Both haplo-bone marrow and double umbilical cord blood grafts can be
obtained rapidly for >90% of patients lacking an HLA-matched donor.
Primary Objective:
To compare progression-free-survival at two years post-randomization between patients who
receive unrelated double cord blood unit transplantation versus HLA haploidentical related bone
marrow transplantation.
To evaluate neutrophil recovery, graft failure, platelet recovery, donor cell engraftment, acute
GVHD and chronic GVHD, overall survival, treatment-related mortality, infections, hospital
admission and length of stay, health related quality of life, relapse/progression, and cost
effectiveness.
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Omar Aljitawi
Joe Antin
Karen Ballen
Name
Claudio Brunstein
Ephraim Fuchs
Paul O’Donnell
Mary Eapen
Kate Barowski
Angie Smith
Brent Logan
Pam Budnick
Email
[email protected]
[email protected]
[email protected]
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
68
10/22/2011
01/09/2012
06/19/2012
N/A
Protocol Number:
BMT CTN 1101
Javier Bolaños-Meade
Shelly Carter
Luciano Costa
Corey Cutler
Steve Devine
Nancy DiFronzo
Mary Horowitz
Chatchada Karanes
Elizabeth Rich
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Key Highlights:
BMT CTN 1101 is a Phase III randomized follow-on study to the Phase II 0603 (haplo-bone marrow)
study, which completed accrual in May 2010, and the 0604 (double umbilical cord blood) study,
which completed accrual in March 2010. The protocol was approved by the PRC in October 2011 and
by the DSMB in January 2012. Version 1 of the protocol was released to centers on February 27,
2012.
Target Accrual:
IND Number:
Additional Members:
Liz Wagner
John Wingard
410
11
11
N/A
11/20/2012
Email
[email protected]
[email protected]
The study was opened to accrual June 19, 2012. Version 2.0 was released to centers on November
20, 2012. Significant changes included in this amendment were the separation of eligibility criteria
into two components, eligibility criteria required prior to randomization and eligibility criteria
required prior to transplant, a revision of disease eligibility criteria. Additionally, the amendment
included a new cost effectiveness companion study, funded by the NHLBI via an R01 grant
obtained by Study Chair, Paul O’Donnell.
BMT CTN #1101
4
35
Cumulative Accrual
30
25
3
20
15
2
10
1
5
0
0
69
Cumulative Accrual
Accrual per Month
5
70
7.2 Protocols that Completed Accrual
BMT CTN Protocols that Completed Accrual (as of March 31, 2013)
BMT CTN
Protocol #
0101
0102
0201
0202
0302
0303
0401
0402
0403
0501
0502 /
CALGB 100103
0603
0604
0701
0703/
SWOG 0410
0704 /
CALGB 100104 /
ECOG 100104
0802
0902
Protocol Title
A randomized double-blind trial of fluconazole versus voriconazole for the prevention of invasive
fungal infections in allogeneic blood and marrow transplant recipients
A trial of tandem autologous stem cell transplants with or without post-second autologous transplant
maintenance therapy versus single autologous stem cell transplant followed by matched sibling nonmyeloablative allogeneic stem cell transplant for patients with multiple myeloma
A Phase III randomized, multicenter trial comparing G-CSF mobilized peripheral blood stem cell
with marrow transplantation from HLA compatible unrelated donors
Autologous versus non-myeloablative allogeneic HCT for patients with chemosensitive follicular
non-Hodgkin lymphoma beyond first complete response or first partial response
Initial systemic treatment of acute GVHD: A phase II randomized trial evaluating etanercept,
mycophenolate mofetil, denileukin diftitox (Ontak), and pentostatin
A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell
depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients
with AML in first or second morphologic complete remission
Phase III Rituxan/BEAM versus Bexxar/BEAM with autologous HCT for persistent or relapsed
chemotherapy-sensitive diffuse large B cell non-Hodgkin lymphoma
A Phase III randomized, multicenter trial comparing sirolimus/tacrolimus with
tacrolimus/methotrexate as GVHD prophylaxis after HLA-matched, related peripheral blood stem
cell transplantation
A randomized double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor Enbrel
(etanercept) for the treatment of acute noninfectious pulmonary dysfunction (idiopathic pneumonia
syndrome) following allogeneic HCT
Multicenter, open label, randomized trial comparing single versus double umbilical cord blood
transplantation in pediatric patients with leukemia and myelodysplasia
A Phase II study of allogeneic transplant for older patients with acute myeloid leukemia in first
morphologic complete remission using a non-myeloablative preparative regimen
A multicenter, Phase II trial of non-myeloablative conditioning and transplantation of partially HLAmismatched bone marrow for patients with hematologic malignancies
A multicenter, Phase II trial of non-myeloablative conditioning and transplantation of umbilical cord
blood from unrelated donors in patients with hematologic malignancies
A Phase II trial of non-myeloablative allogeneic HCT in relapsed follicular non-Hodgkin lymphoma
using related or unrelated donors beyond first complete response
Tandem autologous stem cell transplantation for patients with primary progressive or recurrent
Hodgkin disease (a BMT study), Phase II
A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 or placebo
following autologous stem cell transplantation for multiple myeloma
A multicenter randomized, double blind, Phase III trial evaluating corticosteroids with
mycophenolate mofetil versus corticosteroids with placebo as initial systemic treatment of acute
graft-versus-host disease
A Phase III randomized, multicenter trial testing whether exercise or stress management improves
functional status and symptoms of autologous and allogeneic HCT recipients
71
BMT CTN 0101
Status:
Closed to Accrual
Title:
A randomized double-blind trial of fluconazole versus voriconazole for the prevention of invasive fungal
infections in allogeneic blood and marrow transplant recipients
Rationale:
Invasive fungal infections are a life-threatening complication of allogeneic HCT. Fluconazole prophylaxis has
been found in randomized trials to be an effective prevention of invasive Candida infections. Invasive
Aspergillus infections are a growing threat to transplant recipients; furthermore, treatment options are
toxic, and outcomes are poor. Voriconazole is an extended-spectrum azole that is the most effective
treatment for Aspergillosis. It may offer the potential for preventing Aspergillosis, but its toxicity may offset
its benefit. New diagnostic tests, such as the galactomannan assay permit screening, and early detection of
Aspergillus infection may lead to improved treatment outcomes. This trial compared two strategies to
determine which was more effective in optimizing fungal-free survival: fluconazole prophylaxis plus a
program of intensive screening including serial galactomannan testing versus voriconazole.
Primary Objective: To compare the fungal-free survival rates between the two study arms through day 180.
Secondary
Objectives:
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional
Members:
Nancy DiFronzo
Nancy Geller
Joanne Kurtzberg
Brent Logan
Kieren Marr
Elizabeth Murphy
Richard O'Reilly
Trudy Small
Key Highlights:
To compare the frequencies of invasive fungal infection, time to invasive fungal infection, survival rate,
duration of amphotericin B or caspofungin therapy for possible invasive fungal infection, time to neutrophil
and platelet engraftment, time to and severity of acute and chronic GVHD, and adverse events and routine
laboratory tests; additionally, the study was designed to include an exploratory analysis of the quantitative
aspects of the galactomannan assay.
Name:
Thomas Walsh
John Wingard
Dennis Confer
Iris Gersten
Marcelo Pasquini
Shelly Carter
Pamela Budnick
Email:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
11/15/2002
Email:
DSMB Approval Date:
01/22/2003
[email protected]
Opened to Accrual:
12/01/2003
[email protected]
9/21/2006
[email protected]
Evaluable for Primary Analysis: 09/2007
[email protected]
Target Accrual:
600
[email protected]
600
[email protected]
N/A
[email protected]
IDE Number:
G020306 (closed prior to enrollment)
[email protected]
Last Version Released:
03/29/2006
The study experienced a delay from DSMB approval to study activation due to prolonged negotiations for
drug acquisition and funding. Ultimately, an over-encapsulated blinded drug was secured, and the trial
opened to accrual in December 2003.
The study closed to accrual in September 2006 when 600 patients, as planned, were enrolled. Five
transplant physicians from the Protocol Team assumed the role of Endpoint Review Committee and
conducted an independent assessment of the major events of the primary and major secondary study
endpoints. The Endpoint Review Committee spent considerable time checking and reconciling data,
including a review of primary data documents to confirm diagnoses.
72
Reporting Period
Update:
A secondary pharmacoeconomic analysis was performed, and the manuscript is in press. An additional
secondary pharmacokinetic analysis of voriconazole concentrations in blood samples collected on Day 14
and 28 of therapy; at onset of serious suspected study drug toxicities; and at onset of possible,
presumptive, probable or proven infection (prior to start of antifungal therapy) is in the process of being
analyzed.
Publications:
1. Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus
voriconazole after allogeneic hematopoietic cell transplantation. Clinical Infectious Disease. 2004 Oct
15;39 Suppl 4:S176-180.
2. Primary manuscript: Randomized double-blind trial of fluconazole versus voriconazole for prevention of
invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010 Dec
9;116(24):5111-5118. Epub 2010 Sep 8.
3. Cost-effectiveness analysis of voriconazole compared with fluconazole for prevention of invasive
fungal infection in patients receiving allogeneic hematopoietic cell transplants. American Journal of
Health-System Pharmacy. [In Press]
Presentation:
1. Results of a randomized, double-blind trial of fluconazole vs. voriconazole for the prevention of invasive
fungal infections in 600 allogeneic blood and marrow transplant patients. Presentation: 49th Annual ASH
Meeting, Atlanta, GA, December 2007.
BMT CTN #0101
700
600
25
500
Accrual per Month
30
20
400
15
300
10
200
5
100
0
0
73
Cumulative Accrual
35
Cumulative Accrual
BMT CTN 0102
Protocol Number:
BMT CTN 0102
Status:
Closed to Accrual
A trial of tandem autologous stem cell transplants with or without post-second autologous transplant
maintenance therapy versus single autologous stem cell transplant followed by matched sibling
nonmyeloablative allogeneic stem cell transplant for patients with multiple myeloma
This study compared tandem autologous HCT (auto/auto) with autologous HCT followed by HLA-matched
sibling allogeneic HCT with a nonmyeloablative conditioning regimen (auto/allo) in patients with multiple
myeloma. Autologous HCT is widely accepted as a standard of care for patients with multiple myeloma.
Allogeneic HCT offers a potential graft-versus-myeloma effect, and this study addressed whether it offers
additional benefit compared with tandem autologous HCT. Additionally, the study evaluated the role of
one-year maintenance therapy with thalidomide plus dexamethasone after tandem auto/auto HCT.
Maintenance therapy after autologous HCT has demonstrated improvements in overall survival.
To compare three-year progression-free survival between the two arms.
Title:
Rationale:
Primary Objective:
Secondary
Objectives:
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional
Members:
Nancy DiFronzo
Stephen Forman
Nancy Geller
Sergio Giralt
Elizabeth Murphy
Edward Stadtmauer
David Vesole
John Wingard
Key Highlights:
To compare current myeloma-stable survival, three-year overall survival, and incidence of progression.
Name
Amrita Krishnan
David Maloney
Marcelo Pasquini
Kristin Knust
Marcelo Pasquini
Brent Logan
Pam Budnick
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Evaluable for Primary Analysis:
Target Accrual:
IND Number:
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
11/15/2002
08/11/2003
11/15/2003
03/30/2007
04/2010
710
710
N/A
67956
05/15/2006
Accrual and analysis for this study were based on the anticipated number of standard-risk multiple
myeloma patients with an available HLA-matched sibling donor. Statistical power required that 150
standard-risk patients be assigned to the autologous-allogeneic transplant arm. Enrollment would remain
open until this goal was achieved, with concurrent enrollment of both standard-risk and high-risk patients,
with and without HLA-matched sibling donors. When the protocol was developed, it was estimated that
500–750 total subjects would be required, as it was assumed that 20% to 30% of subjects would have
available HLA-matched sibling donors.
The study closed to enrollment on March 30, 2007, after 150 patients declared their intent to receive an
allogeneic transplant. A total of 710 subjects were required to obtain 189 subjects with standard-risk
disease biologically assigned to the autologous-allogeneic transplant arm. Patients were followed for three
years after their second transplant.
The Endpoint Review Committee formed in July 2008 after all patients completed maintenance therapy;
the Committee conducted an independent assessment of the study’s primary and secondary endpoints.
This preliminary review demonstrated many inconsistencies between the reported data and interpretation
74
Protocol Number:
BMT CTN 0102
of disease response by transplant centers. Adjudication of such discrepancies was required, with source
document review and consultation with the institutional PIs. The Endpoint Review Committee
acknowledged the inherent difficulties in interpreting disease response in multiple myeloma, which
suggests ongoing review of incoming data is preferred during active accrual for future myeloma clinical
trials conducted by the BMT CTN. The Endpoint Review Committee completed review of all patients in
June 2010.
Reporting Period
Update:
Data are being reviewed for a secondary analysis of longer term follow-up. An abstract and manuscript
are expected to be submitted with the next reporting period.
Publications:
1. Correspondence: Tandem vs. single autologous hematopoietic cell transplantation for the treatment of
multiple myeloma: a systematic review and meta-analysis.
2. Design paper: Use of biological assignment in hematopoietic stem cell transplantation clinical trials.
Clinical Trials. 2008;5(6):607-16.
3. Primary manuscript: Autologous haemopoietic stem-cell transplantation followed by allogeneic or
autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102):
a Phase 3 biological assignment trial. Lancet Oncology. 2011 Dec;12(13):1195-1203. [Epub 2011 Sep 29]
Presentations:
1. Biologic assignment trials in hematopoietic stem cell transplantation (HCT): baseline characteristics of
multiple myeloma patients in BMT CTN 0102 by treatment allocation according to donor availability.
Presentation: 49th Annual ASH Meeting, Atlanta, GA, December 2007.
2. Tandem autologous hematopoietic stem cell transplants with or without maintenance therapy versus
single autologous HCT followed by HLA matched sibling nonmyeloablative allogeneic HCT for patients
with standard risk multiple myeloma: results from the BMT CTN 0102 Trial. Presented: 52nd Annual ASH
Meeting, Orlando, FL, December 2010.
3. Tandem autologous HCT (auto-auto) versus single autologous HCT followed by HLA matched sibling nonmyeloablative allogeneic HCT (auto-allo) for patients with standard risk multiple myeloma: results from
the BMT-CTN 0102 trial. Poster Presentation: 13th International Myeloma Workshop, Paris, France, May
2011.
4. Immunoglobulin free light chain (FLC) and heavy chain/light chain (HLC) assays – comparison with
electrophoretic responses in multiple myeloma (MM): results of BMT CTN Protocol #0102. Poster
Presentation: 53rd Annual ASH Meeting, San Diego, CA, December 2011.
Accrual per Month
30
BMT CTN #0102
Cumulative Accrual
800
700
600
25
500
20
400
15
300
10
200
5
100
0
0
75
Cumulative Accrual
35
BMT CTN 0201
Protocol Number:
BMT CTN 0201
Status:
Closed to Accrual
Title:
A Phase III randomized, multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow
transplantation from HLA compatible unrelated donors
Rationale:
Many allogeneic marrow transplantation studies indicate that higher doses of marrow cells correlate with more
robust hematopoietic engraftment and lower mortality from infectious complications. PBSCs collected after
mobilization with G-CSF contain a larger number of CD34+ progenitors and total cells than bone marrow. These
observations led to the hypothesis that transplantation of PBSC would lead to a lower mortality rate when
compared with transplantation of marrow.
PBSC grafts have a higher T cell content, predicting a possibly more powerful anti-leukemic effect. However, the
higher T cell content of PBSC may also lead to an increased incidence and severity of acute and chronic GVHD.
This concern is especially serious when the donor is unrelated to the recipient. This prospective, randomized,
multicenter clinical trial of unrelated donor transplantation tested the hypothesis that transplantation of PBSC
leads to similar patient survival compared to transplantation of marrow.
To compare two-year survival probabilities between patients receiving PBSC versus marrow transplants from
unrelated donors using an intent-to-treat analysis.
Patients randomized to the two study arms and actually transplanted were compared for the following endpoints
(patients who did not receive a transplant were excluded from these analyses): survival, incidences of neutrophil
and platelet engraftment, graft failure, acute GVHD, chronic GVHD, time off immunosuppressive therapy,
relapse, infections, adverse events, immune reconstitution, and quality of life. Donors in each arm of the study
were compared for time to return to baseline toxicity score, complete blood count and white blood count
differential values after donation, and quality of life.
Team Principals:
Name
Email
Chair:
Claudio Anasetti
[email protected]
Officer:
Dennis Confer
[email protected]
Coordinator:
Kristin Knust
[email protected]
Medical Monitor:
Christopher Bredeson
[email protected]
Statistician:
Brent Logan
[email protected]
Contract Rep:
Nancy Poland
[email protected]
Additional Members Email
PRC Approval Date:
05/05/2003
Paolo Anderlini
[email protected]
DSMB Approval Date:
09/04/2003
William Bensinger
[email protected]
Opened to Accrual:
01/20/2004
Shelly Carter
[email protected]
10/16/2009
Nancy DiFronzo
[email protected]
10/2011
Nancy Geller
[email protected]
Target Accrual:
550
Mary Horowitz
[email protected]
551
Stephanie Lee
[email protected]
N/A
Susan Leitman
[email protected]
IND Number:
6821
Scott Rowley
[email protected]
09/15/2006
Edmund Waller
[email protected]
Additional Member
Email
Daniel Weisdorf
[email protected]
John Wingard
[email protected]
Primary Objective:
A total of 551 patients were enrolled on this study, which successfully closed to accrual on October 16, 2009. A
total of 338 unrelated donors were also enrolled.
Key Highlights:
Overall accrual to the study was slower than projected. It was a difficult study due to the need for both donor
and recipient consent, and donor refusal rates ranged from 25% to 30%. Activities implemented to enhance
patient accrual included weekly Eligible Patient Notification emails to transplant centers; quarterly Trial Snapshot
emails to centers, targeting high-accruing centers; coordinator and PI conference calls; presentations at the
NMDP Council Meeting; a PI newsletter; and direct correspondence from the study PI and NMDP Medical
Director. A total of 55 centers participated on the trial, which enrolled 551 recipients including 20 Canadian
76
Protocol Number:
BMT CTN 0201
recipients.
A coordinated effort involving transplant and donor centers and the NMDP Search Coordinating Unit made this
study possible. It is the only study of its kind, and the BMT CTN is the only mechanism through which it could be
accomplished.
The Endpoint Review Committee was formed in January 2010 to review outcomes data and was completed in
November 2011. The trial, through its ancillary laboratory studies, will also provide important information on
multiple parameters of immune reconstitution and their correlation with clinical outcomes.
Reporting Period
Update:
The primary manuscript was published in the New England Journal of Medicine during this period. A secondary
analysis manuscript of the unrelated donor experience was submitted. Also, a secondary immune
reconstitution analysis was presented at EBMT.
Publication:
1. Primary manuscript: Peripheral-blood stem cells versus bone marrow from unrelated donors. New England
Journal of Medicine. 2012 Oct 18;367(16):1487-96.
Presentations:
1. Health-related quality-of-life among adult unrelated stem cell donors: a Blood and Marrow Transplant Clinical
Trials Network randomized trial of marrow versus PBSC donation. Presented: 52nd Annual ASH Meeting,
Orlando, FL, December 2010.
2. Increased incidence of chronic GVHD and no survival advantage with filgrastim-mobilized PBSCs compared to
BM transplants from unrelated donors: results of BMT CTN Protocol #0201, a Phase III prospective
randomized trial. Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011.
