CLL2O Protokoll der DCLLSG

Transcription

CLL2O Protocol
V. 1.1 / 25.04.2007
Page 1 of 60
A prospective, multi-center phase II study of subcutaneous alemtuzumab
combined with oral dexamethasone, followed by alemtuzumab maintenance
or allogeneic stem-cell transplantation, in chronic lymphocytic leukemia
which is associated with 17p deletion or is refractory to fludarabine
– CLL2O Protocol of the German CLL Study Group (GCLLSG) –
Deutsche CLL Studiengruppe (DCLLSG)
in cooperation with the French CLL Study Group
and the European Research Initiative on CLL (ERIC)
EudraCT number 2007-003099-20
Protocol committee
R. Busch, Munich
B. Cazin, Lille
F. Cymbalista, Bobigny
A. Delmer, Reims
H. Döhner, Ulm
P. Dreger, Heidelberg
U. Dührsen, Essen
H. Einsele, Würzburg
B. Emmerich, Munich
J. Finke, Freiburg
A. Ganser, Hannover
M. Hallek, Cologne
M. Hensel, Heidelberg
U. Jäger, Vienna
L. Kanz, Tübingen
M. Kneba, Kiel
E. Lengfelder, Mannheim
V. Levy, Paris
M. Michallet, Lyon
C. Peschel, Munich
M. Pfreundschuh, Homburg
R. Porcher, Paris
S. Raynaud, Nice
M. Ritgen, Kiel
J. Schetelig, Dresden
S. Stilgenbauer, Ulm
L. Trümper, Göttingen
L. Uharek, Berlin
C. Wendtner, Cologne
M. Wilhelm, Nürnberg
Sponsor: Universitätsklinikum Ulm (Ulm University Hospital, Ulm, Germany), represented
by the Vorsitzende des Klinikumsvorstandes (Chairman of the board)
Coordinating investigator, Leiter der
klinischen Prüfung acc. to German law
Prof. Dr. S. Stilgenbauer
Universitätsklinikum Ulm, Klinik für Innere
Medizin III, Robert-Koch-Str. 8,
D–89081 Ulm
Tel.: +49 / 731 / 500-45901 or –45911
Fax: +49 / 731 / 500-45905 or –45915
E-mail: [email protected]
Central study office of the GCLLSG
Universitätsklinikum Köln
Klinikum der Universität zu Köln, Klinik I
für Innere Medizin
D–50924 Köln
Tel.: +49 / 221 / 478-3988
Fax: +49 / 221 / 478-86886
Home page: http://www.dcllsg.de
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CLL2O Protocol (EudraCT 2007-003099-20)
V. 1.1 / 25.04.2007
Coordinating Investigator (France)
Pr. Alain Delmer
Hématologie Clinique
CHU Robert-Debre
Avenue du General-Koenig
F-51092 Reims
Page 2 of 60
Reference laboratory for serum markers
Klinikum Großhadern
Institut für Klinische Chemie
CLL-Studien
Marchioninistr. 15
D-81377 München
Pr. Florence Cymbalista
Service d'Hématologie Biologique
Hopital Avicenne
125 rue de Stalingrad
F-93009 Bobigny Cedex
Reference laboratory for MRD
Dr. M. Ritgen, Dr. S. Böttcher, Prof. Dr. Dr.
M. Kneba
Universitätsklinikum Schleswig-Holstein,
Wiss. Labor/Molekulargenetik,
II. Medizinische Klinik, Chemnitzstr. 33,
D–24116 Kiel
Tel: +49 / 431 / 1697-1265 or –5231
Fax: +49 / 431 / 1697-1264
Biometry
Dipl.-Math. R. Busch
Institut für Medizinische Statistik und
Epidemiologie der Technischen Universität
Ismaninger Str. 22
D–81675 München
Monitoring and Data Management
Dr. Stefan Ibach, Dr. Axel Hinke
WiSP Wissenschaftlicher Service Pharma
GmbH
Karl-Benz-Str. 1
D–40764 Langenfeld
Reference laboratory for genetics
Prof. Dr. S. Stilgenbauer, Prof. Dr. H. Döhner
Universitätsklinikum Ulm, Labor für
Zytogenetik und molekulare Diagnostik,
Klinik für Innere Medizin III
Robert-Koch-Str. 8,
D–89081 Ulm
Tel.: +49 / 731 / 500-45810 or –45888
Fax: +49 / 731 / 500-45905 or –45915
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SIGNATURE PAGE
GCLLSG Protocol: CLL2O
EudraCT number 2007-003099-20
Title: A prospective, multi-center Phase II study of subcutaneous alemtuzumab combined
with oral dexamethasone, followed by alemtuzumab maintenance or allogeneic stemcell transplantation, in chronic lymphocytic leukemia which is associated with 17p
deletion or is refractory to fludarabine
Coordinating investigator, Leiter der klinischen Prüfung:
Signature:
Date signed:
Sponsor: Universitätsklinikum Ulm (Ulm University Hospital, Ulm, Germany), represented
by the Vorsitzende des Klinikumsvorstandes (Chairman of the board)
Prof. Dr. R. Marre
Signature:
Date signed:
Study statistician:
Dipl.-Math. R. Busch, Dr. Axel Hinke
Signatures:
________________________
________________________
Date signed:
________________________
________________________
DATE OF PROTOCOL: ……………………..
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TABLE OF CONTENTS
1. FLOW CHART AND STUDY SCHEDULE ..................................................................... 9
1.1 Flow chart ................................................................................................................... 9
1.2 Schedule of assessments and procedures.................................................................. 10
2. SYNOPSIS ........................................................................................................................ 14
3. INTRODUCTION AND BACKGROUND...................................................................... 16
3.1
3.2
3.3
3.4
3.5
3.6
3.7
Chronic lymphocytic leukemia (CLL)...................................................................... 16
Therapy of CLL with fludarabine and fludarabine combinations ............................ 17
Alemtuzumab in fludarabine-refractory CLL........................................................... 17
Subcutaneous administration of alemtuzumab ......................................................... 17
Combination therapy with alemtuzumab .................................................................. 19
Maintenance therapy with alemtuzumab .................................................................. 19
Safety profile of alemtuzumab.................................................................................. 19
3.7.1 Hematological side effects ............................................................................. 19
3.7.2 Infection ......................................................................................................... 20
3.8 Results from recent DCLLSG trials.......................................................................... 21
3.8.1 Subcutaneous alemtuzumab in fludarabine-refractory CLL (CLL2H Study) 21
3.8.2 Treatment failure of 17p- CLL after fludarabine or fludarabine plus
cyclophosphamide (CLL4 Study) .................................................................. 22
4. RATIONALE .................................................................................................................... 24
5. STUDY DESIGN AND OBJECTIVES............................................................................ 24
5.1 Study design and time schedule................................................................................ 24
5.2 Primary objectives .................................................................................................... 26
5.3 Secondary objectives ................................................................................................ 26
6. PATIENTS ........................................................................................................................ 26
6.1 Inclusion criteria ....................................................................................................... 26
6.2 Exclusion criteria ...................................................................................................... 27
6.3 Registration of patients ............................................................................................. 27
7. TREATMENT PLAN ....................................................................................................... 27
7.1
7.2
7.3
7.4
7.5
7.6
7.7
7.8
7.9
7.10
7.11
General instructions .................................................................................................. 27
Summary of study treatment and procedures ........................................................... 28
Treatment with alemtuzumab ................................................................................... 30
Premedication ........................................................................................................... 30
Infection prophylaxis and treatment of infections .................................................... 30
CMV reactivation and CMV disease ........................................................................ 31
Hematopoietic insufficiency, growth factors, transfusions....................................... 32
Duration and interruption of alemtuzumab therapy.................................................. 32
Therapy after treatment failure (PD)......................................................................... 33
Therapy after remission or stable disease (CR, PR or SD)....................................... 33
Interruption/termination of therapy .......................................................................... 33
8. STUDY ASSESSMENTS................................................................................................. 34
8.1
8.2
8.3
8.4
Screening .................................................................................................................. 34
Assessment in Cycle 1 .............................................................................................. 35
4
8.5
8.6
8.7
8.8
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Treatment and assessment in the maintenance phase ............................................... 37
Concluding examination ........................................................................................... 38
Follow-up contact ..................................................................................................... 39
Laboratory tests......................................................................................................... 40
8.8.1 Locally conducted laboratory tests ................................................................ 40
8.8.2 Centrally conducted laboratory tests.............................................................. 40
8.8.2.1
8.8.2.2
8.8.2.3
Serum markers thymidine kinase, β-2-microglobulin
Genetic tests
MRD diagnosis (quantitative CDR3 PCR, FACS)
40
41
41
8.8.3 Dispatch of samples to the central laboratories ............................................. 41
9. CHARACTERISTICS OF ALEMTUZUMAB ................................................................ 42
9.1 Composition of alemtuzumab ................................................................................... 42
9.2 Method of administration.......................................................................................... 42
9.3 Storage ...................................................................................................................... 42
10. SAFETY ASPECTS OF THE STUDY ............................................................................ 43
10.1 Monitoring the progress of the trial and the safety of patients ................................. 43
10.2 Reporting of adverse events...................................................................................... 43
10.3 Reporting of serious adverse events ......................................................................... 43
10.3.1 Definition ....................................................................................................... 43
10.4 Termination of the study........................................................................................... 45
11. DATA MANAGEMENT, EVALUATION UND STATISTICS ..................................... 45
11.1 Data Management ..................................................................................................... 45
11.2 Statistical aspects ...................................................................................................... 45
11.2.1 General design................................................................................................ 45
11.2.2 Sample-size estimate...................................................................................... 45
11.2.3 Evaluation categories of patients ................................................................... 48
11.2.4 Definition and assessment of efficacy endpoints........................................... 48
11.2.5 Statistical methods ......................................................................................... 49
11.2.6 Interim and final analyses .............................................................................. 49
12. STUDY DOCUMENTATION, ARCHIVING AND QUALITY
ASSURANCE ................................................................................................................... 50
12.1 Documentation and information flow....................................................................... 50
12.2 Data archiving........................................................................................................... 51
12.3 Quality assurance ...................................................................................................... 51
12.3.1 Standardization............................................................................................... 51
12.3.2 Monitoring / source data verification............................................................. 51
12.3.3 Audits ............................................................................................................. 52
13. PROTOCOL AMENDMENTS......................................................................................... 52
14. ETHICAL AND LEGAL REQUIREMENTS .................................................................. 53
14.1
14.2
14.3
14.4
14.5
14.6
14.7
14.8
14.9
General requirements and agreements ...................................................................... 53
Declaration of Helsinki ............................................................................................. 53
Informed consent of the patient ................................................................................ 54
Protection of data confidentiality.............................................................................. 54
Registration and request for authorization of the trial .............................................. 55
Ethics committee....................................................................................................... 55
Subject insurance ...................................................................................................... 55
Information on study drugs to trial investigators...................................................... 56
Financing .................................................................................................................. 56
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15. PUBLICATION POLICY................................................................................................. 56
16. REFERENCES.................................................................................................................. 57
17. APPENDICES................................................................................................................... 60
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LIST OF ABBREVIATIONS
AE
Adverse event
ALAT
Alanine aminotransferase
ANC
Absolute neutrophil count
AP
Alkaline phosphatase
ASAT
Aspartate aminotransferase
b.i.d.
bis in die (twice daily)
B-PLL
B-cell prolymphocytic leukemia
CI
Coordinating investigator
CLL
Chronic lymphocytic leukemia (B-cell type)
CMV
Cytomegalovirus
CR
Complete remission
CRF
Case record/report form
CT
Computer-aided tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCLLSG
Deutsche CLL-Studiengruppe (German CLL Study Group)
DNA
Deoxyribonucleic acid
DSMB
Data Safety Monitoring Board
EC
Ethics Committee
ECG
Electrocardiogram / -ography
ECOG
Eastern Cooperative Oncology Group
EDTA
Ethylene diamine tetra-acetic acid
ESR
Erythrocyte sedimentation rate
FACS
Fluorescence-activated cell-sorting
FC
Fludarabine + cyclophosphamide
GCP
Good Clinical Practice
GCP-V
GCP-Verordnung (GCP rules for Germany)
γ-GT
γ-glutamyl transferase
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HLA
Human leucocyte antigen
IRB
Institutional Review Board
LDH
Lactate dehydrogenase
MRD
Minimal residual disease
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NCI
National Cancer Institutes (of the USA)
NYHA
New York Heart Association
OS
Overall survival
p.o.
per os (orally)
PCR
Polymerase chain reaction
PD
Progressive disease
PFS
Progression-free survival
PI
Principal Investigator
PLL
Prolymphocytic leukemia
PR
Partial remission
s.c.
subcutaneous[ly]
SAE
Serious adverse event
SCT
Stem cell transplantation
SD
Stable disease
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected unexpected serious adverse reaction
WHO
World Health Organization
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1. FLOW CHART AND STUDY SCHEDULE
1.1 Flow chart
Diagnosis of chronic lymphocytic leukemia requiring therapy according to NCI criteria (“active disease”) with at
least one of the following: (1) fludarabine-refractory a (no PR or CR after a fludarabine-based regimen, or
progression within six months after a fludarabine-based regimen) or
(2) associated with 17p deletion (treated or untreated)
Enrolment (signing of informed consent, approval of inclusion and
submission of samples for central diagnostics)
Alemtuzumab 30 mg s.c. 3 × weekly for 28 days (Days 1, 3, 5; 8, 10, 12; etc.)
+ dexamethasone 40 mg p.o. on days 1–4 and 15–18 and prophylactic pegfilgrastim 6 mg on days 1 and 15
Staging in Week 4
CR
PD
PR, SD
Option
A or B*
Alemtuzumab + dexamethasone + pegfilgrastim
4-week course as above
Staging in Week 8
Option
A or B*
CR
PD
PR, SD
Alemtuzumab + dexamethasone + pegfilgrastim
4-week course as above
Mandatory
Decision: A or B
Staging in Week 12
Option A
Alemtuzumab maintenance
30 mg s.c. every 14 days
Staging every three months
Continued for a maximum of
2 years if no PD
CR, complete remission
(including imaging
techniques and bone
marrow histology)
PR, partial remission
SD, stable disease
PD, progressive disease
(For definitions, see
Appendix)
* If and only if
1) age < 65 years, and
2) an HLA-identical
donor and informed
consent are available
PD
Option
A or B*
Within the framework of
this trial, the term
“fludarabine-refractory”
is synonymous to a
refractory status to any
established purine
analogue (i.e. pentostatin,
cladribine)
PD
Option B*
Consolidation with allogeneic SCT after reduced-intensity conditioning (end
of CLL2O study participation) according to current protocol (e.g. CLLX2)
9
End of study participation.
Further treatment possible
according to other protocol
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1.2 Schedule of assessments and procedures
The tables below show the procedures for:
• Screening (Table 1),
• Induction treatment in up to three four-week cycles (total of 36 doses of 30 mg
alemtuzumab and six four-day courses of 40 mg dexamethasone in weeks 1–12; Table 2),
• Maintenance treatment (30 mg alemtuzumab every two weeks, starting in week 13 and
continuing for a maximum of two years; Table 3), and
• The end-of-study examination and follow-up (Table 3).
Table 1.
Screening procedures
The patient is to be informed and the Informed Consent form signed before any study-specific
procedures are performed.
Diagnosis of treated or untreated CLL that requires treatment (“active disease”) and is either
fludarabine-refractory a or associated with 17p deletion detected by central reference diagnostics
Complete medical history
General clinical examination b
Disease staging according to Binet and treatment required acc. to NCI criteria (“active disease”)
Determination of immunophenotype (CD5, CD19, CD23) if not already done
Blood sampling for hematology
Blood sampling for clinical chemistry and pregnancy test (blood or urine)
Blood sampling for HBV, HCV, HIV, CMV serology and CMV viremia
Blood sampling for serum markers, centrally determined c
Blood sampling for genetics, centrally determined c
Blood sampling for MRD, centrally determined c
Bone marrow sampling (cytology and histology) if indicated
Chest X-ray (plain radiograph of the chest), mandatory
Ultrasound of abdomen, mandatory
CT scan if indicated
Organ function tests as indicated (e.g., ECG, echocardiography, creatinine clearance, lung function)
Check: Informed consent signed; all inclusion criteria and no exclusion criteria met.
– Report to DCLLSG Central Study Office for approval of enrolment –
a Within the framework of this trial, the term “fludarabine-refractory” is synonymous to a refractory
status to any established purine analogue (i.e. pentostatin, cladribine)
b Including B-symptoms, infection, familial CLL, WHO performance status, lymph nodes
(bidimensional), liver, spleen.
c Central reference diagnostics; see Section 8.8.2.
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Table 2.