3. BMT CTN Protocol 0201 Results of a Phase III randomized multicenter trial of HLA compatible unrelated donor
transplantation: G-CSF mobilized peripheral blood stem cells (PBSC) versus bone marrow. Presented: 53rd
Annual ASH Meeting Plenary Session, December 2011.
4. Larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic BM grafts
from unrelated donors are associated with improved survival: results from BMT CTN 0201. Presented: 53rd
Annual ASH Meeting, San Diego, CA, December 2011.
5. Grade III - IV acute GvHD and treatment-related mortality are reduced among recipients of larger numbers
of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic BM grafts from
unrelated donors: results from BMT CTN 0201. Presented: EBMT, April 2012.
6. Increased incidence of chronic GVHD and no survival advantage with filgrastim-mobilized PBSCs compared
to BM transplants from unrelated donors: results of BMT CTN Protocol 0201, a Phase III, prospective,
randomized trial. Presented: ASCO Annual Meeting, Chicago, IL, June 2012.
BMT CTN #0201
20
600
Monthly Accrual
Cumulative Accrual
500
400
15
300
10
200
5
100
0
0
77
Cumulative Accrual
Accrual per Month
25
BMT CTN 0202
Protocol Number:
BMT CTN 0202
Status:
Closed to Accrual (closed prematurely due to low enrollment)
Title:
Autologous versus nonmyeloablative allogeneic HCT for patients with chemosensitive follicular
non-Hodgkin lymphoma beyond first complete response or first partial response
Rationale:
Follicular non-Hodgkin lymphoma is the second most common type of non-Hodgkin lymphoma in
the United States. When treatment is indicated, most patients achieve a remission with initial
chemotherapy, but patients with recurrent advanced follicular lymphoma have a median survival of
only four to five years.
At present, the optimal management of patients failing conventional therapy is unknown, with
both autologous HCT and allogeneic HCT being offered to follicular lymphoma patients with
recurrent disease. The results of several studies have shown improved disease-free survival with
autologous HCT; one randomized study showing improved overall survival compared with
conventional chemotherapy. Relapse remains the major cause of treatment failure.
Allogeneic nonmyeloablative HCT is being explored with the goal of harnessing a graft-versuslymphoma effect and circumventing the significant upfront mortality associated with myeloablative
HCT. Allogeneic nonmyeloablative HCT utilizes a less intensive preparative regimen and thus relies
primarily on the immunotherapeutic effect of the allograft to confer antitumor activity rather than
the cytoreductive effects of high-dose chemotherapy. Follicular lymphoma is an ideal disease in
which to study the benefit of a graft-versus-lymphoma effect in a controlled trial against the other
intensive approach of autologous HCT.
Primary Objective:
To compare three-year progression-free survival between the two treatment arms.
To compare three-year overall survival, time to progression, time to complete and partial response,
time to off-study therapy, and incidence of infections and NCI CTCAE Version 3.0 Grade ≥ 3
toxicities. Secondary objectives for the nonmyeloablative allogeneic HCT recipients include the
incidence and severity of acute and chronic GVHD and incidence of primary and secondary graft
failure. Additional objectives are the efficacy of cyclophosphamide plus rituximab in vivo purging,
the prediction of disease relapse by measurement of t(14;18) by quantitative polymerase chain
reaction, and quality of life as measured by the SF-36 and the FACT-BMT.
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Henry Chang
David Maloney
Elizabeth Murphy
Auayporn Nadamanee
Patrick Stiff
Julie Vose
Name
Ginna Laport
Robert Negrin
Marcie Tomblyn
Steve Wease
Mary Eapen
Marian Ewell
Nancy Poland
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Target Accrual:
IND Number:
78
08/01/2003
03/01/2004
07/28/2004
03/02/2006
04/2009
480
30
N/A
N/A
Protocol Number:
BMT CTN 0202
01/17/2006
Key Highlights:
When the study closed to accrual in March 2006, 22 patients were enrolled on the autologous HCT
+ rituximab arm and eight on the allogeneic HCT + rituximab arm. Discussions with BMT CTN and
Cooperative Group investigators and analysis of the CIBMTR database led the Protocol Team to
conclude that poor accrual on this trial came from low referrals of eligible patients by primary care
oncologists. The Network continued to follow the enrolled patients for three-year survival and
adverse events as recommended by the DSMB. (The last patient three-year survival follow-up
finished on April 13, 2009.)
Important questions regarding the role of HCT for patients with follicular lymphoma must still be
addressed. The NCI-funded Cooperative Group Transplant and Lymphoma Committee Chairs
collaborated with the Network to design and implement a new trial with better feasibility (BMT
CTN 0701, which opened on April 27, 2009, and completed accrual during this reporting period).
Publication:
1. Autologous versus reduced intensity allogeneic hematopoietic cell transplantation for patients
with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first
partial response. Biology of Blood and Marrow Transplantation. 2011 Jul;17(7):1051-7. Epub
2010 Nov 10.
Presentation:
1. Autologous vs. reduced-intensity allogeneic hematopoietic cell transplantation for patients with
follicular non-Hodgkin’s lymphoma beyond first complete response or first partial response.
Abstract presented: ASCO Annual Meeting, Chicago, IL, May 2008.
An accrual graph is not included due to premature study closure.
79
BMT CTN 0302
Protocol Number:
BMT CTN 0302
Status:
Closed to Accrual
Title:
Initial systemic treatment of acute GVHD: a Phase II randomized trial evaluating etanercept,
mycophenolate mofetil, denileukin diftitox (Ontak), and pentostatin
Rationale:
Initial therapy of acute GVHD has limited efficacy. New agents that limit the morbidity and duration of
steroid therapy are available for testing; however, they generally have only been tested in singleinstitution, uncontrolled trials. The purpose of this study was to test in a prospective, randomized Phase II
parallel arm trial the use of four promising agents to manage acute GVHD in order to develop suitable
data to initiate a formal follow-up Phase III trial.
Primary Objective:
To estimate the proportion of day 28 complete remissions for newly-diagnosed acute GVHD for each of
these agents given in combination with corticosteroids.
To determine the proportion of patients achieving a partial response, mixed response, and progression at
day 28; proportion of patients with treatment failure (no response, progression, administration of
additional therapy for GVHD, or mortality) by day 14; incidence of GVHD flares requiring increasing
Secondary
therapy before day 90; incidences of discontinuation of immune suppression without flare by days 90,
Objectives:
180, and 270 after initiation of therapy; incidence of chronic GVHD by 9 months; overall survival at 6 and
9 months after initiation of therapy; incidences of systemic infections within three months of initiation of
therapy; and incidence of Epstein-Barr virus-associated lymphoma.
Team Principals:
Name:
Email:
Chair:
Daniel Weisdorf
[email protected]
Officer:
Marcelo Pasquini
[email protected]
Coordinator:
Maggie Wu
[email protected]
Medical Monitor:
Mary Eapen
[email protected]
Statistician:
Brent Logan
[email protected]
Contract Rep:
Nancy Poland
[email protected]
PRC Approval Date:
01/26/2004
Joseph Antin
[email protected]
DSMB Approval Date:
05/13/2004
Nelson Chao
[email protected]
Opened to Accrual:
08/25/2005
Nancy DiFronzo
[email protected]
03/24/2008
James Ferrara
[email protected]
12/2008
Vincent Ho
[email protected]
Target Accrual:
180
Mary Horowitz
[email protected]
180
Eric Leifer
[email protected]
N/A
John Levine
[email protected]
IND Number:
11726
Richard Nash
[email protected]
08/21/2007
Georgia Vogelsang
[email protected]
Key Highlights:
Despite early concerns about slow accrual, the May 2006 amendment had a positive impact on the
accrual rate, and the study was completed on March 24, 2008, with 180 patients enrolled as planned.
That amendment involved four changes: (1) development of a second stratum (3-arm, balanced
randomization with etanercept, pentostatin, and Ontak) for patients previously exposed to
mycophenolate mofetil for GVHD prophylaxis; (2) enrollment of all patients with acute GVHD in whom
the clinical decision to treat with corticosteroids was made at the participating center rather than to
exclude those patients with upper gastrointestinal GVHD or limited skin diseases as the sole
manifestations; (3) consent, enrollment, and randomization within 48 hours (previously 24) of initiating
corticosteroid therapy; and (4) allowing enrollment of patients administered low-dose steroids for less
80
Protocol Number:
BMT CTN 0302
than 7 days prior to enrollment.
The DSMB approved formation of an Endpoint Review Committee (ERC) comprised of six transplant
physicians from BMT CTN 0302 centers. All patients completed follow-up per protocol except two who
were lost to follow up before nine months. The ERC reviewed the study data for each patient and results
are published in a primary manuscript and secondary manuscripts.
The results of the study suggested that mycophenolate mofetil was the most promising candidate for
evaluation in a Phase III study. BMT CTN protocol 0802 was developed as a Phase III, randomized double
blind, placebo controlled trial to evaluate the addition of mycophenolate mofetil vs. placebo to systemic
corticosteroids as initial therapy for acute GVHD. Protocol 0802 was closed due to futility in November
2011.
Reporting Period
Update:
A secondary analysis of lymphocyte phenotypes was published this year. This is the sixth BMT CTN
0302 manuscript to be published.
Publications:
1. Optimal two-stage randomized Phase II clinical trials. Clinical Trials. 2005 Feb;2(1):5-12.
2. Etanercept, mycophenolate, denileukin or pentostatin plus corticosteroids for acute graft-versus-host
disease, a randomized Phase II trial from the BMT CTN. Blood. 2009 Jul;114(3)511-517. Epub 2009 May
14.
3. Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease
treatment from the BMT CTN. Biology and Blood and Marrow Transplantation. 2010 Mar;16(3)421429.
4. Graft-versus-host disease treatment: predictors of survival. Biology of Blood and Marrow
Transplantation. 2010 Dec;16(12):1693-1699. Epub 2010 Jun 10.
5. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes:
a BMT CTN study. Blood. 2012 Apr 19;119(16)3854-3860. Epub 2012 Mar 1.
6. Lymphocyte phenotype during therapy for acute graft versus host disease: a brief report from
BMT-CTN 0302. Biology of Blood and Marrow Transplantation. 2013 Mar;19(3)481-485. Epub 2012
Dec 11.
Presentations:
1. A Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox and
pentostatin in combination with corticosteroids in 180 patients with newly diagnosed acute graft vs.
host disease. Abstract presented: 50th Annual ASH meeting, San Francisco, CA, December 2008.
2. GVHD biomarkers measured during treatment independently predict response to therapy and survival:
a Blood and Marrow Transplant Clinical Trials Network study. Presented: EBMT Congress, Paris, France,
April 2011.
13
12
11
10
9
8
7
6
5
4
3
2
1
0
BMT CTN #0302
200
Cumulative Accrual
150
100
50
0
81
Cumulative Accrual
Accrual per Month
BMT CTN 0303
Status:
Closed to Accrual
Title:
A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell depleted peripheral
blood stem cells isolated by the CliniMACS system in the treatment of patients with AML in first or second
morphologic complete remission
Allogeneic blood or marrow transplantation is the treatment of choice for many patients with advanced AML in
first or second complete remission because the graft-versus-leukemia effect limits the risk of relapse. However,
transplantation of standard unmanipulated allografts is associated with a substantial risk of GVHD and other
complications that limit the overall success of allogeneic HCT in this setting.
Rationale:
T cell depletion (TCD) has been used by many groups to mitigate the risk of GVHD. Effective TCD allows for the
transplantation of allografts without the requirement for pharmacological GVHD prophylaxis. Retrospective data
have suggested TCD is associated with higher risks of opportunistic infection, graft rejection and disease relapse,
which have led some programs to abandon this technique despite the potential advantages over conventional
allografting.
Recently, several single-center trials employing novel TCD techniques report highly encouraging long-term results,
particularly for patients with AML in first or second complete remission. Although the number of cases in each singlecenter series is limited, the consistency of the results suggests that the use of an effective technique for TCD together
with an adequate cytoreductive regimen might yield transplant results superior to those achieved with unmodified
grafts. BMT CTN 0303 was designed to evaluate the results of this approach in a multicenter trial.
Primary Objective:
To assess disease-free survival six months after transplant. Outcome measures to assess this endpoint were death or
relapse.
Secondary
Objectives:
To assess infusional toxicity, time to neutrophil and platelet engraftment, incidence and severity of acute and chronic
GVHD, incidence of transplant-related mortality, incidence of Epstein-Barr virus after transplant, lymphoproliferative
disorder, time to leukemia relapse, probability of survival and disease-free survival at 2 years, and the proportion of
6
5
grafts with both > 5 x 10 /kg CD34+ cells and < 1 x 10 /kg CD3 cells.
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional
Members:
Chris Bredeson
Nancy DiFronzo
Stephen Forman
Nancy Geller
Hillard Lazarus
Elizabeth Murphy
Robert Soiffer
Anthony Stein
Roy Wu
Key Highlights:
Name
Steve Devine
Richard O’Reilly
Marcelo Pasquini
Kristin Knust
Marcie Tomblyn
Shelly Carter
Nancy Poland
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Target Accrual:
IDE Number:
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
03/17/2004
10/15/2004
06/30/2005
12/24/2008
07/2009
45
47
N/A
11965
11/13/2006
There was a delay between PRC and DSMB approvals, due to a determination by the DSMB in April 2004 that safety
data were required for donors and recipients. This required protocol resubmission to the DSMB. The long interval
between DSMB approval and study activation was due to lengthy processing of an IDE. The protocol was submitted
82
on September 30, 2004, to the FDA, which requested changes. It was ultimately approved by the FDA on December
28, 2004, and released to sites in January 2005.
There was an additional delay in activation for training at sites by Miltenyi Biotec, Inc., and for preparation and
submission of laboratory Standard Operating Procedures by each site. The study was opened to accrual on June 30,
2005.
The study completed accrual in December 2008 with 47 patients enrolled. The Endpoint Review Committee
completed an independent assessment of the primary and secondary endpoints of the study.
Reporting Period
Update:
A secondary comparative analysis was published in the Journal of Clinical Oncology. A calcineurin inhibitor-free
GVHD prophylaxis study proposal was approved by the Steering Committee as a follow-up to the BMT CTN 0303
study. A project team, including several 0303 investigators, has created a protocol and plans to apply for
supplemental R01 funding during the upcoming reporting period.
Publications:
1. Low risk of chronic graft-versus-host disease and relapse associated with T cell depleted peripheral blood stem
cell transplantation for acute myeloid leukemia in first remission: results of the Blood and Marrow Transplant
Clinical Trials Network Protocol 0303. Biology of Blood and Marrow Transplantation. 2011 Sep;17(9):1343-51.
Epub 2011 Feb 12.
2. Characteristics of CliniMACS(®) System CD34-enriched T cell-depleted grafts in a multicenter trial for acute
myeloid leukemia-Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303. Biology of
Blood and Marrow Transplantation. 2012 May;18(5):690-7. Epub 2011 Aug 26.
3. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host
disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched
sibling allogeneic hematopoietic cell transplantation. Journal of Clinical Oncology. 30(26):3194-3201, 2012.
Presentations:
1. HLA-identical sibling-matched, CD34+ selected, T cell depleted peripheral blood stem cells following
myeloablative conditioning for first or second remission acute myeloid leukemia, results of BMT CTN Protocol
0303. Presented: 51st Annual ASH Meeting, New Orleans, LA, December 2009.
2. Comparative effectiveness analysis of CD34+ selected, T cell depleted HLA-matched sibling grafts on allogeneic
hematopoietic cell transplantation for patients with acute myeloid leukemia in complete remission. Poster
presented: BMT Tandem Meetings, Orlando, FL, February 2010.
3. Characteristics of CD34-enriched products processed at multiple centers using the CliniMACS System - BMT CTN
0303. Abstract presented: Annual International Society for Cellular Therapy meeting, Philadelphia, PA, May 2010.
BMT CTN #0303
Accrual per Month
5
50
Cumulative Accrual
45
40
35
4
30
3
25
20
2
15
10
1
5
0
0
83
Cumulative Accrual
6
BMT CTN 0401
Protocol Number:
BMT CTN 0401
Status:
Closed to Accrual
Title:
Phase III Rituxan/BEAM versus Bexxar/BEAM with autologous hematopoietic stem cell
transplantation for persistent or relapsed chemotherapy-sensitive diffuse large B cell non-Hodgkin
lymphoma
Rationale:
The protocol was designed to improve the long-term disease-free survival of patients with diffuse
large B cell non-Hodgkin lymphoma by adding either an unlabelled or a radiolabelled anti-CD20
monoclonal antibody to high-dose chemotherapy and autologous HCT.
Primary Objective:
To compare progression-free survival after autologous HCT for chemotherapy-sensitive diffuse
large B cell lymphoma using Rituxan/BEAM versus Bexxar/BEAM as a pre-transplant conditioning
regimen.
To compare overall survival; time to progression; proportion of complete response and partial
response at day 100; time to hematopoietic recovery; hematologic function; incidence of infection;
maximum mucositis score by day 21; immune reconstitution; treatment-related mortality; and
development of myelodysplasia, secondary acute myelogenous leukemia or abnormal cytogenetics.
Team Principals:
Chair:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Linda Burns
Dennis Confer
Nancy DiFronzo
Peter Holman
John Koreth
Eric Leifer
William Merritt
Elizabeth Murphy
Oliver Press
Edward Stadtmauer
Name
Julie Vose
Marcie Tomblyn
Steve Wease
Eneida Nemecek
Pam Budnick
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Key Highlights:
This study was activated on December 7, 2005; 37 centers enrolled patients on the trial.
Although diffuse large B cell non-Hodgkin lymphoma is a common indication for autologous HCT, an
increasing percentage of these procedures are performed in diverse community hospitals without
academic programs, so only a few transplant centers have access to large numbers of eligible
patients. To increase patient accrual, additional centers were recruited, and a collaboration with
SWOG was developed. The study closed on July 17, 2009, after reaching its accrual goal of 224
patients.
An Endpoint Review Committee was formed in April 2011, completing data review in June 2011 and
submitting an abstract for ASH 2011.
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Target Accrual:
IND Number:
84
09/24/2004
02/04/2005
12/07/2005
07/17/2009
07/2011
224
224
N/A
12520
01/14/2009
Protocol Number:
BMT CTN 0401
The primary manuscript was published in the Journal of Clinical Oncology.
Publication:
1. Primary: Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and
melphalan (BEAM) compared with Iodine-131 tositumomab/BEAM with autologous
hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the
BMT CTN 0401 Trial. Journal of Clinical Oncology. 2013 Mar 11. [Epub ahead of print]
Presentation:
1. Randomized Phase III trial of 131Iodine-tositumomab (bexxar)/carmustine, etoposide,
cytarabine, melphalan (BEAM) vs. rituximab/BEAM and autologous stem cell transplantation for
relapsed diffuse large B-cell lymphoma (DLBCL): no difference in progression-free (PFS) or overall
survival (OS). Abstract presentation: 53rd Annual ASH Meeting, San Diego, CA, December 2011.
Accrual per Month
12
BMT CTN #0401
Cumulative Accrual
250
200
10
8
150
6
100
4
50
2
0
0
85
Cumulative Accrual
14
BMT CTN 0402
Protocol Number:
BMT CTN 0402
Status:
Closed to Accrual
Title:
A Phase III randomized, multicenter trial comparing sirolimus/tacrolimus with
tacrolimus/methotrexate as GVHD prophylaxis after HLA-matched, related peripheral blood stem cell
transplantation
Rationale:
GVHD is an important cause of treatment failure after allogeneic HCT. The results of Phase II studies
suggest that acute GVHD prophylaxis with sirolimus and tacrolimus may provide better GVHD control
and reduce transplant-related toxicity when compared with methotrexate and tacrolimus. This trial is
designed to determine whether replacing methotrexate with sirolimus will improve GVHD-free
survival and reduce transplant-related morbidity and mortality in HLA-identical sibling
transplantation.