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Main study treatment (induction)
Treatment cycle
1 to 3 (4 weeks each)
Cycle week (applies to all cycles)
1st – 3rd week
Suggested day of the week:
4th week
Mo
Tu
We
Th
Fr
Mo
Tu
We
Th
Fr
Cycle day (applies to all cycles)
1
8
15
2
9
16
3
10
17
4
11
18
5
12
19
22
23
24
25
26
Visit by patient to study center
yes
no
yes a
no
yes a yes
no
yes a
no
yes
b
•
•
ECGj
•
•
•
•
Blood sampling for clinical chemistry
•
•
•
•
General clinical history and examination
Blood sampling for CMV viremia
Blood sampling for MRD determination
Bone marrow histology
c
•
d
•
Chest X-ray
•
Ultrasound of abdomen
•
•
CT scan if indicated
•
Recording of adverse events
•
e
•
e
•
•e
•––––––•
Staging acc. to Binet and NCI criteria
•
Remission assessment
Treatment: Alemtuzumab 30 mg s.c.
•
f
Dexamethasone 40 mg p.o.
Pegfilgrastim 6 mg s.c.
•
•
g
•
h
•
•
g
•
g
•
•
•
•
•
g
•i
Decision: Continue, stop or maintenance?
Note: For each cycle, day 1 is defined as the date of the first administration of alemtuzumab within that cycle.
No date of administration of alemtuzumab may be advanced. If there is a delay in administration, or if
treatment is interrupted (e.g. because of poor tolerability or toxicity), then all subsequent administrations
will be postponed correspondingly.
Clinical and laboratory tests should be performed more often, if indicated.
a Visit to study center optional, if the patient is able and willing to perform self-administration.
b Including B-symptoms, infection, WHO performance status, lymph nodes (bidimensional), liver and spleen.
c Only if the results of clinical examination, imaging (chest X-ray, ultrasound abdomen and CTs if indicated),
and blood count are all compatible with PR or CR.
d Only if the results of clinical examination, imaging (chest X-ray, ultrasound abdomen and CTs if indicated),
and blood count are all compatible with CR.
e Not if the patient does not attend the investigation site (see note a).
f Including pre-medication and infection prophylaxis (see Sections 7.4 and 7.5 ).
g On days 1–4 and 15–18 only; not on days 8–11.
h On days 1 and 15 only, not on day 8.
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i • If at the end of any cycle PD is established, then study treatment is stopped and the patient is withdrawn
from the study; salvage treatment according to another protocol may be instituted. A peripheral blood or
bone marrow sample is to be sent for genetic analysis.
• If at the end of the first treatment cycle CR is established, the choice is between: (Option A) entering
maintenance phase and (Option B) withdrawal from the trial and allogeneic transplantation within a
currently open clinical trial (e.g. CLLX2), if age < 65 years and an HLA-identical donor and informed
consent are available. In case of PR or SD the patient enters the second cycle.
• At the end of the second treatment cycle the decision procedure is the same as after cycle 1.
• At the end of the third treatment cycle, the choice is between: (Option A) alemtuzumab maintenance
(30 mg s.c. every 14 days for a maximum of two years with staging every three months) and (Option B) , if
age < 65 years and an HLA-identical donor and informed consent are available, allogeneic transplantation
within a currently open clinical trial (e.g. CLLX2).
j On days 1 and 22 only, not on days 8 and 15.
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Table 3.
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Maintenance, study conclusion and follow-up
Maintenance period
Visit(s)
Frequency of visits
Exact timing of visit(s)
General clinical history and examination
e
WHO performance status
Treatment
Examin.
Concluding
visit
14 days
3 months
–
3 months
See (a)
See (b)
See (c)
See (d)
•
•
•
•
•
•
f
•f
•
Blood sampling for clinical chemistry
•
•
•
•
•
•
•
•
•
Bone marrow sampling for histology h
•
•
•
Chest X-ray
•
•
•
Ultrasound of abdomen
•
•
•
CT scan (if indicated)
•
•
•
•
•
•
•
•
•
Blood sampling for MRD determination
Recording of adverse events
g
•
Staging acc. to Binet and NCI criteria
Treatment: Alemtuzumab 30 mg s.c.
i
•
•
f
Blood sampling for CMV viremia
•
•
f
Follow-up
•
•
•j
Decision: Continue or stop?
a Timing of maintenance treatment: Week 13, 15, 17 etc. (if 3 induction cycles were
administered). Each administration of alemtuzumab will take place 14 days after the previous
one (this interval may be increased if necessary to 21 days, but it may not be reduced).
b Timing of examinations during maintenance treatment: Every three calendar months;
examination to take place at a treatment visit as close as possible to that date.
c Timing of concluding visit: After two years of maintenance treatment and in cases of premature
withdrawal (if study conclusion coincides with, or is within 14 days of, an examination visit,
then procedures need not be repeated).
d Timing of follow-up examinations: Every three months after last administration of
alemtuzumab, for a maximum of three years or until new treatment is initiated.
e Including B-symptoms, infection, lymph nodes (bidimensional), liver and spleen.
f For hemoglobin, thrombocytes (platelets) and differential white-blood-cell count.
g Only if the results of clinical examination, imaging (chest X-ray, ultrasound abdomen and CTs if
indicated), and blood count have been all compatible with PR or CR, or if PD is suspected.
h Only if the results of clinical examination, imaging (chest X-ray, ultrasound abdomen and CTs if
indicated), and blood count have been all compatible with CR, or if PD is suspected. Note: no
repeated bone marrow sampling has to be performed (i.e. one documentation of CR is
sufficient), if sampling was already done for documentation of a CR within the staging of the
main study treatment.
i Including infection prophylaxis (see Section 7.5).
j • If at any assessment PD is established, then study treatment is stopped and the patient is withdrawn
from the study; salvage treatment according to another protocol may be instituted. A peripheral
blood or bone marrow sample is to be sent for genetic analysis.
• If at assessment CR, PR or SD is established, maintenance treatment continues for up to 2 years.
• If maintenance treatment has lasted for two years (or if the two-year point has been passed), then
study treatment will be stopped and the follow-up period will be entered.
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2. SYNOPSIS
Aims and objectives
• Assessment of the efficacy of the study treatment in the study population in terms of
response rate, progression-free survival, failure-free survival and overall survival.
• Acquisition of further data to expand the data base on the toxicity of the study treatment.
• Assessment of the efficacy of the study treatment in biological risk groups.
• Assessment of response in terms of minimal residual disease.
Number of patients and estimated duration
Total no. of patients: 95 (~15 with 17p deletion for first-line therapy, ~15 with 17p deletion
for second- or higher-line treatment, ~65 fludarabine-refractory irrespective of 17p status).
Duration for each patient: Max. 12 weeks of treatment in three 4-week cycles, then up to two
years maintenance treatment.
Patients: summary of criteria for enrolment
• CLL requiring treatment (Binet C or A/B with “active disease” according to the NCI
criteria) with at least one of the following: (i) The patient's disease is refractory to a
fludarabine-containing regimen, defined as no complete or partial response according to
NCI criteria, or progression within 6 months after a fludarabine-containing regimen; (ii)
17p deletion is present. (N.B.: Within the framework of this trial, the term “fludarabinerefractory” is synonymous to a refractory status to any established purine analogue (i.e.
pentostatin, cladribine).)
• Patient's age > 18 years (either sex); written informed consent given.
• WHO/ECOG performance status 0, 1 or 2.
• Any previous chemotherapy and/or immunotherapy ended at least four weeks before study
treatment; complete recovery from all such therapy.
• No more than five different previous treatment regimens.
• No major organ dysfunction (heart, lungs, kidneys, uncontrolled diabetes/hypertension).
• No active infection.
• No PLL or Richter's transformation.
• No involvement of the central nervous system.
• No active hepatitis B, hepatitis C, HIV seropositivity or cytomegalovirus viremia.
• No stem-cell transplantation (autologous or allogeneic) in the previous six months.
• No previous treatment with alemtuzumab.
• No long-term systemic corticosteroid treatment or any systemic corticosteroid treatment in
the four weeks before first study treatment.
• No additional active malignancy.
• No history of anaphylactic response to humanized antibodies
• No pregnancy or lactation.
• For fertile men and for women of childbearing potential: Adequate contraception (oral
contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly).
• No drug or alcohol abuse that might lead to inability to comply with the protocol.
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Study treatment
In each four-week cycle, 30 mg alemtuzumab will be administered subcutaneously three times
weekly (total of 12 doses of 30 mg alemtuzumab, in case of interruptions this may take longer
than 4 weeks) with premedication (as needed) and infection prophylaxis; combined with oral
dexamethasone 40 mg total dose for 4 days every two weeks; evaluation at end of cycle (i.e.
after 12 doses of 30 mg alemtuzumab).
If CR (including bone marrow and imaging techniques) is documented after week 4 (12 doses
of 30 mg alemtuzumab) or 8 (24 doses of 30 mg alemtuzumab), maintenance treatment with
alemtuzumab or withdrawal from the study and stem cell transplantation will be instituted at
this time point.
After a maximum of three four-week cycles (total of 36 doses of 30 mg alemtuzumab, in case
of interruptions this may take longer than 12 weeks), maintenance treatment with
alemtuzumab or withdrawal from the study and stem cell transplantation will be instituted.
Maintenance treatment with alemtuzumab will continue for a maximum of two years, with
evaluation every three months, unless there is PD.
German translation of the Synopsis:
Fragestellung und Studienziele
• Bewertung der Wirksamkeit der Studientherapie in der Studienpopulation hinsichtlich
Ansprechrate, progressionsfreiem Überleben und Gesamtüberleben.
• Erhebung weiterer Daten zwecks Erweiterung der Toxizitätsdatenbank für die
Studientherapie.
• Bewertung der Wirksamkeit der Studientherapie in biologischen Risikogruppen.
• Bewertung des Ansprechens anhand minimaler Resterkrankung.
Patientenzahl und geschätzte Dauer
Einschluß von insgesamt 95 Patienten: ~15 Patienten mit 17p-Deletion in Primärtherapie,
~15 Patienten mit 17p-Deletion in sekundär- oder höherer Therapielinie, ~65 Fludarabinrefraktäre Patienten ungeachtet des 17p-Status.
Therapiedauer: Max. 12 Wochen Behandlung in 3 Zyklen von je 4 Wochen; danach bis zu 2
Jahre Erhaltungstherapie.
Patienten: Zusammenfassung der Ein- und Ausschlußkriterien
• Behandlungsbedürftige CLL (Binet C oder A/B mit “active disease” gemäß NCI-Kriterien)
mit mindestens einem der folgenden Charakteristika: (i) Die Erkrankung ist refraktär
gegenüber Fludarabin-haltiger Therapie (Definition: Keine komplette oder partielle
Remission gemäß NCI-Kriterien, oder Progression innerhalb 6 Monate nach einer
beliebigen Fludarabin-haltigen Therapie; (ii) 17p-Deletion liegt vor. (N.B. „Refraktär
gegenüber früherer Fludarabin-haltiger Therapie“ ist im Rahmen dieses Protokolls immer
gleichbedeutend mit „refraktär gegenüber Purinanaloga“, d.h. auch gegenüber Pentostatin
oder Cladribine.)
• Alter > 18 Jahre (beide Geschlechter); schriftliche Einwilligung nach Aufklärung.
• WHO/ECOG Performance Status 0, 1 oder 2.
• Abschluß etwaiger früherer Chemotherapie und/oder Immuntherapie mindestens 4 Wochen
vor Beginn der Studienbehandlung; vollständige Erholung von früherer Therapie.
• Maximal 5 verschiedene frühere Therapieregime.
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V. 1.1 / 25.04.2007
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• Keine erhebliche Einschränkung von Organfunktionen (Herz, Lunge, Niere, unkontrollierte
Diabetes/Hypertonie).
• Keine aktive Infektion.
• Keine PLL oder Richter-Transformation.
• Kein Befall des zentralen Nervensystems.
• Keine aktive Hepatitis B, Hepatitis C, HIV-Seropositivität oder Cytomegalovirus-Virämie.
• Keine Stammzellentransplantation (autolog oder allogen) innerhalb der vorigen 6 Monate.
• Keine frühere Therapie mit Alemtuzumab.
• Keine langfristige systemische Behandlung mit Corticosteroiden; keine systemische
Corticosteroidbehandlung innerhalb der 4 Wochen vor Beginn der Studientherapie.
• Keine zusätzliche aktive Tumorerkrankung.
• Keine Vorgeschichte einer Anaphylaxie auf humanisierte Antikörper.
• Schwangere bzw. stillende Frauen werden ausgeschlossen.
• Bei zeugungsfähigen Männern bzw. gebärfähigen Frauen: Adäquate Kontrazeption (orale
Kontrazeptiva, Spirale oder Barriere-Methode zusammen mit Spermizid).
• Kein Drogen- oder Alkoholmißbrauch, der den Patienten außer Stand setzen könnte, den
Prüfplan einzuhalten.
Behandlungsplan: Zusammenfassung
Während jedes 4-wöchigen Zyklus wird 30 mg Alemtuzumab subkutan dreimal wöchentlich
verabreicht (insgesamt 12 Gaben von 30 mg Alemtuzumab; bei Unterbrechung kann der
Zyklus länger als 4 Wochen dauern); Prämedikation nach Bedarf sowie Infektionsprophylaxe;
orales Dexamethason in einer Gesamtdosis von 40 mg an je 4 Tagen in jeder 2. Woche;
Bewertung am Ende des Zyklus (d.h., nach 12 Gaben von 30 mg Alemtuzumab).
Bei kompletter Remission (inklusive Knochenmarkhistologie und bildgebenden Verfahren)
nach Woche 4 (12 Gaben von 30 mg Alemtuzumab) oder Woche 8 (24 Gaben von 30 mg
Alemtuzumab), Erhaltungstherapie mit Alemtuzumab oder Ausschluß aus der Studie mit
anschließender Stammzellentransplantation.
Nach höchstens drei 4-wöchigen Zyklen (insgesamt 36 Gaben von 30 mg Alemtuzumab; bei
Unterbrechung kann dies länger als 12 Wochen dauern), Erhaltungstherapie mit Alemtuzumab
oder Ausschluß aus der Studie mit anschließender Stammzellentransplantation. Die
Erhaltungstherapie mit Alemtuzumab wird maximal 2 Jahre dauern; Bewertung alle 3
Monate, außer bei Progression.
3. INTRODUCTION AND BACKGROUND
3.1 Chronic lymphocytic leukemia (CLL)
With an annual incidence of around three cases per 100,000 of the population, CLL is the
most common leukemia among adults in the Western world (Rozman and Montserrat, 1995;
Cheson et al., 1996). The stage of disease is of major prognostic importance (Rai et al., 1975;
Binet et al., 1981). Apart from the clinical risk assessment, biological factors have been
found that allow the prediction of the course of disease. Among these prognostic factors are
the serum values β-2-microglobulin, thymidine kinase and sCD23, and also genetic factors
such as the deletion 17p (17p–), 11q (11q–) and unmutated variable regions of the
immunoglobulin genes (IgVH) , as well as surrogate markers such as ZAP-70 (Hallek et al.,
1999; Meinhardt et al., 1999; Döhner et al., 2000; Damle et al., 1999; Hamblin et al., 1999;
16
V. 1.1 / 25.04.2007
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Kröber et al., 2002; Crespo et al., 2003; Rassenti et al., 2004; Kröber et al., 2006). These
factors also appear to have an influence upon the outcome of chemotherapy. Thus, it has been
shown that 17p– (or mutation of the target gene TP53) is associated with failure of therapy,
both in treatment with alkylating agents or purine analogues (Döhner et al., 1995; El Rouby et
al., 1995; Geisler et al., 1997).
3.2 Therapy of CLL with fludarabine and fludarabine combinations
There is currently no curative therapeutic option for CLL with standard chemotherapy, even
though the spectrum of treatments is continually being broadened. In particular, treatment
with the purine analogue fludarabine was shown in randomized studies to result in higher
response rates, and longer progression-free survival, than did therapy with alkylating agents
(Rai et al., 2000). The combination of fludarabine with cyclophosphamide led to a further
improvement in first-line treatment in response rate, increasing this to ~80–100% as well as
progression-free survival (PFS), which increased to ~48 months (Flinn et al., 2000; O'Brien et
al., 2001; Hallek et al., 2001; Eichhorst et al., 2006). A further improvement may be possible
with fludarabine plus cyclophosphamide combined with rituximab as shown in recent phase II
studies (Keating et al., 2005). Nevertheless, fludarabine-containing therapeutic regimens do
fail: occasionally in the first-line treatment, and as a rule after several treatments. Patients
who no longer respond to fludarabine-containing chemotherapy or who only do so for a short
time (i.e., <6 months), have a poor prognosis; the median survival time of these patients,
treated by various salvage methods, is around eight months (Keating et al., 2002). For
patients with fludarabine-refractory CLL, alemtuzumab offers a new therapeutic option.