Primary Objective:
To compare day 114 grades II through IV acute GVHD-free survival rates between patients receiving
sirolimus and tacrolimus with those receiving methotrexate and tacrolimus from the time of patient
randomization, using an intent-to-treat analysis.
To compare time to neutrophil and platelet engraftment, incidence of grades III through IV acute
GVHD, mucositis severity, time to first hospital discharge after transplantation, all infections,
cytomegalovirus reactivation, thrombotic microangiopathy incidence, veno-occlusive disease during
the first 100 days after transplantation, malignant disease relapse, and one-year relapse-free and
overall survival rates.
Team Principals:
Name
Email
Joseph Antin
[email protected]
Corey Cutler
[email protected]
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Sung Choi
Nancy DiFronzo
James Ferrara
Nancy Geller
Stephan Grupp
Mary Horowitz
Laura Johnston
Eric Leifer
Margaret MacMillan
Philip McCarthy
Elizabeth Murphy
Marcelo Pasquini
Kristin Knust
Mary Eapen
Brent Logan
Pam Budnick
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
09/24/2004
DSMB Approval Date:
02/04/2005
Opened to Accrual:
11/20/2006
10/26/2011
Target Accrual:
312
N/A
IND Number:
N/A
12/3/2010
Additional Members:
Email
Ryotaro Nakamura
[email protected]
David Porter
[email protected]
Key Highlights:
Although this protocol was approved by the DSMB in a timely fashion, the Network agreed to delay
activating the study for patient accrual until closure of BMT CTN 0101 to reduce potential
competition for a similar patient population. Initial accrual to this study was slower than projected.
Chairs:
86
Protocol Number:
BMT CTN 0402
Discussion among the investigators led to a protocol amendment aimed at enhancing accrual. The
amendment increased the maximum allowed cholesterol/triglyceride level at study entry to be ≤ 500
mg/dL. In addition, the requirement for donor toxicity assessments was removed, and the required
assessment periods for mucositis were modified. Protocol Version 2 was approved by the DSMB and
released to centers in June 2007 for IRB approval.
On September 26, 2007, the veno-occlusive stopping guideline was crossed, and enrollment was
suspended pending DSMB review. The DSMB approved re-opening the study on October 3, 2007,
with exclusion of busulfan and cyclophosphamide pretransplantation conditioning regimens. The
revised protocol was released to centers for IRB approval in November 2007. Some centers were
unable to transition into a total body irradiation-based conditioning regimen in lieu of the busulfan
regimen, and additional center participation was solicited. Since November 2007, overall enrollment
increased.
Version 4.0 of the protocol was released in December 2010 to allow patients whose primary disease
was acute biphenotypic leukemia in first or subsequent remission.
Twenty-six centers (13 Core and 13 Affiliate) participated on this trial. The study completed accrual in
October 2011. The protocol team began the Endpoint Data Review in December 2011 for patients
who had met the primary endpoint.
An absbtract was submitted and presented at the 2012 ASH meeting. The primary manuscript is in
preparation.
Presentation:
1. Tacrolimus/sirolimus vs. tacrolimus/methotrexate for GVHD prophylaxis after HLA-matched,
related donor hematopoietic stem cell transplantation: Results of BMT CTN Trial 0402.
Presented: Annual ASH Meeting, Atlanta, GA, December 2012.
Target Accrual: 312 patients
BMT CTN #0402
Accrual per Month
10
350
Cumulative Accrual
300
250
8
200
6
150
4
100
2
50
0
0
87
Cumulative Accrual
12
BMT CTN 0403
Protocol Number:
BMT CTN 0403
Status:
Closed to Accrual (closed prematurely due to low enrollment)
Title:
A randomized double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor Enbrel
(etanercept) for the treatment of acute noninfectious pulmonary dysfunction (idiopathic pneumonia
syndrome, IPS) following allogeneic cell transplantation
Rationale:
Despite significant advances in critical care medicine, IPS remains a frequently fatal complication following
allogeneic HCT. Mortality in patients with IPS ranges from 60% to 80%, and the median time from
diagnosis to death is 14 days. New therapeutic strategies are needed. Preclinical data reveal a significant
role for tumor necrosis factor-α (TNF-α) in the development of experimental IPS, and the results of a pilot,
dual-center clinical trial using etanercept, a TNF-α neutralizing agent, are encouraging. This randomized
Phase III study is the culmination of several years of investigation. The central hypothesis is that cytokine
dysregulation and TNF-α production significantly contribute to the development of IPS.
Primary Objective:
To determine the day 28 response rate following treatment with etanercept plus corticosteroids
compared with placebo plus corticosteroids for patients with IPS after allogeneic HCT. (Response is
defined as (1) survival at day 28; and (2) discontinuation of all supplemental oxygen support for more than
72 consecutive hours by day 28.)
To evaluate response to therapy at day 56; overall mortality in patients with IPS; time to discontinuation
of supplemental oxygen; and pro-inflammatory markers of pulmonary disease in both bronchoalveolar
Secondary
lavage fluid and plasma of patients with IPS. The last studies will correlate biologic and genetic markers of
Objectives:
inflammation with clinical response to therapy, and characterize plasma and bronchoalveolar lavage
protein profiles to attempt to identify an inflammatory signature of the disease.
Team Principals:
Name:
Email:
Kenneth Cooke
[email protected]
Chairs:
Gregory Yanik
[email protected]
Officer:
Mary Horowitz
[email protected]
Coordinator:
Steve Wease
[email protected]
Medical Monitor:
Marcie Tomblyn
[email protected]
Statistician:
Brent Logan
[email protected]
Contract Rep:
Nancy Poland
[email protected]
PRC Approval Date:
09/26/2005
Shelly Carter
[email protected]
DSMB Approval Date:
12/01/2005
Nancy DiFronzo
[email protected]
Opened to Accrual:
08/27/2007
Rebecca Drexler
[email protected]
09/14/2011
James Ferrara
[email protected]
Target Accrual:
60
Sergio Giralt
[email protected]
37
Vincent Ho
[email protected]
N/A
Eric Leifer
[email protected]
IND Number:
11726 (Part of 0302 IND)
David Madtes
[email protected]
6/2/2010
Elizabeth Murphy
[email protected]
Additional Member:
Email:
Robert Soiffer
[email protected]
Eric White
[email protected]
Daniel Weisdorf
[email protected]
Key Highlights:
The study was activated August 27, 2007. A protocol amendment was released to centers in January 2008
that adjusted the eligibility criteria to include patients who developed IPS within 120 days after a donor
leukocyte infusion, revised definitions of cytomegalovirus disease and infection, and revised study drug
blinding logistics. An additional protocol amendment released in January 2009 extended eligibility to
patients who develop IPS within 180 days post transplantation or post donor leukocyte infusion. Protocol
88
Protocol Number:
BMT CTN 0403
Version 4 was released to centers in October 2009, relaxing the bronchoscopy requirements for
participants less than 30 days post transplantation who were considered too medically unstable to
undergo the bronchoscopy procedure. Protocol Version 5 was released to centers in June 2010, reducing
the sample size from 120 patients (60 per arm) to 60 patients (30 per arm).
Accrual continued to lag behind projections, despite the amendments. In April 2011, the DSMB approved
the Protocol Team’s accrual plan for two interval assessments of enrollment; accrual of at least four
patients from February 16, 2011, through July 1, 2011, (total of 38 patients) and/or nine patients from
February 16, 2011, through October 1, 2011, (total of 43 patients). These accrual targets were not met,
and the Protocol Team received DSMB approval to close the study on September 14, 2011.
Reporting Period
Update:
The Endpoint Review Committee was formed and reviewed the study data from March to August 2012.
After completion of data review, the study results were presented at the 2013 BMT Tandem Meetings.
The primary manuscript is being written.
Presentation:
1. Randomized, double blind, placebo-controlled trial of a TNF inhibitor (etanercept) for the treatment
of idiopathic pneumonia syndrome after allogeneic stem cell transplant. A BMT CTN study.
Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013.
An accrual graph is not included due to premature study closure.
89
BMT CTN 0501
Protocol Number:
BMT CTN 0501
Status:
Closed to Accrual
Title:
Multicenter, open label, randomized trial comparing single versus double umbilical cord blood
transplantation in pediatric patients with leukemia and myelodysplasia
Rationale:
Unrelated donor umbilical cord blood transplantation (UCBT) has increased access to transplant
therapy for many patients without a fully matched adult donor. However, approximately 20% of
patients undergoing UCBT fail to engraft in a timely manner (before day 42 post transplant).
Engraftment and survival are highly dependent on the dose of cord blood cells delivered by the cord
blood graft. Further, many cord blood units (CBUs) do not contain sufficient numbers of cells to
provide an adequate cell dose, especially for larger patients.
To address this problem, investigators at the University of Minnesota initiated pilot studies using
two rather than one CBU in adults undergoing UCBT. Preliminary results of these studies were very
encouraging, demonstrating increased rates of engraftment in patients transplanted with two CBUs.
Interestingly, one CBU dominated during engraftment, although predictions of which CBU would
dominate engraftment were not possible based on conventional criteria (e.g., cell dose or HLA
matching). While initially developed as a strategy for patients for whom a single CBU of adequate
cell number was not available, results raised the question of whether use of two CBUs to increase
the dose beyond the minimum might improve UCBT outcomes.
This study was conceived to test in a randomized, prospective, Phase III trial whether transplant
outcomes were better with transplantation of one or two CBUs. It was designed for pediatric
patients with hematologic malignancies because this was the only patient population where safe
randomization would be possible, since single CBUs of adequate size are available for most children.
Primary Objective:
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Colleen Delaney
Nancy Geller
Mary Horowitz
Naynesh Kamani
Eneida Nemecek
Michael Pulsipher
Andromachi Scaradavou
Kirk Schultz
Susan Staba
To determine the efficacy of using two CBUs versus one; the primary endpoint is one-year survival
rate.
To compare disease-free survival, incidences of neutrophil and platelet engraftment, chimerism,
acute GVHD, chronic GVHD, transplant-related mortality, infections, immune reconstitution, and
relapse in patients randomized to the two study arms.
Name:
Email:
Joanne Kurtzberg
[email protected]
John Wagner
[email protected]
Mary Eapen
[email protected]
Jason Thompson
[email protected]
Dianna Howard
[email protected]
Shelly Carter
[email protected]
Nancy Poland
[email protected]
Email:
PRC Approval Date:
01/20/2006
[email protected]
DSMB Approval Date:
04/24/2006
[email protected]
Opened to Accrual:
10/16/2006
[email protected]
2/29/2012
[email protected]
Target Accrual:
220
[email protected]
224
[email protected]
N/A
[email protected]
IND Number:
N/A
[email protected]
03/18/2010
[email protected]
90
Protocol Number:
Mike Verneris
Donna Wall
Key Highlights:
BMT CTN 0501
[email protected]
[email protected]
This trial received PRC approval in January 2006 and DSMB approval in April 2006. In September
2006, the protocol was amended to include patient registration procedures for COG. The study was
activated October 16, 2006. Ten BMT CTN Core Centers and 38 COG Centers were activated for
enrollment.
Accrual on this study was completed in February 2012 with 224 patients enrolled.
In April 2011, the DSMB approved the Protocol Team’s request to review blinded data on patients
that have met the primary endpoint; this review process began in January 2012.
The primary study results were presented at ASH, and the results compared to a previous cord
blood transplantation (COBLT) study were presented at the BMT Tandem Meetings. The review
process will continue in April 2013 to complete review of all patients for the primary endpoint
prior to submitting the primary manuscript for publication.
1. No survival advantage after double umbilical cord blood (UCB) compared to single UCB
transplant in children with hematological malignancy: Results of the Blood and Marrow
Transplant Clinical Trials Network (BMT CTN 0501) randomized trial. Abstract presented: 54th
Annual ASH Meeting, Atlanta, GA, December 2012.
2. Superior survival after single unit umbilical cord blood transplantation (UCBT) in children with
hematological malignancies treated on Blood and Marrow Transplant Clinical Trials Network
(BMT CTN) 0501 relative to the cord blood transplantation (COBLT). Abstract presented: BMT
Tandem Meetings, Salt Lake City, UT, February 2013.
Presentations:
9
BMT CTN #0501
Cumulative Accrual
Accrual per Month
8
250
200
7
6
150
5
4
100
3
2
50
1
0
0
91
Cumulative Accrual
10
Protocol Number:
Status:
Closed to Accrual
Title:
A Phase II study of allogeneic transplant for older patients with acute myeloid leukemia in first
morphologic complete remission using a nonmyeloablative preparative regimen
Rationale:
The diagnosis of AML in older patients is associated with a very poor prognosis. For patients aged
60 or older receiving therapy for newly-diagnosed AML, the median survival is approximately seven
months; the five-year survival rate has been <15% for the past three decades. The poor survival
rate in this population is predominantly caused by de novo chemoresistance, which manifests in a
substantially lower complete remission rate after induction chemotherapy and early relapse. Older
patients with AML also have a significantly higher incidence of adverse prognostic and karyotypic
features, which are associated with a worse outcome. Novel approaches are clearly warranted.
One novel approach involves the use of blood cells from allogeneic donors. Recent retrospective
data from multiple groups suggest that allogeneic HCT may yield durable remissions in older AML
patients who, without a transplant, would have likely died of their leukemia. However, the risk of
transplant-related complications in this patient group may be substantial; therefore, formal testing
of this therapy in a prospective trial is logical and timely. This prospective trial is designed to
evaluate the results of allogeneic HCT in patients aged 60 to 74 with AML in first remission.
Primary Objective:
To determine if allogeneic transplantation from an HLA-matched sibling or unrelated donor using a
reduced-intensity preparative regimen results in two-year disease-free survival that is better than
that reported in published trials evaluating standard chemotherapy among patients with AML in
first complete remission who are older than 60 years of age.
To evaluate two-year actuarial risk of transplant-related mortality; acute and chronic GVHD and
relapse rates; rate and extent of recovery of T and B cell number and function; time course of T cell,
B cell, and myeloid progenitor chimerism following this preparative regimen; and pharmacokinetics
of intravenous busulfan when used in a reduced-intensity preparative regimen in patients older
than 60.
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Trini Ajazi
Morgen Alexander-Young
Linda Bressler
Shelly Carter
Nancy DiFronzo
Peggy Edwards
Vera Hars
Kathy Karas
Kouros Owzar
Elizabeth Rich
Name
Steven Devine
Sergio Giralt
Mary Horowitz
Kate Barowski
CALGB
CALGB
Nancy Poland
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Target Accrual:
Accrual as of 4/30/13:
IND Number:
Additional Members:
92
CALGB
CALGB
08/29/2006 CALGB
01/29/2007 BMT CTN
136 total
132 Total
42 BMT CTN
N/A
N/A
12/15/2010
Email
Protocol Number:
Debbie Sawyer
Richard Schilsky
[email protected]
[email protected]
Mary Sherrel
Roy Wu
[email protected]
[email protected]
This protocol is a collaborative effort between CALGB and BMT CTN. CALGB patient accrual began
August 29, 2006; the BMT CTN activated the study January 29, 2007. The study met its original
accrual goal December 29, 2008.
After DSMB review, the study was re-activated in November 2009 after NCI approved a CALGB
amendment to increase the accrual goal to 136 to allow adequate numbers for separate analysis of
related and unrelated donor transplantations.
Key Highlights:
The study closed to enrollment at both CALGB and BMT CTN sites on December 29, 2011, after
enrolling 132 patients. Of the 132 patients enrolled directly through the BMT CTN, 41 were accrued
by five Core Centers and three Affiliate Centers. An additional 72 of the 132 patients were accrued
by six BMT CTN Core Centers that enrolled patients directly through CALGB.
Data review is being completed. An abstract for the study was presented at the December 2012
ASH meeting. The primary manuscript is being written.
Presentation:
1. A Phase II study of allogeneic transplant for older patients with AML in first morphologic
complete remission using a reduced intensity preparative regimen: results from CALGB
100103/BMT CTN 0502. Abstract presented: 54th Annual ASH Meeting, Atlanta, GA,
December 2012.
Target Accrual: 136
BMT CTN #0502/CALGB 100103 (BMT CTN accrual N = 41)
Accrual per Month
6
45
Cumulative Accrual
40
35
5
30
4
25
3
20
15
2
Cumulative Accrual
7
10
1
*
0
5
0
* Note: This study completed accrual in December 2008 and reopened in November 2009 after it was amended to increase
the accrual goal.
93
BMT CTN 0603
Protocol Number:
BMT CTN 0603
Status:
Closed to Accrual
Title:
A multicenter, Phase II trial of non-myeloablative conditioning and transplantation of partially HLAmismatched bone marrow for patients with hematologic malignancies
Rationale:
The purpose of this study was to validate, in a multicenter trial, the safety of a non-myeloablative HCT
regimen for hematologic malignancies using partially HLA-mismatched related (haploidentical) donors.
Preliminary results from two transplant centers suggest that this regimen, which incorporates high-dose,
post-transplantation cyclophosphamide for GVHD prophylaxis, is associated with acceptably low rates of
fatal graft rejection, acute and chronic GVHD, and opportunistic infection. The ultimate goal of this trial,
and the parallel trial of umbilical cord blood transplantation after non-myeloablative conditioning (BMT
CTN 0604), is to extend the availability of allogeneic HCT to patients who lack HLA-matched related or
unrelated donors. If safety is established, this haploidentical regimen could be compared with umbilical
cord blood and/or HLA-matched unrelated donor transplantation for specific disease entities.
Primary Objective:
To determine overall survival 180 days after HLA-haploidentical bone marrow transplantation using a
non-myeloablative preparative regimen and post-transplantation cyclophosphamide
To assess neutrophil and platelet recovery, graft failure, acute GVHD, chronic GVHD, incidence of
Secondary Objectives: infection, treatment-related mortality, time to relapse/progression, overall survival time, and
progression-free survival time
Team Principals:
Name:
Email:
Chair:
Ephraim Fuchs
[email protected]
Officer:
Mary Eapen
[email protected]
Coordinator:
[email protected]
Jason Thompson
Medical Monitor:
Shannon Smiley
[email protected]
Statistician:
Shelly Carter
[email protected]
Contract Rep:
Pamela Budnick
[email protected]
PRC Approval Date:
12/21/2007
Claudio Anasetti
[email protected]
DSMB Approval Date:
06/06/2008
Karen Ballen
[email protected]
Opened to Accrual:
10/17/2008
Claudio Brunstein
[email protected]
05/17/2010
Nancy DiFronzo
[email protected]
12/2010
Mary Horowitz
[email protected]
Target Accrual:
50
Paul O'Donnell
[email protected]
55
John Wagner
[email protected]
N/A
IND Number:
N/A
01/28/2009
Key Highlights:
A single Protocol Team was formed in December 2006 to develop both BMT CTN 0603 and 0604.
Presentation to the DSMB for both protocols was delayed to allow competing protocols to near
completion. The protocols were released to centers for IRB approval in summer 2008. Institutions
participating in both protocols were required to submit allocation schemes or prioritization plans to
avoid bias. These required approval by the Protocol Team before site activation.
The BMT CTN 0603 protocol was activated on October 17, 2008. Eight Core Centers and nine Affiliate
Centers enrolled a total of 55 patients on the trial. The study reached its targeted accrual goal and was
closed to enrollment in May 2010, well ahead of projections.
The Endpoint Review Committee formed in summer 2010 and conducted data review for all the primary
and secondary endpoints of the study.
94
Protocol Number:
BMT CTN 0603
Reporting Period
Update:
A secondary data review with all patients followed for two years is planned for spring 2013. The
0603/0604 Phase III follow-on study, BMT CTN 1101 (haplo-identical vs. double cord blood HCT) was
released during this past year and is open for accrual.
Publication:
1. Primary manuscript: Alternative donor transplantation: results of parallel Phase II trials using HLAmismatched related bone marrow or unrelated umbilical cord blood grafts. Blood. 2011 Jul
14;118(2):282-288. Epub 2011 Apr 28.
Presentation:
1. Phase II trial of nonmyeloablative conditioning and transplantation of partially HLA-mismatched bone
marrow for patients with hematologic malignancies: results of BMT CTN Protocol #0603. Abstract
presented: BMT Tandem Meetings, Honolulu, HI, February 2011. Received a Best Abstract Award.
BMT CTN #0603
60
7
50
Monthly Accrual
6
40
5
4
30
3
20
2
10
1
0
0
95
Cumulative Accrual
8
Cumulative Accrual
BMT CTN 0604
Protocol Number:
BMT CTN 0604
Status:
Closed to Accrual
Title:
A multicenter, Phase II trial of non-myeloablative conditioning and transplantation of umbilical cord
blood from unrelated donors in patients with hematologic malignancies
Rationale:
Preliminary data from single transplant centers suggests that non-myeloablative umbilical cord blood
transplantation with two units is a safe and valuable alternative for patients who lack a suitable related
donor. The purpose of this study was to determine if the single center data can be reproduced in a
multicenter setting.
Primary Objective:
To determine overall survival 180 days after double cord blood transplantation using a nonmyeloablative preparative regimen
To assess neutrophil and platelet recovery, graft failure, acute GVHD, chronic GVHD, incidence of
Secondary Objectives: infection, treatment-related mortality, time to relapse/progression, overall survival time, and
progression-free survival time
Team Principals:
Name:
Email:
Chair:
[email protected]
Claudio Brunstein
Officer:
[email protected]
Mary Eapen
Coordinator:
[email protected]
Jason Thompson
Medical Monitor:
[email protected]
Dianna Howard
Statistician:
[email protected]
Shelly Carter
Contract Rep:
[email protected]
Pamela Budnick
PRC Approval Date:
12/21/2007
Claudio Anasetti
[email protected]
DSMB Approval Date:
06/06/2008
Karen Ballen
[email protected]
Opened to Accrual:
12/23/2008
Nancy DiFronzo
[email protected]
03/31/2010
Ephraim Fuchs
[email protected]
Target Accrual:
50
Mary Horowitz
[email protected]
11/2010
Paul O'Donnell
[email protected]
Total Accrual as of3/31/13:
54
John Wagner
[email protected]
N/A
IND Number:
N/A
01/28/2009
Key Highlights:
A single Protocol Team was formed in December 2006 to develop both BMT CTN 0603 and 0604.
Presentation to the DSMB for 0603 and 0604 was delayed for competing protocols to near completion.
The protocols were released to centers for IRB approval in summer 2008.
Institutions participating in both protocols were required to submit allocation schemes or prioritization
plans to avoid bias. These plans required approval by the Protocol Team before site activation. The 0604
protocol was activated on December 23, 2008. Eight Core Centers and eight Affiliate Centers enrolled a
total of 54 patients on the trial. The protocol closed to enrollment in March 2010, well ahead of
projections.
In April 2010, the DSMB approved release of data to the Protocol Team in anticipation of submitting an
abstract in October 2010. The Endpoint Review Committee formed in summer 2010 to review data for
all of the primary and secondary endpoints of the study.
Reporting Period
Update:
A secondary data review with all patients followed for two years is planned for spring 2013. The
0603/0604 Phase III follow-on study, BMT CTN 1101 (haplo-identical vs. double cord blood HCT) was
released during this past year and is open for accrual.
96
Protocol Number:
BMT CTN 0604
Publication:
1. Primary manuscript: Alternative donor transplantation: results of parallel Phase II trials using HLAmismatched related bone marrow or unrelated umbilical cord blood grafts. Blood. 2011 Jul
14;118(2):282-288. Epub 2011 Apr 28.
Presentation:
1. Phase II trial of nonmyeloablative conditioning double umbilical cord blood transplantation from
unrelated donors in patients with hematologic malignancies: results of Blood and Marrow Transplant
Clinical Trials Network protocol 0604. Abstract presented: BMT Tandem Meetings, Honolulu, HI,
February 2011.
BMT CTN #0604
Monthly Accrual
7
60
Cumulative Accrual
50
6
40
5
4
30
3
20
2
10
1
0
0
97
Cumulative Accrual
8
BMT CTN 0701
Protocol Number:
BMT CTN 0701
Status:
Closed to Accrual
Title:
Allogeneic HCT using reduced-intensity conditioning for relapsed follicular cell non-Hodgkin lymphoma
using related or unrelated donors
Rationale:
Follicular non-Hodgkin lymphoma is the second most common type of non-Hodgkin lymphoma in the
United States. When treatment is indicated, most patients achieve remission with initial chemotherapy,
but patients with recurrent advanced follicular lymphoma have a median survival of only four to five
years. Numerous treatment options exist, including autologous and allogeneic HCT.
Results of several studies using autologous HCT show improved disease-free survival, but relapse
remains the predominant cause of treatment failure. High-dose chemo-radiotherapy with allogeneic
HCT is sometimes offered with the goal of harnessing a graft-versus-lymphoma effect. Indeed, lower
relapse rates are reported when compared with autologous HCT. However, high treatment-related
mortality offsets any survival benefit this might confer.
Reduced-intensity approaches to allogeneic HCT rely primarily on the immunotherapeutic effects of the
allograft to confer anti-lymphoma activity rather than the cytoreductive effects of high-dose
chemotherapy. The incorporation of lower doses of chemotherapy has resulted in lower treatmentrelated mortality and has thereby extended eligibility for allogeneic HCT to older patients who are
unable to tolerate myeloablative regimens. Whether this approach offers substantial long-term diseasefree survival with good quality of life is uncertain.
Primary Objective:
To measure two-year progression-free survival after allogeneic HCT with a reduced-intensity pretransplant conditioning regimen of fludarabine, cyclophosphamide and rituximab.
To examine two-year overall survival; time to complete response and partial response; time to off-study
therapy; incidences and severity of acute and chronic GVHD; treatment-related mortality; and
incidences of primary and secondary graft failure; quality of life, as measured by the SF-36 and the
FACT-BMT; and the ability to predict disease relapse by measuring t(14;18) using a quantitative
polymerase chain reaction.
Team Principals:
Chair:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Nancy DiFronzo
Hillard Lazarus
William Merritt
Auayporn Nademanee
Thomas Shea
Liz Wagner
Name:
Ginna Laport
Marcie Tomblyn
Iris Gersten
Gabrielle Meyers
Brent Logan
Nancy Poland
Email:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Key Highlights:
Email:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
04/01/2008
DSMB Approval Date:
05/20/2008
Opened to Accrual:
04/27/2009
10/22/2012
Target Accrual:
65
65
14
IND Number:
Exempt
05/12/2011
The study was placed on the CTSU roster in February 2009 and endorsed by SWOG, CALGB, and ECOG.
The study was activated on April 27, 2009, after several centers received IRB approval. Twelve Core
Centers and 25 Affiliate Centers were activated for enrollment, 13 of which participated through the
98
Protocol Number:
BMT CTN 0701
CTSU.
Several initiatives were implemented to address slower-than-anticipated enrollment, including periodic
study updates to transplant center PIs and Coordinators; template referral and insurance appeal letters
to centers; a campaign to encourage all non-enrolling centers to enroll; and advertisements in CTSU,
American Society of Blood and Marrow Transplant, Leukemia/Lymphoma Society, and Leukemia
Research Foundation newsletters.
Protocol Version 5 amendment was approved May 12, 2011. This amendment clarified the inclusion
criteria to allow patients with stable follicular lymphoma to enroll if all lymph node masses are ≤ 3 cm
and are smaller or unchanged in size to the most recent salvage regimen.
Reporting Period
Update:
The study closed to accrual in October 2012 when 65 patients, as planned, were enrolled. The
Endpoint Review Committee will begin reviewing data once the majority of patients have completed
two year follow-up.
BMT CTN #0701
10
70
60
Cumulative Accrual
50
6
40
30
4
20
2
10
0
0
99
Cumulative Accrual
Accrual per Month
8
Protocol Number:
Status:
Closed to Accrual
Title:
Tandem autologous stem cell transplantation for patients with primary progressive or recurrent
Hodgkin disease (a BMT study), Phase II
Hodgkin lymphoma (HL) comprises approximately 11% of all lymphomas in western countries and
accounts for 15% of all cancers in young adults. Fortunately, nearly 80% of Hodgkin lymphoma
patients are cured with frontline chemoradiotherapy. For patients with relapsed or refractory,
chemosensitive disease, high-dose chemotherapy with autologous HCT is the standard of care
and confers cure rates of 40% to 50%. Only about 25% of patients with poor-risk recurrent
Hodgkin lymphoma (i.e., patients with symptoms, extranodal involvement, or chemorefractory
disease at relapse) are cured.
Rationale:
The overall outcome of this poor-risk group might be improved if a minimal disease status could
be achieved before conventional transplant. The result of a pilot study showed that high-dose
melphalan with stem cell support is feasible as a salvage cytoreductive treatment. After achieving
a minimal disease state or maximum debulking of the disease, a standard, defined conditioning
regimen can be administered as "consolidation," followed by a second stem cell infusion. The
tolerability of this very intensive regimen was encouraging; therefore, the pilot study is extending
into a Phase II study in the Cooperative Group setting to further evaluate the efficacy of this
approach.
Primary Objective:
To assess the two-year progression-free survival for patients with primary progressive or
recurrent Hodgkin lymphoma treated with a tandem transplant program (two cycles of high-dose
therapy with autologous stem cell rescue).
To evaluate the response rate and toxicity in patients with primary progressive or recurrent
Hodgkin lymphoma treated with this regimen.
Team Principals:
Name:
Email:
Ginna Laport (BMT CTN)
[email protected]
Patrick Stiff (SWOG)
[email protected]
Eileen Smith (SWOG)
[email protected]
Marcie Tomblyn (BMT CTN)
[email protected]
Coordinator:
Laura Devillier
[email protected]
Medical Monitor:
SWOG
Statistician:
SWOG
Contract Rep:
Nancy Poland
[email protected]
Additional Members:
Email:
PRC Approval Date:
N/A
Gilbert Carrizales
[email protected]
DSMB Approval Date:
N/A
Jeri Jardine (SWOG)
[email protected]
Opened to Accrual:
10/15/2005 SWOG;
03/18/2008 BMT CTN
02/01/2009
Target Accrual:
85
9 BMT CTN, 89 SWOG
Chairs:
Officers:
100
Protocol Number:
N/A
IND Number:
N/A
11/07/2007 SWOG
Key Highlights:
This protocol was a collaborative effort between SWOG and BMT CTN. Six BMT CTN Core Centers
enrolled patients. SWOG closed the study upon accrual completion on February 1, 2009. An
analysis is being performed by SWOG, and the BMT CTN provided data as requested.
Results are anticipated to be published during the next reporting period.
A graph is not displayed with this protocol, BMT CTN 0701 / SWOG 0410, due to limited BMT CTN accrual to the study
during its 11 months of participation.
101
BMT CTN 0704 / CALGB 100104 / ECOG 100104
Protocol Number:
Status:
Closed to Accrual
Title:
A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 or placebo following autologous
stem cell transplantation for multiple myeloma
Autologous HCT is a major component of standard, upfront therapy for multiple myeloma, resulting in major tumor
reduction and improved response and survival rates. The majority of patients, however, will have disease
progression or recurrence within two to three years after autologous HCT. No standard treatment to maintain
response after autologous HCT exists.
Rationale:
Thalidomide has shown promise as a maintenance agent; however, patients may not tolerate prolonged
administration of thalidomide and/or other agents, such as glucocorticoids. Lenalidomide (CC-5013), a derivative of
thalidomide, may prove useful as a maintenance agent after single autologous HCT to prolong response to
induction therapy. This agent does not cause major neurotoxicity, which is a limiting factor for prolonged
thalidomide therapy. It is expected that CC-5013 toxicity will be low and lead to improved compliance with
maintenance therapy.
This Phase III, placebo-controlled study was designed to determine the importance of maintenance therapy for
prolonging disease response and survival in these patients.
Primary Objective:
To compare the efficacy of lenalidomide and placebo as maintenance therapy after autologous HCT in terms of
time to disease progression in patients with multiple myeloma.
Secondary
Objectives:
To compare complete response rates, progression-free, and overall survival times and to determine the feasibility
of long-term treatment with lenalidomide in these patients.
Team Principals:
Name:
Kenneth Anderson (CALGB)
Sergio Giralt (BMT CTN)
Philip Greipp (ECOG)
Philip McCarthy (CALGB)
Marcelo Pasquini
CALGB
CALGB
CALGB
Nancy Poland
Email:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Email:
Opened to Accrual:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
CALGB
CALGB
Target Accrual:
IND Number:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional
Members:
Martha Hering
Michael Kelly
William Merritt
Lena Muwakki
David Vesole
PRC Approval:
DSMB Approval:
Key Highlights:
[email protected]
12/15/2004 (CALGB)
05/15/2007 (BMT CTN)
07/02/2009
529 (172 BMT CTN)
40 BMT CTN; 533 total
N/A
12/2009
N/A
06/15/2008
This CALGB-led, ECOG-endorsed trial opened in December 2004. It was designed to determine the importance of
maintenance therapy with lenalidomide for prolonging disease response and survival in patients who have
undergone HCT for treatment of multiple myeloma. Its target patient population overlapped with that of BMT CTN
0102, which opened in November 2003. The Multiple Myeloma Intergroup considered a follow-on trial to BMT CTN
0102 at that time, and the accrual difficulties of CALGB 100104 were discussed. Rather than open another
competing trial, BMT CTN endorsed the CALGB trial and urged its centers to open the trial through local CALGB and
ECOG mechanisms as soon as 0102 reached its enrollment target, which it did in May 2007.
To allow BMT CTN centers that were not part of CALGB or ECOG to participate, the DCC worked with NCI to have
102
Protocol Number:
the trial posted to the NCI Cancer Trials Support Unit roster. The BMT CTN Accrual Coordinator and other DCC staff
worked with the CALGB Protocol Team to develop an accrual enhancement plan that included identifying and
contacting centers with potentially large numbers of eligible patients, using the CIBMTR’s database of transplant
activity. Webinars were also conducted to increase awareness of the trial. Network centers began accruing patients
to this trial in summer 2007, and all of these strategies resulted in significant improvement (at least a doubling) in
accrual.
In December 2009, the CALGB Data and Safety Monitoring Board decided to release the trial results early, due to
the significantly longer time to disease progression in patients who received lenalidomide maintenance than those
receiving placebo. Timely completion of this trial answered an important question in post-transplant treatment in
multiple myeloma, and led well into the Stem Cell Transplantation for Multiple Myeloma Incorporating Novel
Agents (STaMINA) trial (BMT CTN 0702), which incorporates maintenance therapy in all treatment arms. This effort
is a good example of how the BMT CTN has played a leadership role in developing and completing transplant trials
by fostering collaboration on a national level.
Reporting Period
Update:
The primary manuscript was published in the New England Journal of Medicine and was highlighted as a
contributor to one of ASCO’s 17 Major Advances in Clinical Cancer Research in 2012. A secondary analysis of
longer-term follow-up was conducted, and the abstract will be presented at the International Myeloma
Workshop in April 2013. A subsequent publication is anticipated during the next reporting period.
Publication:
1. Phase III study of lenalidomide versus placebo after HCT for multiple myeloma. New England Journal of
Medicine. 2012 May 10;366(19):1770-81.
Presentations:
1. Maximizing accrual to transplant trials in multiple myeloma, lessons from the BMT CTN, ECOG and CALGB.
Presented: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2020.
2. Phase III intergroup study of Lenalidomide versus placebo maintenance therapy following single autologous stem
cell transplant for multiple myeloma: CALGB 100104. Presented: ASCO Annual Meeting, Chicago, IL, June 2010.
cell transplant for multiple myeloma: CALGB 100104. Presented: ASH Annual Meeting, Orlando, FL, December
2010.
cell transplant for multiple myeloma: CALGB ECOG BMT-CTN 100104. Presented: International Myeloma
Workshop, Paris, France, May 2011.
Target Accrual: 40 BMT CTN patients (actual 172); 533 total patients
BMT CTN #0704 / CALGB 100104
30
Cumulative Accrual
500
400
20
300
15
10
200
5
100
0
0
BMT CTN opened this study to accrual on May 15, 2007.
103
Cumulative Accrual
Monthly Accrual
25
BMT CTN 0802
Protocol Number:
BMT CTN 0802
Status:
Closed to Accrual
Title:
A multicenter randomized, double blind, Phase III trial evaluating corticosteroids with mycophenolate
mofetil versus corticosteroids with placebo as initial systemic treatment of acute graft-versus-host
disease
Rationale:
Acute GVHD is one of the most common complications of allogeneic HCT, yet its therapy (the use of
high doses of corticosteroids) has changed very little in the past 30 years. BMT CTN 0302 identified
mycophenolate mofetil as a promising agent to test in combination with corticosteroids for acute
GVHD treatment. This study is a Phase III, randomized, double-blind, placebo-controlled trial
evaluating the addition of mycophenolate mofetil versus placebo to systemic corticosteroids as initial
therapy for acute GVHD.
Primary Objective:
To estimate GVHD-free survival (acute or chronic) at day 56 after randomization without additional
therapy.
To evaluate proportions of complete, partial, mixed response, no response and progression among
surviving patients at day 14, 28 and 56; treatment failure (defined as no response, progression,
administration of additional therapy for GVHD, or mortality) at day 14, 28, and 56; incidence of acute
GVHD flare prior to day 90; and incidence of discontinuation of immune suppression without acute
GVHD flare and without disease progression/ recurrence by days 56, 180, and 360 post therapy.
Additional secondary endpoints include steroid dose at day 28 and 56 post randomization, incidence
of topical/non-absorbable therapy given by day 56, incidence of chronic GVHD by 6 and 12 months
post randomization, overall and GVHD-free survival at 6 and 12 months post randomization,
incidences of systemic infections within 6 months of initiation of therapy, incidence of Epstein-Barr
virus-associated lymphoproliferative disorder or reactivation requiring therapy, malignancy-free
survival at 6 and 12 months post randomization, non-relapse mortality at 6 and 12 months, and
change in patient-reported outcomes from enrollment to day 56.
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Amin Alousi
Joseph Antin
Shelly Carter
Nancy DiFronzo
James Ferrara
Eric Leifer
John Levine
Margaret MacMillan
Paul Martin
Marco Mielcarek
Georgia Vogelsand
Name
Vincent Ho
Mary Horowitz (temporary)
Kate Barowski
Dianna Howard
Brent Logan
Nancy Poland
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Target Accrual:
IND Number:
Additional Members:
Liz Wagner
Daniel Weisdorf
104
05/18/2009
06/30/2009
02/01/2010
11/14/2011
372
236
N/A
N/A
01/31/2011
Email
[email protected]
[email protected]
Protocol Number:
BMT CTN 0802
Key Highlights:
BMT CTN 0802 is a follow-on study to the randomized Phase II 0302 study, which completed accrual
and follow up in May 2008. The protocol was approved by the PRC in May 2009 and by the DSMB in
June 2009. The study experienced a delay in its progress from DSMB approval to activation due to
negotiations for drug acquisition. It was activated on February 1, 2010.