3.3 Alemtuzumab in fludarabine-refractory CLL
Alemtuzumab (MabCampath®) is a humanized monoclonal antibody directed against the
CD52 antigen. CD52 is expressed on the surface of normal and malignant B- and Tlymphocytes, but not on CD34-positive stem cells. Alemtuzumab was granted marketing
authorization in July 2001 for the treatment of CLL in patients who had already been treated
with alkylating agents and were refractory (i.e. had no response or a response shorter than 6
months) to fludarabine. In the pre-marketing study (CAM211), in which patients had
fludarabine-refractory CLL and had been extensively pre-treated, intravenous alemtuzumab
resulted in a clinical response rate of 33% (Keating et al., 2002). The median survival time of
the entire patient collective was 16 months, and that of the group of responders was 32
months (Keating et al., 2002). Clinical advantage of alemtuzumab was already seen for most
of the patients (without the formal attainment of remission) in terms of improvements in Bsymptoms, performance status, blood counts and spleen enlargement. Alemtuzumab showed
an acceptable side-effect profile. Treatment-related effects appeared mostly in the first week
of therapy, especially chills, fever, nausea, vomiting, skin eruption, and hypotension. Further
effects were transient myelosuppression and – for about one patient in four – severe infection.
Alemtuzumab is usually administered as a two-hour intravenous infusion, three times weekly,
with a view to a total duration of therapy of 12 weeks. This entails hospitalization – or outpatient visits of several hours duration three times a week – for a long period.
3.4 Subcutaneous administration of alemtuzumab
As an alternative method of application of alemtuzumab, subcutaneous administration was
investigated in a study conducted by the Karolinska Institute in Stockholm. Response rates of
above 80% were obtained in the first-line treatment, which indicated that the subcutaneous
application may be efficacious. First pharmacokinetic data indicated that subcutaneously
injected alemtuzumab has a bioavailability comparable to that of the intravenous dose
(G. Hale, personal communication, 2002). However, the side-effect profile of alemtuzumab
administered subcutaneously differed distinctly from that of the same substance given
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intravenously (see Table 4 and Keating et al., 2002). Although the patient collectives differed
in respect to both previous therapy and stage of disease, it is none the less noteworthy that
after subcutaneous administration there were hardly any side effects except for local reactions
at the injection site (87%) und fever (69%), mostly of Grade I or II. In particular, dyspnea,
hypotension, skin eruption and gastro-intestinal side effects were not observed at all (Table 4).
Table 4.
Side effects of alemtuzumab administered subcutaneously or
intravenously
Study
Karolinska Institute study
(subcutaneous, N = 32) *
CAM211 study
(intravenous, N = 93) **
Grade according to NCI
I or II
III or IV
I or II
III or IV
Fever
69%
3%
69%
13%
Rigor
12%
3%
77%
11%
Exanthema/urticaria
–
–
44%
4%
Hypotension
–
–
14%
1%
Dyspnea
–
–
11%
6%
Nausea/vomiting
–
–
78%
–
Diarrhea
–
–
12%
1%
Headache
–
–
13%
–%
Fatigue
6%
3%
14%
3
Injection-site reaction
87%
–
n.a.
n.a.
* Interim evaluation of the Phase II study, subcutaneous MabCampath (A. Österborg,
Karolinska Institute, Stockholm, Sweden). ** Keating et al. (2002). n.a., not applicable.
Data on the tolerability and efficacy of subcutaneously administered alemtuzumab are
available from three studies. Bowen et al. treated seven patients (six B-CLL, one B-PLL)
who had relapsed after fludarabine-containing therapy, with alemtuzumab administered
subcutaneously. Apart from local reactions at the injection site, in particular after the first
subcutaneous application, hardly any treatment-related effects were observed, in comparison
with the intravenous administration. All patients responded to the treatment (Bowen et al.,
1997).
In another study, nine untreated CLL patients were treated with alemtuzumab; four of these
received it subcutaneously. Fever and chills were observed in all patients but one after the
first administration of alemtuzumab, but no serious allergic reaction occurred. Remission in
the bone marrow was recorded for all the subcutaneously treated patients and for three of the
five intravenously treated patients (Österborg et al., 1996).
In a Phase II study the efficacy and tolerability of subcutaneously administered alemtuzumab
(up to 18 weeks, 3 × 30 mg every week) was investigated in 41 untreated CLL patients who
required therapy. The overall response rate was 87% (45% CR, 34% PR). 95% of the
patients attained CR in the blood, 87% showed a response in the lymph nodes and 79% in the
bone marrow. The median time to therapeutic failure had, after more than 18 months, not yet
been reached (Lundin et al., 2001; Lundin et al., 2002). Subcutaneous administration induced
a local inflammatory reaction at the injection site rather than general, cytokine-releasemediated influenza-like symptoms. During the first week of treatment, the majority of
patients developed transient grade I or II injection site skin reactions that required an
individual dose escalation slower than with intravenous administration. The authors
concluded that alemtuzumab is a highly active agent in previously untreated CLL patients.
Prolonged treatment appeared to be of major importance in the achievement of high-quality
18
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remissions in the bone marrow. The side effects indicated that alemtuzumab has an
acceptable safety profile when used as first-line treatment in CLL, provided that antibiotic
prophylaxis is used and the patients are closely observed, especially concerning the risk of
CMV reactivation. It was further concluded that the subcutaneous route of administration
may confer major advantages once the injection-site skin reactions have subsided, both for the
patient (self-administration is feasible) and in reducing costs.
3.5 Combination therapy with alemtuzumab
At present there is no satisfactory therapeutic option for CLL patients whose disease is
refractory towards alemtuzumab and fludarabine. Only data from very small patient cohorts
are available. Kennedy et al. (2002) treated six extensively pre-treated CLL patients, all of
whom failed to respond to alemtuzumab and fludarabine separately, with a combination of
these. Fludarabine was administered every four weeks at a dose level of 25 mg/m2 for three
days, in parallel with the thrice-weekly administration of alemtuzumab. This combination
therapy showed a response in five of the six patients (one with complete and four with partial
remission). Three patients showed complete remission in the bone marrow, which was
confirmed by sensitive four-color flow cytometry. Pettitt et al. (2006) recently reported on
five patients treated with a combination of alemtuzumab 30 mg thrice-weekly and high-dose
corticosteroids (methylprednisolone 1.0g/m2 IV day 1-5, every 28 days). Three patients were
heavily pretreated and all had p53 defects. All five patients responded to therapy, three
achieving a complete remission and two of these achieving negativity for minimal residual
disease. All three complete responders remained free of progression after a median follow-up
period of 8 months. Treatment-related infections were frequent but resolved with appropriate
antimicrobial therapy.
3.6 Maintenance therapy with alemtuzumab
To prolong time to progression, a small Phase II study was conducted, with standard
alemtuzumab treatment until partial response, followed by a maintenance therapy lasting for
at least four months (Thieblemont et al., 2004). A comparison with patients (historical data)
treated with the standard regimen without maintenance was performed. Objective response
was reached by nine (82%) patients with maintenance and three (60%) patients on standard
regimen. After the treatment, eight (73%) maintenance patients and all standard-regimen
patients progressed, with median times to progression of 12.2 and 3 months, respectively.
Survival time in the alemtuzumab maintenance group was significantly longer (p < 0.005).
The authors concluded that maintenance therapy with alemtuzumab seems to increase the
time to progression and the survival, without additional hematological toxicity or infection
complications.
3.7 Safety profile of alemtuzumab
The summary presented here is based upon experience with 149 pre-treated CLL patients who
received 3 × 30 mg intravenous alemtuzumab once weekly within the earlier studies
CAM211, CAM005 and CAM009 alemtuzumab (see also the product information for
MabCampath). Side effects, mostly of mild or moderate severity, were observed with >80%
of all patients treated. The frequency of side effects decreased clearly after the first week of
treatment. The most frequent of these were acute infusion-associated side effects, followed in
frequency by infection and hematological changes. These effects are described in more detail
below.
3.7.1
Hematological side effects
Although hematological side effects were frequently observed, for most patients the
respective laboratory values returned towards normal either during or shortly after the
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treatment period. A transient decrease in hemoglobin levels was observed during therapy.
After treatment had been concluded, values recovered rapidly, so that after two months 87%
of the patients had reached, or even surpassed, their initial hemoglobin values. Five to eight
weeks after the start of treatment, 47% of the patients showed transient severe neutropenia
(Grade 3, 27%; Grade 4, 20%). Transient Grade 3/4 thrombocytopenia was seen in the first
two weeks for 37% of the patients and, again, this later normalized in the majority of cases.
Pancytopenia was also reported, in some cases reaching Grade 3 or 4; for this reason, patients
receiving alemtuzumab should be followed closely. If severe hematotoxicity is encountered,
then treatment with alemtuzumab should be interrupted until this side effect has abated. The
treatment can then be continued.