The study was closed to enrollment on November 14, 2011 due to crossing a futility boundary. A
total of 236 patients were enrolled from 36 centers.
The endpoint review for this study began in March 2012. An absbtract was submitted and accepted
Reporting Period Update: for oral presentation at the February 2013 BMT Tandem meetings. The primary manuscript will be
written and submitted during the next reporting period.
1. A multi-center, randomized, double blind, Phase III clinical trial comparing steroids/placebo vs.
steroids/mycophenolate mofetil as initial therapy for acute graft-versus-host disease. Blood and
Marrow Transplant Clinical Trials Network Study 0802. Presented: BMT Tandem Meetings, Salt
Lake City, UT, February 2013.
Presentation:
BMT CTN #0802
Accrual per Month
20
250
Cumulative Accrual
200
15
150
10
100
5
50
0
0
105
Cumulative Accrual
25
BMT CTN 0902
Protocol Number:
BMT CTN 0902
Status:
Closed to Accrual
Title:
A Phase III randomized, multicenter trial testing whether exercise or stress management improves
functional status and symptoms of autologous and allogeneic HCT recipients
Rationale:
HCT patients experience numerous aversive symptoms (e.g., nausea, fatigue and sleep disturbance)
accompanied by declines in physical and mental well-being. Although most longitudinal studies show
return to baseline functioning for the majority of patients, it may take 6 to 12 months or longer to
reach this goal.
Clinical trials have shown that training in stress management techniques and participation in formal
exercise programs each offered in isolation are effective in improving quality of life in patients
receiving standard-dose chemotherapy and HCT. Review of these studies suggests that stress
management interventions primarily improve mental health outcomes and nausea. The impact of
exercise training interventions is more variable; most studies report physical health benefits, with
some studies also reporting mental health benefits. Small studies suggest that combining stress
management training and exercise are feasible and well tolerated, but whether the combination
provides an additive or synergistic impact on quality-of-life outcomes has not been directly
investigated.
The purpose of this study is to test whether exercise or stress management training delivered to
autologous and allogeneic HCT patients prior to transplantation can improve functional status and
the transplantation experience.
Primary Objective:
To determine whether exercise or stress management improves self-reported physical and mental
functioning compared to standard care at 100 days post transplant, using an intent-to-treat analysis
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Smita Bhatia
Shelly Carter
Nancy Geller
Heather Jim
Navneet Majhail
Douglas Rizzo
To evaluate whether exercise or stress management improves physical and mental functioning
compared to standard care at 100 days, limiting the analysis to patients who survive and provide a
day 100 self-assessment (conditional analysis with main effects); physical and mental functioning
among the four groups, limiting the analysis population to patients who provide a day 100 selfassessment; symptoms (fatigue, pain, sleep, nausea, cancer and treatment distress) at 100 days
among patients who provide a day 100 self-assessment; the number of hospital days within the first
100 days; durability of effects by comparing functional status and symptoms at 6 months; and overall
survival at 6 months.
Name:
Email:
Paul Jacobsen
[email protected]
Stephanie Lee
[email protected]
Mary Horowitz
[email protected]
Laura Devillier
[email protected]
Gabrielle Meyers
[email protected]
Brent Logan
[email protected]
Pamela Budnick
[email protected]
Email:
PRC Approval Date:
12/23/2009
[email protected]
DSMB Approval Date:
03/18/2010
[email protected]
Opened to Accrual:
01/03/2011
[email protected]
06/01/2012
[email protected]
Target Accrual:
700
[email protected]
[email protected]
156
[email protected]
IND Number:
N/A
106
Protocol Number:
Galen Switzer
Karen Syrjala
John Wingard
BMT CTN 0902
[email protected]
[email protected]
[email protected]
Key Highlights:
This is the Network’s first trial examining quality of life as its primary endpoint. This trial was
identified as one of 11 high-priority trials during the 2007 State of the Science Symposium.
The protocol was approved by the PRC on December 23, 2009, and by the DSMB on March 18, 2010.
The trial experienced a delay from DSMB approval to trial activation due to the time required to
develop the patient materials for the study, including exercise and stress management videos and
brochures. Patient materials were finalized in September 2010 and released to centers for IRB
approval. The trial opened for enrollment on January 3, 2011, when the first center received IRB
approval. Protocol Version 2 was released to centers on March 30, 2011; the amendment specified
three new exclusion criteria.
Additional Member:
William Wood
03/30/2011
Email:
[email protected]
Accrual was completed this year. Twenty-one centers enrolled a total of 711 patients on the trial,
Reporting Period Update: resulting in completion of accrual 17 months earlier than projected. Endpoint review is underway
with publication of results anticipated in the next reporting period.
BMT CTN #0902
800
Cumulative Accrual
Accrual per Month
600
500
400
300
200
100
0
107
Cumulative Accrual
700
108
7.3 Protocols Released to Centers
BMT CTN Protocols Released to Centers (as of March 31, 2013)
BMT CTN
Protocol #
1202
Protocol Title
A prospective multicenter trial establishing a cohort of biologic samples
collected prospectively as a shared biospecimen resource for future allogeneic
HCT correlative studies evaluating biomarkers
109
BMT CTN 1202
Protocol Number:
BMT CTN 1202
Status:
Released to Centers
Title:
Prospective Multi-Center Cohort for the Evaluation of Biomarkers Predicting Risk of Complications
and Mortality Following Allogeneic HCT
Rationale:
While HCT offers the only cure for many patients with malignant and non-malignant hematologic
diseases, this treatment is associated with significant risks, leading to high rates of morbidity and
mortality. There is a critical need for more effective prevention and treatment strategies for HCTassociated complications. The most serious of the latter include GVHD, cancer recurrence, organ
toxicity and opportunistic infection. Although some clinical variables (e.g., recipient age, donorrecipient HLA mismatch) predict higher risk of some events (e.g., GVHD, infection), no diagnostic tests
exist that reliably predict occurrence, severity or response to therapy of any of these complications.
Recent compelling results from single center studies suggest that biomarkers can be identified that
stratify patients into discrete risk groups for some outcomes and for overall mortality. However, these
relatively small studies generally lack the statistical power or validation necessary to allow their
results to be incorporated into practice. One key factor in the success of biomarker studies is the
quality of clinical outcomes data that is linked to the specimens being analyzed. An adequate
resource for these studies requires longitudinal sample collection integrated with longitudinal
collection of comprehensive, standardized, high quality clinical data regarding complications, from
onset to resolution, and regarding other clinical variables affecting risk of post-HCT outcomes.
The goal of this protocol is to establish a cohort of biologic samples collected prospectively from
patients treated in BMT CTN centers that will be a shared biospecimen resource for conducting future
allogeneic HCT correlative studies. This resource is designed to allow genomic, proteomic and
transcriptional data to be integrated with high quality clinical phenotype and outcomes data to
identify risk factors for development and severity of acute GVHD, chronic GVHD, organ toxicity,
relapse, mortality, infection and other clinically significant complications occurring after allogeneic
HCT.
Primary Objective:
The goal of this protocol is to establish a cohort of biologic samples collected prospectively from
patients treated in BMT CTN centers that will be a shared biospecimen resource for conducting future
allogeneic HCT correlative studies.
Team Principals:
Chairs:
Officer:
Coordinator:
Medical Monitor:
Statistician:
Contract Rep:
Additional Members:
Asad Bashey
Shelly Carter
Dennis Confer
James Ferrara
Theresa Hahn
Vincent Ho
N/A
Name:
John Levine
John Hansen
Wael Saber
Jason Thompson
TBD
Renee Carby
Email:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Email:
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
PRC Approval Date:
DSMB Approval Date:
Opened to Accrual:
Target Accrual:
110
11/19/2012
12/17/12
TBD
N/A
1500
N/A
N/A
Protocol Number:
BMT CTN 1202
Mary Horowitz
Alan Howard
Leslie Kean
Eric Leifer
Phillip McCarthy
Bill Merritt
Miguel-Angel Perales
[email protected]
[email protected]
[email protected]
[email protected]
Key Highlights:
The BMT CTN 1202 Protocol Team was formed in March 2012.
Reporting Period
Update:
In November 2012, the protocol received PRC approval, followed by DSMB approval in December
2012. It was released to centers for IRB submission in January 2013 and is anticipated to open to
accrual in spring 2013. Several members of the protocol team also played a significant role in the
development of a DCC-lead R24 application for funding opportunity to extend the research scope of
the BMT CTN 1202 study, furthering the potential impact of this national resource. A final NHLBI
determination of funding is expected within the next two to three months.
IND Number:
Additional Members:
Stefanie Sarantopoulos
[email protected] Steve Spellman
[email protected]
Elizabeth Wagner
[email protected]
111
N/A
1/4/2013
Email:
[email protected]
[email protected]
[email protected]
112
Attachment A: Data and Coordinating Center Organizational Structure
Attachment A: Data and Coordinating Center Organizational Structure
Shelly Carter, ScD
DCC Co-Principal Investigator
Peter Dawson, PhD
Adam Mendizabal, MS
Yanli Wang, MS
Maggie Wu, MS
Statisticians
Erica Anderson, MA
Kate Barowski
Laura Devillier
Moira Lewis, MPH
Courtney Nelson
Alyssa Ramirez
Jason Thompson, MS
Connie Weaver
Protocol Coordinators
Linda Johnson
Sandi Sykes
Admin Coordinators
Michelle LaMotteo
Rus Maxwell
Programmer / Analysts
Iris Gersten, MS
Project Director
Kristin Knust, MS
Mary Magliocco
Ravi Sinani
Sunny Verma
Data Systems
Coordinators
Alan Ramnath
Regulatory
Coordinator
Jeanette Carreras, MPH
Brent Logan, PhD
Jennifer Le-Rademacher, PhD
Waleska Perez, MPH
Biostatisticians
Angela Soriano
Steve Wease, MPH
Integrity
Coordinators
Cara Brown, RN, MN
Cynthia Couture, RN
Protocol Monitors
NMDP / CIBMTR Minneapolis
Dennis Confer, MD
^ DCC Co-Principal Investigator
Sue Lorenz
Business Manager
Rebecca Drexler
Senior Manager,
Prospective Research
Stephen Spellman, MBS
Director, Immunobiology
& Observational Research
Cheryl Reiter
Administrative Asst
Leslie Bellamy
Administrative Asst
Alan Howard, PhD
Principal Immunobiology
Research Specialist
Kavita Bhavsar
BMT CTN Data
Coordinator
Amy Foley, MA
BMT CTN Project
Manager
Mita Desai
Data Entry
Coordinator
NMDP Support
Services
TBD
AE Coordinator
KEY
^
*
CIBMTR Milwaukee
Mary Horowitz, MD, MS
^ DCC Principal Investigator
^ * Mary Eapen, MD
^ * Marcelo Pasquini, MD
^ * Wael Saber, MD
^ * Willis Navarro, MD
* Christopher Bredeson, MD
* Dianna Howard, MD
* Tammy Kindwall-Keller, MD
* Gabrielle Meyers, MD
* Eneida Nemecek, MD
* Bipin Savani, MD
* Shannon Smiley, MD
* Angie Smith, MD
^ * Marcie Tomblyn, MD
EMMES Corporation, Rockville, MD
CIBMTR, Milwaukee, WI
CIBMTR/NMDP, Minneapolis, MN
Various Locations
Protocol Officer
Medical Monitor
Brian Lindberg, JD
Senior VP &
General Counsel
Bruce Schmaltz
Director, Finance /
Controller
Elizabeth Murphy,
EdD, RN
VP, Patient Services
Nancy Poland, MA
Sr Mgr, Contracts
& Procurement
Gina Graves
Sr Manager /
Asst Controller
Ellen Denzen, MS
Sr Manager, Health
Services Research
Pam Budnick
Renee Carby, MS
Kiila Lee
Scott Westre
Contract
Representatives
Kevin Weber
Gov’t Cost Analyst,
Clinical Trials
Heather Moore,
MPH, CHES
Program Specialist
Anh Vorarath
Supervisor, Gov’t
Accounting
Lensa Idossa
Program Analyst
Susanne Lahti
Paralegal
Tom Switzer
Senior Buyer
113
Stephanie Waldvogel
Immunobiology
Research Specialist
Paula Washington
Bookkeeper, Gov’t
Accounting
Peggy Schmidt
Cost Accountant,
Gov’t Accounting
Attachment B: Core and Affiliate Centers
Attachment B: Core and Affiliation Centers
Attachment B1: Core Centers
Baylor College of Medicine
Methodist Hospital, Houston, TX
Principal Investigator: Catherine Bollard, MD
Case Western Reserve University (Consortium)
Ireland Cancer Center, Cleveland, OH
Principal Investigator: Hillard Lazarus, MD
Consortium Centers:
Oregon Health Sciences University, Portland, OR. Principal Investigator: Richard Maziarz, MD
Cleveland Clinic. Principal Investigator: Matthew Kalaycio, MD
City of Hope National Medical Center
Duarte, CA
Principal Investigator: Stephen Forman, MD
Dana-Farber/Partners Cancer Care (Consortium)
Boston, MA
Principal Investigator: Joseph Antin, MD
Consortium Centers:
Brigham & Women’s Hospital, Massachusetts General Hospital and Boston Children’s Hospital, Boston, MA.
Principal Investigator: Joseph Antin, MD
Duke University Medical Center
Durham, NC
Principal Investigator: Joanne Kurtzberg, MD
Fred Hutchinson Cancer Research Center
Seattle, WA
Principal Investigator: Frederick Appelbaum, MD
H. Lee Moffitt Cancer Center
Tampa, FL
Principal Investigator: Claudio Anasetti, MD
Johns Hopkins University Oncology Center
Baltimore, MD
Principal Investigator: Richard Jones, MD
114
Memorial Sloan-Kettering Cancer Center
New York, NY
Principal Investigator: Sergio Giralt, MD (Steering Committee Immediate Past Chair)
Northside Hospital Atlanta
Atlanta, GA
Principal Investigator: Asad Bashey, MD
Ohio State University Comprehensive Cancer Center (Consortium)
Columbus, OH
Principal Investigator: Steven Devine, MD
Consortium Centers:
Roswell Park Cancer Institute, Buffalo, NY.
Principal Investigators: Philip McCarthy, MD and Theresa Hahn, PhD
University of North Carolina, Chapel Hill, NC.
Principal Investigator: Thomas Shea, MD
University of California, San Francisco.
Principal Investigator: Lloyd Damon, MD
Medical College of Virginia Hospital / Virginia Commonwealth University Medical Center, Richmond, VA.
Principal Investigator: John McCarty, MD
Pediatric Blood and Marrow Transplant Consortium
Primary Children’s Medical Center/University of Utah, Salt Lake City, UT
Principal Investigator: Michael Pulsipher, MD
Stanford Hospital and Clinics
Stanford, CA
Principal Investigator: Ginna Laport, MD (Steering Committee Chair)
University of Florida College of Medicine (Consortium)
Gainesville, FL
Principal Investigator: John Wingard, MD
Consortium Center:
Emory University, Atlanta, GA. Principal Investigator: Edmund Waller, MD, PhD
University of Michigan Medical Center
Ann Arbor, MI
Principal Investigator: James Ferrara, MD
115
Minneapolis, MN
Principal Investigator: Daniel Weisdorf, MD
University of Nebraska Medical Center (Consortium)
Omaha, NE
Principal Investigator: Julie Vose, MD
Consortium Center:
University of Kansas Medical Center, Kansas City, KS. Principal Investigator: Joseph McGuirk, DO
University of Pennsylvania Hospital
Philadelphia, PA
Principal Investigator: Edward Stadtmauer, MD
University of Texas MD Anderson Cancer Center
Houston, TX
Principal Investigator: Richard Champlin, MD
Washington University
St. Louis, MO
Principal Investigator: Peter Westervelt, MD
116
Attachment B2: Affiliate Centers
Advocate Lutheran General Hospital, Park Ridge, IL
All Children's Hospital, St Petersburg, FL
Arizona Cancer Center/University of Arizona, Tucson, AZ
Avera Hematology & Transplant Center, Sioux Falls, SD
Banner Research Institute, Sun City, AZ
Baylor University Medical Center, Waco, TX
Beth Israel Deaconess Medical Center, Boston, MA
British Columbia Children's Hospital, Vancouver, Canada
Cancer Centers of the Carolinas, Greenville, SC
Cancer Institute of New Jersey/Robert Wood Johnson University, New Brunswick, NJ
CancerCare Manitoba BMT Program, Canada
Cedars-Sinai Medical Center, West Hollywood, CA
Centre Hopital Affilie Enfant-Jesus, Quebec, Canada
Children's Healthcare of Atlanta, Atlanta, GA
Children’s Hospital at Oakland, Oakland, CA
Children's Hospital at Westmead, Australia
Children's Hospital Los Angeles, Los Angeles, CA
Children's Hospital of Denver, Denver, CO
Children's Hospital of New Orleans, New Orleans, LA
Children's Hospital of Philadelphia, Philadelphia, PA
Children's Medical Center of Dallas, Dallas, TX
Children's Mercy Hospital and Clinics, Kansas City, MO
Children’s National Medical Center, Washington, DC
Christiana Care Health System, Wilmington, DE
Colorado Blood Cancer Institute, Denver, CO
Columbia River Oncology Program, Portland, OR
Cook Children's Medical Center, Fort Worth, TX
DeKalb Medical Center, Lithonia, GA
Florida Hospital Cancer Institute, Orlando, FL
Fox Chase - Temple University BMT Program, Philadelphia, PA
Geisinger Medical Center, Danville, PA
Georgia Health Sciences University, Augusta, GA
Hackensack University Medical Center (Adult and Pediatric), Hackensack, NJ
Hamilton Health Sciences, Ontario, Canada
Henry Ford Health System, Detroit, MI
Hopital Maisonneuve Rosemont, Montreal, Canada
Hopital Sainte-Justine, Montreal, Canada
117
Hopital Saint-Louis, France
Indiana BMT Clinics, Beech Grove, IN
Indiana University Medical Center/Riley Hospital, Indianapolis, IN
Intermountain BMT Program, Salt Lake City, UT
Jewish Hospital BMT Program, Cincinnati, OH
Kansas City Cancer Centers, Kansas City, MO
Kapi'olani Medical Center for Women and Children – University of Hawaii, Honolulu, HI
Karmanos Cancer Institute/Children's Hospital of Michigan, Detroit, MI
Lahey Clinic, Burlington, MA
Louisiana State University Health Sciences Center, Baton Rouge, LA
Loyola University Medical Center, Chicago, IL
Mayo Clinic, Phoenix, AZ
Medical College of Wisconsin (Adult and Pediatric), Milwaukee, WI
Medical University of South Carolina (Adult and Pediatric), Charleston, SC
Montefiore Medical Center, New York, NY
Mount Sinai Medical Center, New York, NY
National Cancer Institute – NIH, Bethesda, MD
Nationwide Children's Hospital, Columbus, OH
Nemours Children’s Clinic, Jacksonville, FL
New York Medical College, Valhalla, NY
North Shore University Hospital, Manhasset, NY
Ottawa Hospital, Canada
Penn State College of Medicine - The Milton S. Hershey Medical Center, Hershey, PA
Phoenix Children's Hospital, Phoenix, AZ
Providence Portland Medical Center, Portland, OR
Queen Elizabeth II Health Sciences Centre – Halifax, Canada
Rush University Medical Center, Chicago, IL
Sarah Cannon BMT Program, Nashville, TN
St. Louis University, St. Louis, MO
St. Lukes Mountain States Tumor Institute, Boise, ID
SUNY Upstate Medical University, Syracuse, NY
Sydney Children's Hospital, Australia
Texas Transplant Institute (Adult and Pediatric), San Antonio, TX
Thompson Cancer Survival Center, Knoxville, TN
Tom Baker Cancer Centre-Calgary, Canada
Tufts Medical Center, Boston, MA
University of California Los Angeles-Center for Clinical AIDS Research and Education, Los Angeles, CA
University of California San Diego Medical Center, San Diego, CA
University of Alabama at Birmingham, Birmingham, AL
118
University of California Davis Medical Center, Sacramento, CA
University of Chicago, Chicago, IL
University of Illinois at Urbana-Champaign, Champaign, IL
University of Iowa Hospitals and Clinics, Iowa City, IA
University of Kentucky, Lexington, KY
University of Louisville/Kosair Children's Hospital, Louisville, KY
University of Maryland Medical Systems - Greenebaum Cancer Center, Baltimore, MD
University of Massachusetts/Memorial Medical Center, Worcester, MA
University of Miami, Miami, FL
University of Mississippi Medical Center, Jackson, MI
University of Oklahoma Medical Center, Norman, OK
University of Pittsburgh Cancer Institute, Pittsburgh, PA
University of Rochester Medical Center (Adults and Pediatric), Rochester, NY
University of Texas Southwestern Medical Center, Dallas, TX
University of Toronto - Princess Margaret Hospital, Canada
University of Wisconsin Hospital & Clinics, Madison, WI
Utah BMT/University of Utah Medical School, Salt Lake City, UT
Tennessee Valley Healthcare, Nashville, TN
Vancouver General Hospital, Canada
Vanderbilt University Medical Center (Adult and Pediatric), Nashville, TN
Wake Forest University Health Sciences, Winston-Salem, NC
Washington University / St. Louis Children’s Hospital, St. Louis, MO
Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY
West Virginia University Hospital, Morgantown, WV
Wichita Community Clinical Oncology Program, Wichita, KS
Yale University School of Medicine/Yale-New Haven Hospital, New Haven, CT
119
Attachment C: Publications, Abstracts, and Presentations
Attachment C1: Publications
Number
Protocol
Number
Publication
PMCID
2004
1
Wingard JR. Design issues in a prospective randomized doubleblinded trial of prophylaxis with fluconazole versus voriconazole after
allogeneic hematopoietic cell transplantation. Clinical Infectious
Disease. 2004 Oct 15;39 Suppl 4:S176-180.
BMT CTN 0101
N/A
(pre-dates
PMCID
requirements)
BMT CTN 0302
N/A
(pre-dates
PMCID
requirements)
N/A
(pre-dates
PMCID
requirements)
2005
2
3
Logan BR. Optimal two-stage randomized Phase II clinical trials.
Clinical Trials. 2005 Jan 01;2(1):5-12.
Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J,
Soiffer R and Giralt S. BMT CTN Toxicity Committee consensus
summary, thrombotic microangiopathy after hematopoietic stem cell
transplantation. Biology of Blood and Marrow Transplantation. 2005
Aug 01;11(8):571-575.
N/A
Network
publication
2007
4
5
Weisdorf D, Carter S, Confer D, Ferrara J and Horowitz M. BMT CTN:
Addressing unanswered questions. Biology of Blood and Marrow
Transplantation. 2007 Mar 01;13(3):257-62; discussion 255-256.
N/A
Network
publication
Ferrara J, Anasetti C, Stadtmauer E, Antin J, Wingard J, Lee SJ, Levine
J, Schultz K, Appelbaum F, Negrin R, Giralt S, Bredeson C, Heslop H
and Horowitz M. BMT CTN State of the Science Symposium 2007.
Biology of Blood and Marrow Transplantation. 2007 Nov 01;13:12681285.
N/A
Network
publication
N/A
(pre-dates
PMCID
requirements)
N/A
(pre-dates
PMCID
requirements)
2008
6
Logan B, Leifer E, Bredeson C, Horowitz M, Ewell M, Carter S and
Geller N. Use of biological assignment in hematopoietic stem cell
transplantation clinical trials. Clinical Trials. 2008 Jan 01;5(6):607616.
120
BMT CTN 0102
PMC2671015
Number
Publication
7
Cutler C, Stevenson K, Kim HT, Richardson P, Ho VT, Linden E, Revta
C, Ebert R, Warren D, Choi S, Koreth J, Armand P, Alyea E, Carter S,
Horowitz M, Antin JH, Soiffer R. Sirolimus is associated with venoocclusive disease of the liver after myeloablative allogeneic stem cell
transplantation. Blood. 2008 Dec 01;112(12):4425-4431. Epub 2008
Sep 5.
Protocol
Number
BMT CTN 0402
PMCID
PMC2597119
2009
BMT CTN 0302
PRIMARY
MANUSCRIPT
PMC2713466
BMT CTN 0102
N/A
Author reply
BMT CTN 0302
PMC3104501
10
Jacobson PA, Huang J, Wu J, Kim M, Logan B, Alousi A, Grimley M,
Bolaños-Meade J, Ho V, Levine JE, Weisdorf D. Mycophenolate
pharmacokinetics and association with response to acute GVHD
treatment from the BMT CTN. Biology of Blood and Marrow
Transplantation. 2010 Mar 01;16(3):421-429.
BMT CTN 0302
PMC2955996
11
Levine JE, Logan B, Wu J, Alousi AM, Ho V, Bolaños-Meade J,
Weisdorf D, On behalf of the BMT CTN. Graft-versus-host disease
treatment: predictors of survival. Biology of Blood and Marrow
Transplantation. 2010 Dec 01;16(12):1693-1699. Epub 2010 Jun 9.
BMT CTN 0101
PRIMARY
MANUSCRIPT
PMC3012532
12
Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR,
Gersten ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT,
Stadtmauer EA, Bolaños-Meade J, Brown J, Dipersio JF, Boeckh M,
Marr KA; BMT CTN. Randomized double-blind trial of fluconazole
versus voriconazole for prevention of invasive fungal infection after
allogeneic hematopoietic cell transplantation. Blood. 2010 Dec
09;116(24):5111-8. Epub 2010 Sep 8.
8
9
Alousi A, Weisdorf D, Logan B, Bolaños-Meade J, Carter S, DiFronzo
N, Pasquini M, Goldstein S, Ho V, Hayes-Lattin B, Wingard J, Horowitz
M and Levine J. Etanercept, mycophenolate, denileukin or
pentostatin plus corticosteroids for acute GVHD: A randomized
Phase II trial from the BMT CTN. Blood. 2009 Jul 16;114(3):511-517.
Epub 2009 May 14.
Giralt S, Vesole DH, Somlo G, Krishnan A, Stadtmauer E, McCarthy P,
Pasquini MC, BMT CTN Multiple Myeloma Working Group. Re:
Tandem versus single autologous hematopoietic cell transplantation
for the treatment of multiple myeloma: A systematic review and
meta-analysis. Journal of the National Cancer Institute. 2009 Jul
01;101(13):964; author reply 966-967. Epub 2009 Jun 17. [Comment
on: Journal of the National Cancer Institute 101(2):100-106, 2009].
2010
121
Protocol
Number
BMT CTN 0301
PMC3053041
BMT CTN 0202
PRIMARY
MANUSCRIPT
PMC3114272
[Available on
2012/7/1]
14
Tomblyn MR, Ewell M, Bredeson C, Kahl BS, Goodman SA, Horowitz
MM, Vose JM, Negrin RS and Laport GG. Autologous versus reduced
intensity allogeneic hematopoietic cell transplantation for patients
with chemosensitive follicular non-Hodgkin lymphoma beyond first
complete response or first partial response. Biology of Blood and
Marrow Transplantation. 2011 Jul 01;17(7):1051-1057. Epub 2010
Nov 10.
N/A
Network
publication
PMC Journal – In
Process
15
Horwitz EM, Horowitz MM, DiFronzo NL, Kohn DB, Heslop HE, BMT
CTN State of the Science Cell and Gene Therapy Committee.
Guidance for developing Phase II cell therapy trial proposals for
consideration by the BMT CTN. Biology of Blood and Marrow
Transplantation. 2011 Feb 01;17(2):192-196. Epub 2010 Dec 21.
BMT CTN 0303
PRIMARY
MANUSCRIPT
PMC3150599
[Available on
2012/9/1]
N/A
Network
publication
PMC3048197
BMT CTN 0603 /
BMT CTN 0604
PRIMARY
MANUSCRIPT
PMC3138683
[Available on
2012/7/14]
Number
Publication
13
Pulsipher MA, Young NS, Tolar J, Risitano AM, Deeg HJ, Anderlini P,
Calado R, Kojima S, Eapen M, Harris R, Scheinberg P, Savage S,
Maciejewski JP, Tiu RV, DiFronzo N, Horowitz MM, Antin JH.
Optimization of therapy for severe aplastic anemia based on clinical,
biological and treatment response parameters: conclusions of an
international working group on severe aplastic anemia convened by
the BMT CTN, March 2010. Biology of Blood and Marrow
Transplantation. 2011 Mar 01;17(3):291-299. Epub 2010 Oct 27.
PMCID
2011
16
17
18
Devine SM, Carter S, Soiffer RJ, Pasquini MC, Hari PN, Stein A, Lazarus
HM, Linker C, Stadtmauer EA, Alyea EP 3rd, Keever-Taylor CA,
O'Reilly RJ. Low risk of chronic graft-versus-host disease and relapse
associated with T cell depleted peripheral blood stem cell
transplantation for acute myeloid leukemia in first remission: results
of the BMT CTN protocol 0303. Biology of Blood and Marrow
Transplantation. 2011 Sep 01;17(9):1343-51. Epub 2011 Feb 12.
Kohn DB, Dotti G, Brentjens R, Savoldo B, Jensen M, Cooper LJ, June
C, Rosenberg S, Sadelain M and Heslop HE. CARs on track in the
clinic: workshop of the BMT CTN sub-committee on cell and gene
therapy. Molecular Therapy. 2011 Mar 01; 19(3): 432-438. Epub
2011 Mar 1.
Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine
SM, Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen
M, O'Donnell PV. Alternative donor transplantation: results of
parallel Phase II trials using HLA-mismatched related bone marrow or
unrelated umbilical cord blood grafts. Blood. 2011 Jul 14;118(2):282288. Epub 2011 Apr 28.
122
Protocol
Number
N/A
Network
publication
Number
Publication
PMCID
19
Denzen EM, Burton Santibáñez ME, Moore H, Foley A, Gersten I,
Gurgol G, Majhail NS, Spellecy R, Horowitz MM, Murphy EA. Easy-toread informed consent forms for hematopoietic cell transplantation
clinical trials. Biology of Blood and Marrow Transplantation. 2012
Feb 01;18(2):183–189. Epub 2011 Jul 30.
BMT CTN 0303
PMC Journal – In
Process
20
Keever-Taylor CA, Devine SM, Soiffer RJ, Mendizabal A, Carter S,
Pasquini MC, Hari PN, Stein A, Lazarus HM, Linker C, Goldstein SC,
Stadtmauer EA, O'Reilly RJ. Characteristics of CliniMACS(®) System
CD34-enriched T cell-depleted grafts in a multicenter trial for acute
myeloid leukemia-BMT CTN Protocol 0303. Biology of Blood and
Marrow Transplantation. 2012 May 01;18(5):690-7. Epub 2011 Aug
26.
BMT CTN 0102
PRIMARY
MANUSCRIPT
PMC3611089
[Available on
2013/3/29]
21
Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E
3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash
MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu
J, Geller NL, Horowitz MM, Giralt S, Maloney DG. Autologous
haemopoietic stem-cell transplantation followed by allogeneic or
autologous haemopoietic stem-cell transplantation in patients with
multiple myeloma (BMT CTN 0102): a Phase 3 biological assignment
trial. Lancet Oncology. 2011 Dec 01;12(13):1195-1203. Epub 2011
Sep 29.
BMT CTN 0601
PMC3618440
[Available on
2013/8/1]
22
Kamani NR, Walters MC, Carter S, Aquino V, Brochstein JA,
Chaudhury S, Eapen M, Freed BM, Grimley M, Levine JE, Logan B,
Moore T, Panepinto J, Parikh S, Pulsipher MA, Sande J, Schultz KR,
Spellman S, Shenoy S. Unrelated donor cord blood transplantation
for children with severe sickle cell disease: results of one cohort from
the Phase II study from the BMT CTN. Biology of Blood and Marrow
Transplantation. 2012 Aug 01;18(8):1265-1272. Epub 2012 Feb 16.
BMT CTN 0302
23
Levine J, Logan BR, Wu J, Alousi AM, Bolaños-Meade J, Ferrara JLM,
Ho VT, Weisdorf DJ, Paczesny S. Acute graft-versus-host disease
biomarkers measured during therapy can predict treatment
outcomes: a BMT CTN study. Blood. 2012 Apr 19;119(16):3854-3860.
Epub 2012 Mar 1.
PMC3335389
[Available on
2013/4/19]
BMT CTN 0301
PMC Journal –
In Process
24
Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty J, Adams R,
Ewell M, Leifer E, Gersten I, Carter S, Horowitz MM, Nakamura R,
Pulsipher MA, Difronzo NL, Confer D, Eapen M, Anderlini P.
Fludarabine-based conditioning for marrow transplantation from
unrelated donors in severe aplastic anemia: early results of a
cyclophosphamide dose deescalation study show life-threatening
adverse events at predefined cyclophosphamide dose
levels.Biology of Blood and Marrow Transplantation. 2012 July 01;
18(7):1007-1011. Epub 2012 Apr 30.
PMC3242929
[Available on
2013/2/1]
2012
123
Protocol
Number
BMT CTN 0704 /
CALGB 100104 /
ECOG 100104
PRIMARY
MANUSCRIPT
Number
Publication
PMCID
25
McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H,
Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS,
Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA,
Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B,
Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S,
Bressler L, Kelly M, Sexton M, Rosenbaum C, Hari P, Pasquini MC,
Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Phase III
study of lenalidomide versus placebo after HCT for multiple
myeloma. New England Journal of Medicine. 2012 May 10;
366(19):1770-1781.
BMT CTN 0303
PMC Journal –
In Process
26
Pasquini M, Devine S, Mendizabal A, Baden L, Wingard J, Lazarus H,
Appelbaum F, Keever-Taylor C, Horowitz M, Carter S, O’Reilly R,
Soiffer R. Comparative outcomes of donor graft CD34+ selection
and immune suppressive therapy as graft-versus-host disease
prophylaxis for patients with acute myeloid leukemia in complete
remission undergoing HLA-matched sibling allogeneic
hematopoietic cell transplantation. Journal of Clinical Oncology.
2012 Sep 10;30(26):3194-3201. Epub 2012 Aug 6.
BMT CTN 0201
PRIMARY
MANUSCRIPT
PMC Journal –
In Process
27
Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR,
Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G,
Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S,
McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF,
Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL; Blood
and Marrow Transplant Clinical Trials Network. Peripheral blood
stem cells versus bone marrow from unrelated donors. New
England Journal of Medicine. 2012 Oct 18;367(16):1487-1496.
BMT CTN 0302
PMC Journal –
In Process
28
Bolanos-Meade J, Wu J, Logan BR, Levine JE, Ho VT, Alousi AM,
Weisdorf DJ, Luznik L. Lymphocyte phenotype during therapy for
acute graft versus host disease: a brief report from BMT-CTN 0302.
Biology of Blood and Marrow Transplantation. 2013 Mar
01;19(3):481-485. Epub 2012 Dec 11.
BMT CTN 0401
PRIMARY
MANUSCRIPT
PMC Journal –
In Process
PMC Journal – In
Process
2013
29
Vose JM, Carter S, Burns LJ, Ayala E, Press O, Moskowitz CH,
Stadtmauer EA, Mineshi S, Ambinder RF, Fenske TS, Horowitz MM,
Fisher RI, Tomblyn M. Phase III randomized study of
rituximab/carmustine, etoposide, cytarabine, melphalan (BEAM)
compared with 131-Iodine tositumomab/BEAM with autologous
stem cell transplantation for relapsed diffuse large B-Cell
lymphoma: results from the Blood and Marrow Transplant Clinical
Trials Network (BMT CTN) 0401 trial. Journal of Clinical Oncology.
2013 Mar 11 [Epub ahead of print]
124
Number
Publication
30
Giralt S, McCarthy PL, Anderson KC, Carter SL, Richardson PG,
Rajkumar SV, Laport GG, Stadtmauer EA, Pasquini MC, Horowitz
MM. Anatomy of a successful practice-changing study: a Blood and
Marrow Transplant Clinical Trials Network-National Cancer Institute
Cooperative Group Collaboration. Biology of Blood and Marrow
Transplantation. [In press]
31
Mauskopf J, Chirila C, Graham J, Gersten I, Mullins D, Maziarz R,
Baden L, Bolanos-Meade J, Brown J, Walsh T, Horowitz M,
Kurtzberg J, Marr K and Wingard J. Cost-effectiveness analysis of
voriconazole compared With fluconazole for prevention of invasive
fungal infection in patients receiving allogeneic hematopoietic cell
transplants. American Journal Health-System Pharmacy. [In press]
125
Protocol
Number
BMT CTN 0704
/ CALGB 100104
/ ECOG 100104
BMT CTN 0101
PMCID
PMC Journal –
In Process
PMC Journal –
In Process
Attachment C2: Abstracts and Presentations
Number
Meeting/Presentation
Protocol
Number
2007
1
Pasquini M, Ewell M, Stadtmauer E, Bredeson C, Alyea E, Stockerl-Goldstein K, Krishnan
A, Shebi F, Rowley S, Maloney D, Vesole D, Horowitz M, Carter S, Geller N, Giralt S.
Biologic assignment trials in hematopoietic stem cell transplantation: baseline
characteristics of multiple myeloma patients in BMT CTN 0102 by treatment allocation
according to donor availability.
Presented: 49th Annual ASH Meeting, Atlanta, GA, December 2007
BMT CTN 0102
2
Wingard J, Carter S, Walsh T, Kurtzberg J, Small T, Gersten I, Mendizabal A, Leather H,
Confer D, Baden L, Maziarz R, Stadtmauer E, Bolaños-Meade J, Brown J, DiPersio J,
Boeckh M, Marr K. Results of a randomized, double-blind trial of fluconazole versus
voriconazole for the prevention of invasive fungal infections in 600 allogeneic blood and
marrow transplant patients.
Presented: 49th Annual ASH Meeting, Atlanta, GA, December 2007
BMT CTN 0101
2008
3
Laport G, Bredeson C, Tomblyn MR, Kahl BS, Goodman SA, Ewell M, Klein J, Horowitz
MM, Vose JM, Negrin RS. Autologous versus reduced-intensity allogeneic hematopoietic
cell transplantation for patients with follicular non-Hodgkin lymphoma beyond first
complete response or first partial response (abstract).
Presented: ASCO Annual Meeting, Chicago, IL, May-June, 2008
BMT CTN 0202
4
Alousi A, Weisdorf D, Logan B, Bolaños-Meade J, Goldstein S, Ho V, Hayes-Lattin B,
Wingard J, Horowitz M, Levine J. BMT CTN 0302, a Phase II randomized trial evaluating
etanercept, mycophenolate mofetil, denileukin diftitox and pentostatin in combination
with corticosteroids in 180 patients with newly diagnosed acute GVHD (abstract).