During treatment with alemtuzumab, the complete blood count (Hb, leucocytes, platelets)
must be checked at regular intervals, which should be reduced if cytopenia is observed. A
Coombs test has frequently given a positive result during treatment with alemtuzumab, and in
isolated cases clinically manifest hemolysis was observed. Furthermore, there have been
individual reports of positive influence of autoimmune hemolytic anemia during treatment
with alemtuzumab (Lundin et al., 2005). In one patient, after treatment, fatal idiopathic
thrombocytopenic purpura occurred. On the other hand, there are reports on the efficacy of
alemtuzumab in refractory autoimmune cytopenia (Marsh & Gordon-Smith, 2001).
As may be expected, lymphocytopenia occurs as a direct consequence of treatment. The
number of T cells (CD3-positive) and of CD4 and CD8 subpopulations clearly decreased
during treatment. After the end of therapy, values returned to normal, independently of the
cumulative total dose of alemtuzumab that the patient had received. The nadir of
CD3+/CD4+ lymphocyte counts (0.002 × 109/l) was in Week 4; six months after the end of
treatment, a count 75% of the initial count was observed. Similar results were obtained for
CD3+/CD4+ lymphocytes.
3.7.2
Infection
Infections were reported for 59% of all patients in the alemtuzumab studies CAM005,
CAM009 und CAM211 (149 patients in toto). Of these patients, 28% experienced severe
infection (Grade 3 or 4). Opportunistic infections, including Pneumocystis carinii pneumonia
and Aspergillus pneumonia, and also cytomegalovirus (CMV) und herpes zoster infections
were observed, and – in one case – rhinocerebral mucor mycosis. However, none of the
patients with Pneumocystis carinii pneumonia or herpes zoster had received adequate
infection-prophylactic treatment. The risk of opportunistic infection can be substantially
reduced by adopting and consistently maintaining appropriate prophylaxis, as was
demonstrated in the CAM211 study.
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Table 5.
V. 1.1 / 25.04.2007
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Grade 3/4 infections in Phase II studies with alemtuzumab
Type of
infection
Pneumonia
Bacteremia
Herpes
Origin of infective
agent
Any
Number of cases
(N = 149)
n
%
23
15.4
Bacterial
8
5.4
PCP*
5
3.4
Mould
4
2.7
Interstitial
2
1.3
Other
5
3.4
Any
15
10.1
Catheter infection
8
5.4
Sepsis
7
4.7
Any
7
4.7
CMV infection
4
2.7
Herpes simplex
1
0.7
Herpes zoster
2
1.3
* Pneumocystis carinii pneumonia
3.8 Results from recent DCLLSG trials
In view of the documented clinical activity of fludarabine, FC and alemtuzumab in CLL, the
DCLLSG has conducted several studies relating these treatments to the outcome of subgroups
of patients.
3.8.1
Subcutaneous alemtuzumab in fludarabine-refractory CLL (CLL2H Study)
The CLL2H trial of the DCLLSG was initiated to evaluate the subcutaneous application of 3
× 30 mg alemtuzumab weekly for a maximum of 12 weeks in fludarabine-refractory CLL
after intravenous dose escalation (3, 10, 30 mg). An interim analysis is available based on the
first 46 patients treated (Stilgenbauer et al. 2004; Stilgenbauer et al. 2005a). The median age
was 62 (range 35–79) years, 74% were male, and a median number of 4 (range 1–9) previous
lines of therapy had been given. Intravenous dose escalation was accompanied by Grade I/II
rigors and fever after premedication with paracetamol and antihistamines in the majority of
patients, while Grade III/IV infusion reactions were rare (n = 3). Subcutaneous treatment was
continued on an out-patient basis in all cases but had to be temporarily interrupted in 29
patients owing to neutropenia (n = 15), anemia (n = 3), thrombocytopenia (n = 3), infections
(n = 8; CMV reactivations, n = 3), and was stopped early in 26 cases because of lack of
response (n = 9), CMV reactivation (n = 3), hematotoxicity (n = 7), or infection (n = 4). The
median alemtuzumab dose given was 838 mg (range, 6–1981 mg). During subcutaneous
treatment, toxicity was mostly of Grade I/II apart from hematotoxicity (Grade III/IV anemia,
24%; thrombocytopenia, 50%; neutropenia, 67%) and Grade III/IV infections (35%). After a
median follow-up time of 12.2 months, 18 deaths have occurred (progression, n = 11; sepsis,
n = 4; causes not CLL-related, n = 2; before treatment start, n = 1). The overall response rate
was 37% (CR 4%, PR 33%), the median PFS time was 10.8 months, and median overall
survival time was 17.4 months. Genetic high-risk factors were present in a large majority of
patients (73% unmutated VH, 30% 17p–, 27% 11q–, 18% +12q). Responses (CR or PR) were
observed in 38% of VH unmutated, 33% of 11q–, 38% of +12, and 46% of 17p– patients. In
conclusion, the subcutaneous administration of alemtuzumab appears to be feasible in an outpatient setting in a high-risk population with fludarabine-refractory CLL, and its efficacy
21
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appears to be comparable to that of intravenous administration. Importantly, genetic high-risk
subgroups with unmutated VH, 11q– or 17p– patients appear to respond to alemtuzumab.
Figures 1 below summarizes some of the results for the CLL2H study, in particular regarding
the response of specific genetic subgroups.
60%
40%
PR
CR
20%
V
un H
m
ut
11
q+1
2q
13
q-
17
p-
A
N ll
=4
6
0%
Figure 1a. Remission rates according to genetic subgroups. Data from the DCLLSG CLL2H trial
(subcutaneous alemtuzumab in fludarabine-refractory CLL). Alemtuzumab appears to be
effective irrespective of genetic risk group, i.e., also in 17p– CLL (updated).
PFS
OS
100
100
17p-
75
75
11q-
50
50
25
25
0
others
0
0
6
12
18
24
36
0
6
12
18
Months
Figure 1b. OS and PFS according to genetic subgroups. Data from the DCLLSG CLL2H trial.
Again, alemtuzumab appears to be effective irrespective of genetic risk group (updated).
3.8.2
Treatment failure of 17p- CLL after fludarabine or fludarabine plus
cyclophosphamide (CLL4 Study)
The CLL4 trial evaluated first-line treatment with fludarabine and fludarabine +
cyclophosphamide among 375 CLL patients up to 65 years of age, enrolled between 1999 and
2003. The clinical results have recently been published (Eichhorst et al., 2006). Fludarabine
+ cyclophosphamide resulted in the higher overall response rate (94% vs. 83%; p = 0.001),
longer median PFS times (48 vs. 20 months; p = 0.001), but no difference in overall survival
22
V. 1.1 / 25.04.2007
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(OS). At enrollment, genomic aberrations and the VH mutation status were analyzed and the
clinical outcome was evaluated in subgroups defined by genomic aberrations and VH status
(Stilgenbauer et al., 2005b).
In univariate analyses, significant associations were found for the following:
• The overall response rate was significantly lower in the subgroup with 17p– (53.8% vs.
89.6%, p = 0.001).
• The median PFS time was significantly shorter in the subgroups with 11q– (17.4 vs. 26.8
months, p = 0.044), 14q– (14.5 vs. 24.5 months, p = 0.018) and 17p– (11.0 vs. 24.1 months,
p = 0.002).
• The median OS was significantly shorter in the subgroup with 17p– (15.9 months vs. not
reached, 75% survival at 43.8 months, p < 0.001).
Multivariate analysis was performed, including as possible prognostic factors the treatment
arms (fludarabine or fludarabine + cyclophosphamide), specific genomic aberrations, and VH
mutation status. The parameters with significant adverse impact were fludarabine
monotherapy (hazard ratio 1.70, 95% CI 1.12–2.58, p = 0.013) and 17p– (hazard ratio 3.67,
95% CI 1.66–8.14, p = 0.001) regarding PFS, but only 17p– (hazard ratio 7.32, 95% CI 2.44–
21.90, p < 0.001) regarding OS. Similar results showing an inferior outcome of 17p- CLL
after first-line treatment with alkylators and fludarabine are becoming available from
prospective studies conducted in the UK and in the USA.
It was concluded that CLL with the 17p- aberration is characterized by a short OS after
fludarabine-based first-line therapy and that, in future trials, alternative primary treatment
strategies of proven efficacy in 17p– CLL such as alemtuzumab should be considered for
these patients.
100
No 17p50
17p0
0
12
24
36
48
60
months
Figure 2. Data from the DCLLSG CLL4 trial (first line fludarabine versus
fludarabine plus cyclophosphamide). Overall survival of
patients according to the presence or absence of the 17p–
aberration for both treatment arms combined.
23
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4. RATIONALE
CLL refractory to therapy based on fludarabine or with 17p deletion has a poor prognosis.