Presented: 50th Annual ASH Meeting, San Francisco, CA, December 2008
BMT CTN 0302
2009
5
Devine S, Soiffer R, Carter S, Pasquini M, Hari P, Devore S, Stein A, Lazarus H, Linker C,
Goldstein S, Keever-Taylor C and O’Reilly R. HLA-identical sibling-matched, CD34+
selected, T cell depleted peripheral blood stem cells following myeloablative
conditioning for first or second remission acute myeloid leukemia, results of BMT CTN
Protocol 0303.
Presented: 51st Annual ASH Meeting, New Orleans, LA, December 2009
BMT CTN 0303
2010
6
Pasquini M, Devine S, Mendizabal A, Baden L, Wingard J, Lazarus H, Appelbaum F,
Keever-Taylor C, O'Reilly R and Soiffer R. Comparative effectiveness analysis of CD34+
selected, T cell depleted HLA-matched sibling grafts on allogeneic hematopoietic cell
transplantation for patients with acute myeloid leukemia in complete remission
(poster).
Presented: BMT Tandem Meetings, Orlando, FL, February 2010
126
BMT CTN 0303
Number
Protocol
Number
7
Gurgol C, Foley A, Belt P, Denzen E, Duffy S, Gallagher C, Grodman C, Horowitz M,
Confer D, Carter S, on behalf of the BMT CTN Sponsored by NHLBI and NCI. Developing
materials for transplant centers to share BMT CTN clinical trial results with their
patients, a pilot study (poster).
Presented: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2010
N/A
Network
publication
8
Foley A, Horowitz M, Confer D, Carter S on behalf of the BMT CTN, sponsored by NHLBI
and NCI. Development of an accrual assessment tool for BMT CTN transplant trials, a
proactive approach (poster).
N/A
Network
publication
9
Pasquini M, Foley A, Carter S, Confer D, Horowitz M, Gurgol C, Giralt S, Schilsky R,
McCarthy P on behalf of the Cancer and Leukemia Group B and the Blood and Marrow
Transplant Clinical Trial Network. Maximizing accrual to transplant trials in multiple
myeloma, lessons from the BMT CTN, Eastern Cooperative Oncology Group, and Cancer
and Leukemia Group B Collaboration (poster).
BMT CTN 0704 /
CALGB 100104 /
ECOG 100104
10
Keever-Taylor C, Devine SM, Soiffer RJ, Carter SL, Pasquini MC, Hari P, Stein A, Lazarus
HM, Linker C, Goldstein S, O’Reilly RJ on behalf of the BMT CTN. Characteristics of CD34enriched products processed at multiple centers using the CliniMacs System - BMT CTN
0303.
Presented: 16th Annual International Society for Cellular Therapy Meeting, Philadelphia,
PA, May 2010
BMT CTN 0303
11
McCarthy PL, Owzar K, Anderson KC, Hofmeister CC, Hassoun H, Hurd DD, Stadtmauer
EA, Giralt S, Hars V, Linker CA. Phase III intergroup study of lenalidomide versus placebo
maintenance therapy following single autologous stem cell transplant for multiple
myeloma: BMT CTN 0704 / CALGB 100104 / ECOG 100104.
Presented: ASCO Annual Meeting, Chicago, IL, June 2010
BMT CTN 0704 /
CALGB 100104 /
ECOG 100104
12
McCarthy PL, Owzar K, Anderson K, Hofmeister CC, Hurd DD, Hassoun H, Giralt S,
Stadtmauer EA, Richardson PG, Weisdorf DJ, Vij R, Moreb JS, Callander N, Van Besien K,
Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Oazilbash MH,
Levitan D, McClune B, Hars V, Postiglione J, Jiang C, Bennett E, Barry SS, Bressler L, Kelly
M, Sexton M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM,
Linker C. Phase III intergroup study of lenalidomide versus placebo maintenance therapy
following single autologous hematopoietic stem cell transplantation for multiple
myeloma: BMT CTN 0704 / CALGB 100104 / ECOG 100104 (oral).
Presented: 52nd Annual ASH Meeting, Orlando, FL, December 2010
BMT CTN 0704 /
CALGB 100104 /
ECOG 100104
13
Krishnan A, Pasquini MC, Ewell M, Stadtmauer EA, Alyea EP, Antin JA, Comenzo RL,
Goodman S, Hari P, Negrin R, Qazilbash MH, Rowley SD, Sahebi F, Somlo G, Vesole DH,
Vogl DT, Weisdorf DJ, Geller N, Horowitz MM, Giralt S and Maloney DG. Tandem
autologous hematopoietic stem cell transplants with or without maintenance therapy
versus single autologous HCT followed by HLA matched sibling non-myeloablative
allogeneic HCT for patients with standard risk multiple myeloma: results from the BMT
CTN 0102 Trial.
127
BMT CTN 0102
Protocol
Number
Number
14
Stadtmauer EA, Krishnan A, Pasquini MC, Ewell M, Alyea EP, Antin JH, Castro-Malaspina
H, Kassim AA, Negrin R, Qazilbash MH, Rizzo JD, Rowley SD, Sahebi F, Somlo G, Vesole
DH, Vogl DT, Weisdorf DJ, Geller N, Horowitz MM, Maloney DG, Giralt S. Tandem
autologous stem cell transplants with or without maintenance therapy versus single
autologous transplant followed by HLA-matched sibling non-myeloablative allogeneic
stem cell transplant for patients with high risk multiple myeloma: Results from the BMT
CTN 0102 Trial.
BMT CTN 0102
15
Switzer GE, Harrington D, Haagenson MD, Drexler R, Foley A, Confer DL, Bishop M,
Anderlini P, Rowley SD, Leitman S, Anasetti C, Wingard Jr. Health-related quality-of-life
among adult unrelated stem cell donors: a BMT CTN randomized trial of marrow versus
stem cell donation.
BMT CTN 0201
2011
16
Fuchs EJ, Wu J, Carter S, Brunstein C, Costa L, Wingard J, Jagasia M, D’Elia J, Eapen M,
O’Donnell PV. Phase II trial of non-myeloablative conditioning and transplantation of
partially HLA-mismatched bone marrow for patients with hematologic malignancies:
results of BMT CTN Protocol #0603.
Presented: BMT Tandem Meetings, Honolulu, HI, February 2011
*Received a Best Abstract Award
BMT CTN 0603
17
Brunstein CG, Carter S, Fuchs EJ, Karanes C, Devine S, Cutler C, Ballen KK, Thompson J,
O'Donnell PV, Eapen M. Phase II trial of non-myeloablative conditioning double
umbilical cord blood transplantation from unrelated donors in patients with
hematologic malignancies: results of BMT CTN Protocol 0604.
Presented: BMT Tandem Meetings, Honolulu, HI, February 2011
BMT CTN 0604
18
Levine JE, Logan BR, Wu J, Alousi AM, Bolaños-Meade J, Ho VT, Weisdorf DJ, Paczesny S.
GVHD biomarkers measured during treatment independently predict response to
therapy and survival: a BMT CTN study.
Presented: European Group for Blood and Marrow Transplantation Congress, Paris,
France, April 2011
BMT CTN 0302
19
McCarthy P, Owzar K, Anderson K, Hofmeister C, Richardson P, Hassoun H, Stadtmauer
E, Giralt S, Hurd D, Hars V, Jiang C, Postiglione J, Bressler L, Devine S, Linker C. Phase III
intergroup study of lenalidomide versus placebo maintenance therapy following single
autologous stem cell transplant for multiple myeloma: BMT CTN 0704 / CALGB 100104 /
ECOG 100104.
Presented: 13th International Myeloma Workshop, Paris, France, May 2011
BMT CTN 0704 /
CALGB 100104 /
ECOG 100104
20
Krishnan A, Pasquini M, Logan B, Stadtmauer EA, Alyea III E, Antin J, Comenzo R,
Goodman S, Hari P, Negrin R, Qazilbash M, Rowley S, Sahebi F, Somlo G, Vesole D, Vogl
D, Weisdorf D, Wu J, Geller N, Horowitz MM, Giralt S, and Maloney D. Tandem
autologous HCT (auto-auto) versus single autologous HCT followed by HLA matched
sibling non-myeloablative allogeneic HCT (auto-allo) for patients with standard risk
multiple myeloma: results from the BMT-CTN 0102 Trial.
Poster presented: 13th International Myeloma Workshop, Paris, France, May 2011
BMT CTN 0102
128
Number
Protocol
Number
21
Hari P, Pasquini M, Logan B, Stadtmauer E, Krishnan A, Howard A, Alvi S, Harding S,
Carter S, Rajkumar V, Alyea E, Qazilbash M, LaPort G, Maloney D, Giralt S, Vesole D.
Immunoglobulin free light chain and heavy chain/light chain assays – comparison with
electrophoretic responses in multiple myeloma: results of BMT CTN Protocol #0102.
Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011
BMT CTN 0102
22
Anasetti C, Logan B, Lee SJ, Waller EK, Weisdorf D, Wingard JR, Cutler C, Westervelt P,
Woolfrey A, Couban S, Johnston L, Maziarz R, Pulsipher M, Anderlini P, Bensinger W,
Leitman S, Rowley SD, Carter SL, Horowitz MM, Confer DL. Increased incidence of
chronic graft-versus-host disease and no survival advantage with filgrastim-mobilized
peripheral blood stem cells compared to bone marrow transplants from unrelated
donors: Results of BMT CTN Protocol #0201, a Phase III prospective randomized trial.
Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011 [Plenary Session]
BMT CTN 0201
23
Waller EK, Harris WAC, Devine S, Porter DL, Mineishi S, McCarty JM, Gonzalez CE, Spitzer
TR, Krijanovski OI, Linenberger ML, Woolfrey A, Howard A, Gurgol C, Logan BR, Confer
DL, Anasetti C. Larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic
cell precursors in allogeneic Bone marrow grafts from unrelated donors are associated
with improved survival: results from BMT CTN #0201.
BMT CTN 0201
24
Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty J, Adams R, Eapen M, Ewell M,
Leifer E, Gersten I, Carter SL, Horowitz MM, Confer D, Nakamura R, Pulsipher MA,
DiFronzo N, Anderlini P. Fludarabine-based conditioning for allogeneic marrow
transplantation from unrelated donors in severe aplastic anemia: serious and
unexpected adverse events in pre-defined cyclophosphamide dose levels: results from
BMT CTN protocol #0301.
BMT CTN 0301
25
Vose JM, Carter SL, Burns L , Ayala E, Press O, Moskowitz C, Stadtmauer E, Mineshi S,
Ambinder R, Fenske T, Horowitz M, Tomblyn M. Randomized Phase III trial of 131IodineTositumomab (Bexxar)/Carmustine, Etoposide, Cytarabine, Melphalan (BEAM) versus
Rituximab/BEAM and autologous stem cell transplantation for relapsed diffuse large B
cell lymphoma: no difference in progression-free or overall survival.
BMT CTN 0401
26
Spellecy R, Denzen E, Burton Santibáñez M, Moore H, Foley A, Gersten I, Gurgol C,
Horowitz M, Majhail N, Murphy E. Informed consent: improving the form and the
process.
Presented: Public Responsibility in Medicine and Research, National Harbor, MD,
December 2011
129
N/A
Network
publication
Number
Protocol
Number
2012
27
Waller EK, Harris WA, Devine S, Porter DL, Ferrara J, McCarty JM, Gonzalez CE, Spitzer
TR, Krijanovski OI, Howard A, Gurgol C, Logan BR, Confer DL, Anasetti C. Grade III-IV
acute GVHD and treatment-related mortality are reduced among recipients of larger
numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in
allogeneic bone marrow grafts from unrelated donors: results from BMT CTN 0201.
Presented: 38th Annual European Group for Blood and Marrow Transplantation
Congress, Geneva, Switzerland, April 2012
BMT CTN 0201
28
Anderlini P, Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty JM, Adams RH, Ewell
M, Leifer E, Gersten I, Carter SL, Horowitz MM, Confer DL, Nakamura R, Pulsipher M,
DiFronzo NL, Eapen M. Fludarabine-based conditioning for allogeneic marrow
transplantation from unrelated donors in severe aplastic anaemia: serious and
unexpected adverse events in pre-defined cyclophosphamide dose levels.
Poster presented: 38th Annual European Group for Blood and Marrow Transplantation
Congress, Geneva, Switzerland, April 2012
BMT CTN 0301
29
Crann ME, Mendizabal AM, Gersten ID, and Carter SL. Adverse event reporting for
hematopoietic cell transplantation.
Poster presented: Society for Clinical Trials Annual Meeting, Miami, FL, May 2012
30
Anasetti C, Logan B, Lee SJ, Waller EK, Weisdorf D, Wingard JR, Cutler C, Westervelt P,
Woolfrey A, Couban S, Johnston L, Maziarz R, Pulsipher M, Anderlini P, Bensinger W,
Leitman S, Rowley SD, Carter SL, Horowitz MM, Confer DL. Increased incidence of
chronic graft-versus-host disease and no survival advantage with filgrastim-mobilized
peripheral blood stem cells compared to bone marrow transplants from unrelated
donors: results of BMT CTN Protocol #0201, a Phase III prospective randomized trial.
Presented: ASCO Annual Meeting (ASCO/ASH Joint Session), Chicago, IL, June 2012
BMT CTN 0201
31
Cutler C, Logan BR, Nakamura R, Johnston L, Choi SW, Porter DL, Hogan WJ, Pasquini
MC, MacMillan ML, Wingard JR, Waller EK, Grupp SA,McCarthy PL, Wu J, Hu Z, Carter
SL, Horowitz MM, Antin JH. Tacrolimus/sirolimus vs. tacrolimus/methotrexate for
graft-vs.-host disease prophylaxis after HLA-matched, related donor hematopoietic
stem cell transplantation: results of Bone Marrow Transplant Clinical Trials Network
0402.
Presented: 54th Annual ASH Annual Meeting, Atlanta, GA, December 2012
BMT CTN 0402
32
Wagner JE, Eapen M, Carter SL, Haut P, Perez E, Schultz K, Thompson J, Wall D,
Kurtzberg J. No survival advantage after double umbilical cord blood (UCB) compared
to single UCB transplant in children with hematological malignancy: results of the
Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501) randomized
trial.
BMT CTN 0501
130
N/A
Network
publication
Number
33
Devine SM, Owzar K, Blum W, DeAngelo DJ, Stone RM, Hsu JW, Champlin R, Chen YA,
Vij R, Slack JL, Soiffer RJ, Larson RA, Shea TC, Hars V, Bennett E, Spangle S, Giralt SA,
Carter SL, Horowitz MM, Linker C, Alyea EP. A Phase II study of allogeneic
transplantation for older patients with AML in first complete remission using a
reduced intensity conditioning regimen: results from CALGB 100103/BMT CTN 0502.
Protocol
Number
BMT CTN 0502 /
CALGB 100103
2013
34
Yanik D, Ho VT, Horowitz MM, Weisdorf DJ, Logan BR, Wu J , Soiffer RJ, Wingard JR,
Levine JE, Ferrara JL, Giralt SA, White E, Carter SL, DiFronzo N, Cooke KR. Randomized,
double blind, placebo-controlled trial of a TNF inhibitor (etanercept) for the treatment
of idiopathic pneumonia syndrome (IPS) after allogeneic stem cell transplant (SCT), a
Blood and Marrow Transplant Clinical Trials Network (BMT CTN) study.
Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013
BMT CTN 0403
35
Kurtzberg J, Carter SL, Mendizabal A, Wall DA, Schultz KR, Kernan NA, Eapen M,
Wagner JE. Superior survival after single unit umbilical cord blood transplantation
(UCBT) in children with hematological malignancies treated on Blood and Marrow
Transplant Clinical Trials Network (BMT CTN) 0501 relative to the cord blood
transplantation (COBLT).
BMT CTN 0501
36
Bolaños-Meade J , Logan BR, Alousi AM, Antin JH, Barowski K, Carter SL, Hexner EO,
Horowitz MM, Levine JE, MacMillan ML, Martin PJ, Nakamura R, Pasquini MC,
Weisdorf DJ, Westervelt P, Ho VT. A multi-center, randomized, double blind, Phase III
clinical trial comparing steroids/placebo vs. steroids/mycophenolate mofetil as initial
therapy for acute graft-versus-host disease, Blood and Marrow Transplant Clinical
Trials Network Study 0802.
BMT CTN 0802
37
McCarthy P, Owzar K, Hofmeister C, Richardson P, Hassoun H, Stadtmauer E, Giralt S,
Hurd D, Qazilbash M, McClune B, Pasquini M, Hars V, Jiang C, Postiglione J, Kelly M,
Bressler L, Devine S, Anderson K, Linker C. Analysis of overall survival (OS) in the
context of cross-over from placebo to lenalidomide and the incidence of second
primary malignancies (SPM) in the Phase III study of lenalidomide versus placebo
maintenance therapy following autologous stem cell transplant (ASCT) for multiple
myeloma (MM), CALGB (Alliance) ECOG, BMT CTN 100104.
To be presented: 14th International Myeloma Workshop, Kyoto, Japan April 2013
BMT CTN 0704 /
CALGB 100104 /
ECOG 100104
131
Attachment D: Committee Rosters
Committee Chairs are bolded.
Attachment D1: Steering Committee
Core Center Principal Investigators
Center
Claudio Anasetti, MD
H. Lee Moffitt Cancer Center, Tampa, FL
Joseph Antin, MD
Dana-Farber Cancer Institute, Boston, MA
*Frederick Appelbaum, MD (Chair-Elect)
Fred Hutchinson Cancer Research Center, Seattle, WA
Asad Bashey, MD
Northside Hospital, Atlanta, GA
Catherine Bollard, MD
Baylor College of Medicine, Houston, TX
Richard Champlin, MD
MD Anderson Cancer Center, Houston, TX
Steven Devine, MD (Vice-Chair)
Ohio State University, Columbus, OH
James Ferrara, MD
University of Michigan, Ann Arbor, MI
Stephen Forman, MD
City of Hope National Medical Center, Duarte, CA
Sergio Giralt, MD
Memorial Sloan-Kettering Cancer Center, New York, NY
Richard Jones, MD
Johns Hopkins University, Baltimore, MD
Joanne Kurtzberg, MD
Duke University, Durham, NC
*Ginna Laport, MD (Chair)
Stanford University, Stanford, CA
Hillard Lazarus, MD
Case Western Reserve University, Cleveland, OH
Michael Pulsipher, MD
University of Utah, Salt Lake City, UT
Edward Stadtmauer, MD
University of Pennsylvania, PA
Julie Vose, MD
University of Nebraska, Omaha, NE
Daniel Weisdorf, MD
University of Minnesota, Fairfield, MN
Peter Westervelt, MD
Washington University, St. Louis, MO
John Wingard, MD
University of Florida, Gainesville, FL
Cooperative Group Representatives
Alliance: Steven Devine, MD
SWOG: Patrick Stiff, MD
COG: Stephan Grupp, MD, PhD
ECOG: Hillard Lazarus, MD
Center
Ohio State University, Columbus, OH
Loyola University, Chicago, IL
Children’s Hospital of Philadelphia, PA
Case Western Reserve University, Cleveland, OH
Affiliate Center Representatives
Henry Fung, MD
Parameswaran Hari, MD, MS
Voravit Ratanatharathorn, MD
Center
Rush University, Chicago, IL
Medical College of Wisconsin, Milwaukee, WI
Karmanos Cancer Institute, Detroit, MI
132
DCC Principal Investigators
*Shelly Carter, ScD (Co-PI)
*Dennis Confer, MD (Co-PI)
*Mary Horowitz, MD, MS (PI)
Organization
The EMMES Corporation, Rockville, MD
NMDP, Minneapolis, MN
CIBMTR, Milwaukee, WI
NHLBI and NCI Project Officers
*Nancy DiFronzo, PhD
*William Merritt, PhD
*Elizabeth Wagner, MPH
*Roy Wu, PhD
Organization
National Heart, Lung, and Blood Institute, NIH, Bethesda, MD
National Cancer Institute, NIH, Bethesda, MD
National Heart, Lung, and Blood Institute, NIH, Bethesda, MD
National Cancer Institute, NIH, Bethesda, MD
The Executive Committee is a subcommittee of the Steering Committee. Individuals who serve on the Executive
Committee are identified by an asterisk (*).
133
Attachment D2: Publications, Abstracts & Presentations Committee
Name
Organization
Term
Expiration
Joseph Antin
([email protected])
Dana-Farber Cancer Institute
Boston, MA
2015
Edward Stadtmauer (co-chair)
([email protected])
University of Pennsylvania
Philadelphia, PA
2015
Mark Litzow
([email protected])
Mayo Clinic
Rochester, MN
2014
Peter Westervelt
([email protected])
Washington University School of Medicine
St. Louis, MO
2014
Mort Cowan
([email protected])
University of California San Francisco Medical Center
San Francisco, CA
2013
John Wingard (co-chair)
([email protected])
Shands HealthCare & University of Florida
Gainesville, FL
2013
Shelly Carter (ex-officio)
([email protected])
Rockville, MD
-
Dennis Confer (ex-officio)
([email protected])
NMDP
Minneapolis, MN
-
Nancy Geller (ex-officio)
([email protected])
National Heart, Lung, and Blood Institute, NIH
Bethesda, MD
-
Mary Horowitz (ex-officio)
([email protected])
CIBMTR
Milwaukee, WI
-
Nancy Poland (ex-officio)
([email protected])
CIBMTR
Minneapolis, MN
-
Roy Wu (ex-officio)
([email protected])
National Cancer Institute, NIH
Bethesda, MD
-
134
Attachment D3: Biomarkers Committee
Name
Organization
Term
Expiration
Edward Agura
([email protected])
Baylor University
Dallas, TX
2015
Philip McCarthy (chair)
([email protected])
Roswell Park Cancer Institute
Buffalo, NY
2015
Joseph Pidala
([email protected])
Tampa, FL
2015
Jerald Radich
([email protected])
Seattle, WA
2014
James Ferrara
([email protected])
University of Michigan Medical School
Ann Arbor, MI
2013
Marcel van de Brink
([email protected])
New York, NY
2013
([email protected])
Rockville, MD
-
([email protected])
NMDP
Minneapolis, MN
-
Nancy DiFronzo (ex-officio)
([email protected])
Bethesda, MD
-
John Hansen (ex-officio)
([email protected] )
Seattle, WA
-
Alan Howard (ex-officio)
([email protected])
CIBMTR
Minneapolis, MN
-
John Levine (ex-officio)
([email protected])
Ann Arbor, MI
-
William Merritt (ex-officio)
([email protected])
National Cancer Institute, NIH
Bethesda, MD
-
Marcelo Pasquini (ex-officio)
([email protected])
CIBMTR
Milwaukee, WI
-
135
Attachment D4: Clinical Research Associates Committee
Name
Organization
Term
Expiration
Stacey Brown
([email protected])
Northside Hospital
Atlanta, GA
2015
Michael Gates
([email protected])
All Children’s Hospital
St. Petersburg, FL
2015
Romelia May
([email protected])
Baylor College
Houston, TX
2015
Alex Stentz
([email protected])
Oregon Health Sciences University
Portland, OR
2015
Shawnda Tench
([email protected])
Cleveland Clinic
Cleveland, OH
2015
Terry Furlong
([email protected])
Seattle, WA
2014
Gwen Konsler
([email protected])
University of North Carolina at Chapel Hill School of Medicine
Chapel Hill, NC
2014
Andrea Ortega
([email protected])
Hackensack University Medical Center
Hackensack, NJ
2014
Laura Hancock
([email protected])
Cure Search for Children’s Cancer
Bethesda, MD
2013
Bertha Villa
([email protected])
Stanford University
Palo Alto, CA
2013
([email protected])
Rockville, MD
-
Cynthia Couture (ex-officio)
([email protected])
Rockville, MD
-
([email protected])
Bethesda, MD
-
Mary Magliocco (chair) (ex-officio)
([email protected])
Rockville, MD
-
Connie Weaver (ex-officio)
([email protected])
Rockville, MD
-
136
Attachment D5: Pharmacy Committee
Name
Organization
Term
Expiration
John Rogosheske (chair)
([email protected])
Fairview Health Services
Minneapolis, MN
2015
Jamie Shapiro
([email protected])
Tampa, FL
2015
Kristan Augustin
([email protected])
Barnes-Jewish Hospital
St. Louis, MO
2014
Celalettin Ustun
([email protected])
University of Minnesota Medical Center
Minneapolis, MN
2014
Alison Gulbis
([email protected])
University of Texas MD Anderson Cancer Center
Houston, TX
2013
Ashley Morris
([email protected])
Duke University
Durham, NC
2013
([email protected])
NMDP
Minneapolis, MN
-
Iris Gersten (ex-officio)
([email protected])
Rockville, MD
-
137
Attachment D6: Special Populations (Pediatrics/Human Subjects) Committee
Name
Organization
Term
Expiration
Partow Kebriaei
([email protected])
M.D. Anderson Cancer Center
Houston, TX
2015
Carrie Kitko
([email protected])
Ann Arbor, MI
2015
Mark Walters
([email protected])
Children’s Hospital and Research Center Oakland
Oakland, CA
2015
John Horan
([email protected])
Children’s Healthcare of Atlanta
Atlanta, GA
2014
Michael Nieder
([email protected])
H Lee Moffitt Cancer Center
Tampa, FL
2014
William Wood
([email protected])
University of North Carolina at Chapel Hill School of Medicine
Chapel Hill, NC
2014
Ginna Laport (non-peds)
([email protected])
Stanford University School of Medicine
Palo Alto, CA
2013
Alison Loren
([email protected])
University of Pennsylvania Medical Center
Philadelphia, PA
2013
Michael Pulsipher (chair)
([email protected])
University of Utah Primary Children’s Medical Center
Salt Lake City, UT
2013
([email protected])
Rockville, MD
-
([email protected])
Bethesda, MD
-
([email protected])
CIBMTR
Milwaukee, WI
-
Brent Logan (ex-officio)
([email protected])
CIBMTR
Milwaukee, WI
-
138
Attachment D7: Toxicity and Supportive Care Committee
Name
Organization
Term
Expiration
Richard Maziarz (chair)
([email protected])
Oregon Health Sciences University
Portland, OR
2015
John McCarty
([email protected])
Virginia Commonwealth University
Richmond, VA
2015
Angela Smith
([email protected])
Minneapolis, MN
2015
Kenneth Cooke
University Hospitals Case Medical Center
([email protected])
Cleveland, OH
2014
Jeffrey Schriber
([email protected])
Phoenix, AZ
2014
Mohamed Sorror
([email protected])
Seattle, WA
2014
([email protected])
Johns Hopkins Hospital
Baltimore, MD
2013
David Porter
([email protected])
University of Pennsyvania Health System
Philadelphia, PA
2013
Trudy Small
([email protected])
New York, NY
2013
([email protected])
Rockville, MD
-
([email protected])
CIBMTR
Milwaukee, WI
-
139
Attachment E: Center Performance Report
CENTER PERFORMANCE REPORT
Center Name:
Date of Evaluation: January 1, 2013
ADMINISTRATIVE ACTIVITY
Items
# Protocol
N
%
Protocol Chairs or Co-chairs
3
Protocol Team members

Protocol Team conf call participation2 in 2012
/=%
Steering Comm Chair/Chair-elect/Past-chair in 2012

%
Steering Comm meeting/call participation in 2012

%
Notes:
1
Total N for all sites and all protocols.
2
Percentages for call are calculated based on the protocols that the center is one of the chairs/members.
3
― means not applicable or not calculated.
Protocol Team Conference Call Participation in 2012
Protocol
Total # Calls
# Calls Participated (%)
0301
0401
0402
Total
140
Total N1
ACTIVATION AND ENROLLMENT
PROTOCOL #
Protocol
activated
# Accrual in
2012
Projected
Accrual in 20121
(%2)
0301
0402
0403
0501
0601
0701
0702
0801
0802
0803
0804
0805
141
# Days to
consent preview1
# Days to
activation
# Days from
activation to 1st
patient
PROTOCOL #
Protocol
activated
# Accrual in
2012
Projected
Accrual in 20121
(%2)
# Days to
consent preview1
# Days to
activation
N_Total=
(/=%)
[85%]
Median_Overall=
Median_Recent=
[56]
Median_Overall=
Median_Recent=
[180]
# Days from
activation to 1st
patient
0901
0902
0903
1101
Total/Overall
N_Total=
N_Recent=
[4]
N_Total=
Median_Overall=
Median_Recent=
[56]
Notes:
1
Protocols that have closed accrual before Jan 1, 2011, are not included in this table.
2
% is the actual accrual total over projected accrual total (including only protocols “activated”). If projected accrual number not available, the actual accrual number
was used as projected number.
3
N_Recent means N only counts the protocols opened within the preceding 4 years (the evaluated year plus 3 previous years).
Median_Recent means median only counts the protocols opened within the preceding 4 years.
4
5
 for row “Protocol activated” means site is not participating the study.  for other rows mean not activated yet or not applicable or information not
available.
Targets are in “[ ]”.
142
DATA QUALITY
PROTOCOL #
# Accrual in
total
Data audit error
rate (%)
# Protocol deviations in 2012
(% of enrolled patients)
0102
0201
0301
0303
0401
0402
0403
0501
0601
0603
0604
0701
0702
0801
0802
143
# Required
forms
# Forms > 30
days overdue
Forms > 30 days
overdue/Patient
PROTOCOL #
# Accrual in
total
Data audit error
rate (%)
# Protocol deviations in 2012
(% of enrolled patients)
# Required
forms
# Forms > 30
days overdue
Forms > 30 days
overdue/Patient
0803
0901
0902
0903
1101
Total/Overall
[2%]
(%)
[2%]
[5]
Notes:
1
Protocols that have finished following up patients before Jan 1, 2011, are not included in this table. Protocols that EMMES do not monitor data quality are not
included.
2
 for row “# Accrual” means site is not participating the study or not activated yet.  for row “Data audit error rate” means there were no data audit performed
within the preceding 3 years.  for other rows means not applicable due to no patients.
3
Targets are in “[ ]”.
CIBMTR REPORT FORM COMPLIANCE
# BMT CTN Patients
# Patients Registered with CIBMTR (%)
# CIBMTR Report Forms Due
(%)
# CIBMTR Report Forms Received (%)
(%)
144
LABORATORY EVALUATION COMPLIANCE
Protocol #
Lab Compliance
0102
0201
0401
0402
0403
0501
0601
0701
0702
0801
0802
0803
0901
Center Overall Evaluation
Annual Center Performance Report Rating
Note: AC means acceptable. MA means marginally acceptable. NA means not acceptable.
145
CENTER PERFORMANCE RATING
Score
Administrative
Accrual
Activation and Enrollment
Data Quality
Laboratory Compliance
Overall Assessment
146
Rating
Attachment F: Center Performance Rating
Administrative Activity
Accrual
max=10 points
Outstanding (10 points)
Holds Steering Committee Chair, Past-Chair or Chair- Elect position
OR
Protocol Team Chair + > 70% of team calls participation
Acceptable (3-9 points)
% Call Participation × 10
Needs Improvement (0 points)
Attends < 33% of Protocol Team calls
max=60 points
Activation and Enrollment
max=10 points
 # protocols activated within preceding 4 years [4]
 # days to consent preview [56]
Accrues more than 24 patients and meets ≥ 100% of projected
accrual
OR
Enrolls > 48 patients
Acceptable (40-59 points)
Score = (Actual/Projected) x 60 then adjust for maximum
For centers enrolling 20 or more patients, can get a maximum
score of 60; for centers enrolling < 20 patients, can only get a
maximum of 45 points even if meeting or exceeding projections
Needs Improvement
(<40 points)
Score < 40 points
For centers enrolling < 18 patients, can only get a maximum of 10
points even if meeting or exceeding projections
Meets 4 of 4 metrics
Acceptable (5 points)
Meets 2-3 of 4 metrics
Meets < 2 of 4 metrics
 # days to activation [180]
 # days activation to 1st patient [56]
Data Quality
 Data audit error rate [2%]
max=10 points Outstanding (10 points)
 % protocol deviations [2%]
Meets 4 of 4 metrics
Acceptable (5 points)
Meets 2-3 of 4 metrics
Meets < 2 of 4 metrics
 Forms >30 days past due per patient [5]
 CIBMTR form compliance [90%]
147
OS
 Average compliance percentage for all
participating protocols
Acceptable (3.0-8.0 points)
AA - Above Average 7.5; AC - Acceptable 5.0
 Evaluated by Alan Howard
Needs Improvement
(0-3 points)
UN – Unacceptable; MA - Marginally Acceptable 2.5
Outstanding
> 90 points
Acceptable
60 – 90 points
Needs Improvement
< 60 points; center required to submit action plan
Laboratory Compliance
Overall Assessment
max=10 points
max=100 points
148
Attachment G: Total Accrual by Month
Attachment G: Total Accrual by Month
149
Attachment H: Accrual Plan Assessment
<CTN #>: <CTN Study Short Name>
PI(s):
Coordinator:
Total accrual:
Accrual period:
Anticipated study activation date:
Number participating BMT CTN core sites:
Projected BMT CTN core site annual accrual:
Optimal number of sites:
Number of affiliate sites to recruit:
Identified affiliate sites based on CIBMTR registry data:
Cooperative or special interest group collaboration:
Cooperative/special interest group contacts:
Anticipated accrual barriers:
1.
2.
3.
Competing protocols:
Competing treatment preference/bias:
Recruitment focus:
Participating sites
Patient
Referring MD
Yes / No
Yes / No
Yes / No
Via coop/special interest group Yes / No
Other:
Yes / No
Associated conferences/meetings:
Additional notes:
150
Attachment H: Accrual Plan Assessment
Attachment I: Review Checklist
Protocol # _____________
BMT CTN Reviewer Checklist
* Please provide an explanation/comments for all questions answered “NO”
I.
Background and Rationale
1. The background information included in this protocol is up to date, complete
and relevant to the study.
2. The objective of this trial is clearly stated in the background.
3. The protocol synopsis is consistent with the information in the protocol.
4. Comments
II. Study Design
1. Eligibility is inclusive and will not lead to slow accrual.
2. Inclusion Criteria-Comments:
Rating Scale
YES
NO
YES
YES
NO
NO
YES
NO
YES
YES
NO
NO
YES
NO
YES
NO
3. Exclusion Criteria-Comments:
4. The description of the study treatment is unambiguous and sufficiently detailed.
5. The description of the study treatment will not cause undue conflicts with institutional
guidelines for supportive care.
6. The study treatment and procedures are appropriately described.
III. Study Endpoints:
1. Are there any concerns with the primary endpoints of the study?
If yes, please explain:
151
2. Are there any concerns with the secondary endpoints of the study?
IV. Patient Evaluation
1. The patient evaluations are clear, easy to follow and include tests that are standard
of care and will not likely result in an excessive reporting burden.
2. Please list any evaluations that you think could be omitted without compromising the
integrity of the study:
V. Statistical Considerations
1. Sample Size-Comments
2. Power Calculations-Comments
3. Stopping Guidelines-Comments
152
YES
NO
YES
NO
4. General Statistical Considerations-Comments
VI. Informed Consent
1. The Informed Consent is written at a 6th grade reading level.
2. The Informed Consent is concise and comprehensible.
3. The Informed Consent clearly outlines the risks associated with the trial.
VII. Ancillary Studies
1. Do you have any issues about the type of ancillary studies that
are being requested? If yes, please explain:
2. Do you have any issues with the frequency of which the ancillary
studies are being requested? If yes, please explain:
VIII.Overall Assessment of Protocol
1. This trial is ready for PRC submission and does not require any additional revisions.
2. Are there any additional issues related to this protocol that need to be addressed?
153
YES
YES
YES
NO
NO
NO
YES
NO
YES
NO
YES
YES
NO
NO
IX. Participation
Would you consider participating in this study? If not, please explain why.
YES
X. Additional Comments
Name and date of the person completing this form ____________________________
PLEASE PRINT
154
NO
Attachment J: Terms and Abbreviations
Term /
Abbreviation
AIDS
ALL
AML
ASCO
ASH
BEAM
BMT
BMT CTN
acquired immunodeficiency syndrome
acute lymphoblastic leukemia
acute myelogenous leukemia
American Society of Clinical oncology
American Society of Hematology
carmustine (BCNU), etoposide, cytarabine, and melphalan
bone marrow transplant / transplantation
Blood and Marrow Transplant Clinical Trials Network (also “the Network”)
CALGB
Cancer and Acute Leukemia Group B (member Alliance for Clinical Trials in Oncology)
CBMTG
CBU
CIBMTR
CIR
CLL
CNI
COG
CR
CTCAE
CTSU
CVAD
DCC
DSMB
EBMT
ECOG
ECP
FACT
FDA
G-CSF
GVHD
HAART
HCT
HIV
HLA
IDE
IND
IPS
IRB
MCW
MDS
Canadian Blood and Marrow Transplant Group
cord blood unit
Center for International Blood and Marrow Transplant Research
CIBMTR Immunobiology Research
chronic lymphocytic leukemia
calcineurin inhibitor
Children’s Oncology Group
complete remission
common terminology criteria for adverse events
Cancer Trials Support Unit
cyclophosphamide, vincristine, adriamycin and dexamethasone
Data and Coordinating Center
Data and Safety Monitoring Board
European Group for Blood and Marrow Transplantation
Eastern Cooperative Oncology Group
extracorporeal photophoresis
Foundation for the Accreditation of Cellular Therapy
Food and Drug Administration
granulocyte-colony stimulating factor
graft-versus-host disease
highly-active antiretroviral therapy
hematopoietic stem cell transplantation
human immunodeficiency virus
human leukocyte antigen
investigational new device
investigational new drug
idiopathic pneumonia syndrome
Institutional Review Board
Medical College of Wisconsin
myelodysplastic syndrome
Definition
155
Term /
Abbreviation
NCI
NHL
NHLBI
NIAID
NIH
NMDP
PBMC
PBMTC
PBSC
PFS
PI
PRC
RIC
SCD
SCURT
National Cancer Institute
non-Hodgkin lymphoma
National Heart, Lung, and Blood Institute
National Institute of Allergy and Infectious Diseases
National Institutes of Health
National Marrow Donor Program
peripheral blood mononuclear cell
Pediatric Blood and Marrow Transplant Consortium
peripheral blood stem cell
progression-free survival
principal investigator
protocol review committee
reduced-intensity conditioning
sickle cell disease
Sickle Cell Unrelated Transplantation; BMT CTN Protocol 0601
STaMINA
Stem Cell Transplantation for Multiple Myeloma Incorporating Novel Agents; BMT CTN Protocol 0702
TCD
TNF
Tregs
TRM
UCBT
T cell depletion
tumor necrosis factor
regulator T cells
transplant-related mortality
umbilical cord blood transplantation
Definition
156

PROGRESS REPORT JUNE 2013

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