Patients with F-refractory CLL have a remission rate of 20% after various salvage regimens
and a median overall survival (OS) of <12 months (Keating et al., 2002a). CLL patients with
17p deletion have a median OS of 16 months after first-line treatment with fludarabine or FC
in the CLL4 trial of the GCLLSG (Figure 2; Stilgenbauer et al., 2005b; Eichhorst et al.,
2006).
Alemtuzumab is the most active single agent in fludarabine-refractory CLL, with remission
rates of 30–40% and median OS of 16–28 months (Keating et al., 2002b, Rai et al., 2002).
Furthermore, alemtuzumab is of proven efficacy in CLL with 17p deletion and the
subcutaneous administration is as effective as the intravenous application (Stilgenbauer &
Döhner, 2002, Lozanski et al., 2004, Stilgenbauer et al., 2004).
However, the outcome of fludarabine-refractory CLL is still poor, owing to the facts that the
majority of patients do not achieve a remission and that the average duration of remission is
short. Therefore, the current trial aims at achieving: (i) a higher remission rate, by adding
high-dose dexamethasone to alemtuzumab, and (ii) prolongation of remission duration and
survival by alemtuzumab maintenance or allogeneic stem-cell transplantation (SCT). Highdose steroids have shown activity independently of 17p and p53 status, and are effective in
debulking large lymph nodes, a weakness of alemtuzumab (Bellosillo et al., 2002, Thornton et
al., 2003, Pettitt et al., 2006). Maintenance treatment with alemtuzumab improved remission
duration in the CLL4B trial and allogeneic SCT resulted in disease control in high-risk CLL
in the CLL3X trial (Wendtner et al., 2004, Dreger et al., 2005).
5. STUDY DESIGN AND OBJECTIVES
5.1 Study design and time schedule
This is a prospective, open, multi-center Phase II study conducted by the Deutsche CLL
Studiengruppe (DCLLSG; German CLL Study Group, GCLLSG). There will be only one
treatment group and thus no randomization. The study will be conducted at approximately 40
investigation sites in Germany, Austria and France.
The study will be conducted according to the EG Directive on Good Clinical Practice, the
German Arzneimittelgesetz (AMG, 12. Novelle) as well as - with respect to the local activities
and regulations - to the corresponding laws in France and Austria. Cf. section 14.1 for details.
A total of 95 patients (adults, males and females, in-patients and out-patients; 2 to 10 patients
are expected to be recruited by each of the centers) will be recruited, with stratification by
detailed diagnosis (Section 11.2.2). The distribution of female and male patients is not
relevant for the study as both sexes are affected by CLL and treatment effects are not different
in both groups (GCP-V § 7, 2). Recruiting will stop when the 95th. patient has completed the
first four-week cycle of treatment. The study will be concluded when the last patient has
completed treatment with alemtuzumab according to this protocol (see e.g. the flow diagram,
Section 1.1). The retrieval of additional follow-up data may be appropriate to achieve mature
data in the survival endpoints.
Subcutaneous alemtuzumab (30 mg) will be administered three times weekly (days 1, 3 and
5) along with oral dexamethasone (40 mg/day, days 1–4, every 2 weeks) for at least 4 weeks
(corresponding to 12 doses of alemtuzumab, in case of treatment interruption this may take
longer than 4 weeks) and, for patients who show at least SD, a maximum of 12 weeks (36
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doses of alemtuzumab, in case of treatment interruption this may take longer than 12 weeks).
Thereafter, maintenance therapy with alemtuzumab will be instituted for a maximum of two
years. If CR (including bone marrow histology and imaging (chest X-ray and ultrasound, CT
if indicated) is documented before week 12, i.e. after week 4 (12 doses of 30 mg
alemtuzumab) or 8 (24 doses of 30 mg alemtuzumab), maintenance treatment with
alemtuzumab will be instituted at this time point.
In this study (unlike some earlier ones) the dose of alemtuzumab is not to be increased
gradually, but will start directly at 30 mg.
Staging will be performed at inclusion to the study and after 12 doses of alemtuzumab (aim:
at the end of Week 4), after 24 doses of alemtuzumab (aim: at the end of Week 8), and after 36
doses of alemtuzumab (aim: at the end of Week 12) of treatment. Patients showing
progressive disease (PD) (according to NCI criteria, see Appendix) will be withdrawn from
the study. If hematological or other toxicity is seen, treatment will be interrupted and the dose
will be reduced according to the prescription information (Section 7.10).
If after 12 weeks there is stable disease (SD), partial response (PR) or complete response
(CR), then maintenance treatment will be given, with continued subcutaneous alemtuzumab
(30 mg every 14 days). Patients for whom stem-cell transplantation is a realistic treatment
option will be offered the possibility of receiving allogeneic stem-cell treatment in another
clinical trial (CLLX2 or other GCLLSG trial). The latter will however only be offered if (1)
the patient is not more than 65 years of age at the time of staging and (2) an HLA-identical
donor is available who has given his/her informed consent. There should be a treatment-free
period of at least 2 months before SCT, details are specified in the corresponding protocol.
Appropriate premedication and infection prophylaxis will be administered (see Sections 7.4
and 7.5).
After each disease staging (i.e. every three months during the maintenance phase), if there is
SD, PR or CR, then patients will continue study therapy (alemtuzumab maintenance).
Maintenance therapy will be stopped after two years.
During the study, continual monitoring of efficacy and toxicity will be performed. Early
stopping rules will be applied if major intolerability is observed (Section 10.4).
Response will be assessed by clinical examination, blood counts, clinical chemistry, chest
X-ray (plain radiograph of the chest), ultrasound of the abdomen, CT scanning (if indicated),
bone marrow cytology and histology (only in cases of possible CR), and assessment of MRD
(for molecular response rate only). Time points for response evaluation according to NCI
criteria will be after 12 doses, 24 doses, and 36 doses of alemtuzumab. For an uninterrupted
treatment course, this will be after 4, 8 and 12 weeks respectively. (If treatment with
alemtuzumab is interrupted, then the time points for all subsequent doses, assessments and
other procedures will be delayed correspondingly; i.e., the number of doses is the determining
factor for elapsed treatment time, and not the calendar date; see above, “Staging will be
performed...”.) Follow-up assessment will continue at three-month intervals for at least three
years.
The following time schedule is anticipated for the study:
•
Start of recruitment: October 2007
•
End of recruitment: June 2010
•
End of study procedures (conclusion of maintenance therapy): September 2012 (plus
eventual additional follow-up)
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5.2 Primary objectives
• Assessment of the efficacy of the study treatment in the study population in terms of:
– Response rate
The corresponding definitions and target variables are given in Section 11.2.4.
5.3 Secondary objectives
• Progression-free survival, defined as time from study entry until diagnosis of PD or death
of any cause
• Failure-free survival, defined as time from study entry until initiation of next treatment,
diagnosis of PD or death of any cause.
• Overall survival, defined as time from study entry until death.
• Acquisition of further data to expand the data base on the toxicity of the study treatment.
• Assessment of the efficacy of the study treatment in biological risk groups.
• Assessment of response in terms of MRD.
The corresponding definitions and target variables are given in Section 11.2.4.
6. PATIENTS
CLL patients of either sex will be included in the study, according to the following inclusion
and exclusion criteria.
6.1 Inclusion criteria
The following criteria are to be checked at the time of study entry. The patient may only be
included if all of the following statements are true:
1. The patient has CLL requiring treatment (Binet C or A/B with “active disease” according
to the NCI criteria).
2. One or both of the following is true:
• The patient's disease is refractory to a previous fludarabine-containing regimen,
defined as no CR or PR according to NCI criteria, or progression within 6 months after
a fludarabine-containing regime. (N.B.: Within the framework of this trial, the term
“fludarabine-refractory” is synonymous to a refractory status to any established purine
analogue (i.e. pentostatin, cladribine).)
• 17p deletion is present (irrespective of whether previously treated or untreated).
3. The patient is at least 18 years of age.
4. The patient's performance status is 0, 1 or 2 on the WHO/ECOG scale.
5. Any previous chemotherapy and/or immunotherapy ended at least four weeks before the
first study treatment with alemtuzumab.
6. The patient has recovered from all previous chemotherapy and/or immunotherapy.
7. For fertile men and for women of childbearing potential: Adequate contraception (oral
contraceptives, intrauterine device or barrier method in conjunction with spermicidal
jelly).
8. The patient has given written informed consent to participate in the study.
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6.2 Exclusion criteria
The following criteria are to be checked at the time of study entry. The patient must be
excluded if any one (or more) of the following statements is true:
1. The patient has received more than five different prior therapeutic regimens.
2. Any major organ dysfunction is present (e.g. unstable angina pectoris, NYHA III/IV heart
insufficiency, significant coronary stenoses, uncontrolled diabetes mellitus, uncontrolled
hypertension, pulmonary disease with hypoxemia, renal failure).
3. Any of the following laboratory values are found at the screening visit to be >2 × the
upper limit of the normal range: serum creatinine, serum bilirubin, ASAT, ALAT.
4. Any active infection is present.
5. B-PLL or Richter transformation is diagnosed or suspected (e.g. symptoms or cytology).
6. There is involvement of the central nervous system.
7. The patient is known to be positive for human immunodeficiency virus (HIV).
8. CMV viremia is present, as demonstrated by pp65 EA or CMV-DNA.
9. The patient has previously been treated with alemtuzumab.
10. The patient has received autologous or allogeneic SCT within the past six months.
11. The patient is receiving long-term systemic treatment with corticosteroids or has received
such treatment in the four weeks before first treatment with alemtuzumab.
12. Any additional active malignancy is present.
13. The patient has ever had an anaphylactic response to humanized antibodies.
14. For female patients: The patient is pregnant or lactating.
15. The patient has a history of drug or alcohol abuse that might lead to inability to comply
with the protocol.
6.3 Registration of patients
All patients enrolled (i.e., who give their written informed consent to participate) will be
registered at the Central Study Office of the German CLL Study Group (GCLLSG) (for
contact details see title page of this protocol). After confirmation by the Central Study Office,
the patient may enter the protocol. Registration information will be immediately forwarded by
the Central Study office to WiSP and the coordinating investigator (for contact details see title
page) in order to allow for the initiation of monitoring procedures.
7. TREATMENT PLAN
7.1 General instructions
It should be noted that the treatment in this study differs in two respects from the standard
treatment with alemtuzumab as commercially licensed: (i) Study treatment with alemtuzumab
is exclusively by subcutaneous injection. (ii) The initial dosage level is 30 mg; thus, the
initial dose-raising (3 mg, then 10 mg, then 30 mg) will not take place in this study.
Oral treatment with dexamethasone will be according to standard methods.
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Allogeneic stem-cell transplantation (“Option B”; see the flow diagram in Section 1.1) will be
outside the scope of this protocol, i.e. patients will be withdrawn from the study. Screening for
participation will be according to the relevant SCT study (e.g. CLLX2 protocol of the
GCLLSG). There should be a treatment-free period of at least 2 months before SCT.
Salvage treatment (after end of study; see the flow diagram in Section 1.1) will be according
to standard methods (if appropriate, within another study), as decided by the investigator.
In case of successful treatment, the outline of the protocol has to be followed. If a responding
patient has to leave the protocol for reasons other than toxicity or progression, it is up to the
investigator to continue with a treatment containing alemtuzumab, as the drug is registered
and generally available for prescription.
Self-administration of alemtuzumab is allowed after adequate training of the patient if the
investigator decides that the patient is able to perform this. Adequate storage and details on
the administration of alemtuzumab (time, dose etc.) must be documented.
7.2 Summary of study treatment and procedures
CLL patients who satisfy the in- and exclusion criteria will be treated as follows (see also the
flow diagram in Section 1.1). For exact timings of procedures, please refer to the schedule
tables in Section 1.2.
• Diagnosis of CLL that is either
– fludarabine-refractory (defined as showing no remission, or remission duration <6
months) (N.B.: Within the framework of this trial, the term “fludarabine-refractory” is
synonymous to a refractory status to any established purine analogue (i.e. pentostatin,
cladribine).), or
– associated with 17p deletion (this must be confirmed by the reference genetics
laboratory as specified below and in Section 8.8.2).
• Screening procedures and staging.
• Registration at the Central Study Office of the German CLL Study Group (GCLLSG) using
the form provided. Note: Approval of enrolment by the GCLLSG central study office
before initiation of study treatment is mandatory.
• Submission of samples for genetic analysis.
Note: The analysis is to be performed at the reference genetics laboratory in Ulm (see title
page) unless approved otherwise in writing by the Ulm laboratory.
• Only after the screening has been completed, all inclusion and exclusion criteria are met
and approval from the GCLLSG central study office is granted, may the study treatment
commence.
• First four-week cycle: Treatment will be with alemtuzumab 30 mg s.c. three times weekly.
Dexamethasone 40 mg p.o. is given for four days in the first and third weeks only.
Premedication will be with paracetamol und antihistamine (according to the product
information) only before the initial doses; at the discretion of the investigator, pethidin and
corticosteroids may be added if clinically indicated.
• At the end of the first 4 week treatment cycle (i.e., after 12 doses of alemtuzumab), the
patient's disease will be staged, with the following decisions on the basis of the result of the
staging:
- PD: The patient is withdrawn from the study.
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SD, or PR: The patient enters the second 4 week (12 doses of alemtuzumab,
dexamethasone 40 mg p.o. for four days every 2 weeks) treatment cycle.
CR: One of the following two treatment options will be chosen:
Option A: The patient enters maintenance treatment.
Option B: The patient leaves the study and enters a separate allogeneic SCT study (this
presupposes the availability of a consenting, HLA-identical donor).
• Second four-week cycle: Treatment will be as in the first cycle.
• At the end of the second 4 week treatment cycle (i.e., after 24 doses of alemtuzumab), the
patient's disease will be staged, with the following decisions on the basis of the result of the
staging:
- SD, PR: The patient enters the third 4 week (12 doses of alemtuzumab, dexamethasone
40 mg p.o. for four days every 2 weeks) treatment cycle.
- CR: One of the following two treatment options will be chosen:
- Option A: The patient enters maintenance treatment.
- Option B: The patient leaves the study and enters a separate allogeneic SCT study (this
presupposes the availability of a consenting, HLA-identical donor).
• Third four-week cycle: Treatment will be as in the first and second cycles.
• At the end of the third treatment cycle (i.e., after 36 doses of alemtuzumab), the patient's
disease will be staged, with the following decisions on the basis of the result of the staging:
- SD, PR or CR: One of the following two treatment options will be chosen:
- Option A: The patient enters maintenance treatment.
- Option B: The patient leaves the study and enters the separate allogeneic SCT study
(with consenting, HLA-identical donor).
• During maintenance treatment, the patient will receive treatment with alemtuzumab 30 mg
every two weeks (no dexamethasone), and disease staging will be performed every three
months (or earlier if there is evidence for PD). According to the results of the staging, the
following decisions will be made:
- SD, PR or CR: The patient continues with maintenance treatment, up to a maximum
total of two years' maintenance treatment (thereafter this option will not be offered).
Throughout study treatment:
• Infection prophylaxis with cotrimoxazol (e.g. Cotrim forte®) or equivalent alternative (e.g.
pentamidine inhalation) and valaciclovir (e.g. Valtrex®) or equivalent will be administered
and will be continued until at least four months after the end of therapy with alemtuzumab.
• CMV pp65 EA or DNA PCR monitoring will be performed.
• Disease staging will be performed according to the NCI criteria (see Appendix).
After the end of study treatment:
• A single concluding visit will take place (Table 3), unless the procedures of this visit have
been conducted within the previous 14 days.
• Every three months, the patient will be followed up to determine his/her remission status,
adverse events and WHO performance status.
• In case of fertile men and for women of childbearing potential: The patient has to be
advised that adequate contraception (oral contraceptives, intrauterine device or barrier
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method in conjunction with spermicidal jelly) is required for at least 6 months after
termination of alemtuzumab therapy. At study visits, this has to be documented and if
despite this pregnancy occurs, this is to be recorded in the medical record and CRF (for
both male and female patients).
7.3 Treatment with alemtuzumab
For induction therapy in cohort (1) (refractory patients), alemtuzumab will be prescribed by
the treating physician, as this prescription is within the framework of standard, approved
usage of the antibody. For treatment in cohort (2) (17p deletion) and generally for
maintenance treatment alemtuzumab will be delivered free of charge by the Bayer Schering
AG via the Central Study Office of the German CLL Study Group. Corresponding forms have
to be filled out on registration of the patient.
Treatment with alemtuzumab will begin not less than four weeks after any previously
administered chemotherapy and after full recovery from this (cf. inclusion criteria nos. 5
and 6).
Before administration of alemtuzumab, premedication will be given (Section 7.4), and during
the entire period of treatment with alemtuzumab infection prophylaxis will be administered
(Section 7.5). In addition, owing to the possibility of acute cell lysis at the start of therapy,
the usual precautionary measures are to be taken (hydration, allopurinol) and attention is to be
paid to possible symptoms of tumor lysis. Anti-emetic treatment is not usually necessary.
7.4 Premedication
Before alemtuzumab is administered,
• an analgesic, such as 1000 mg paracetamol (e.g. Ben-u-ron®), and
• an antihistamine, such as 4 mg dimetinden maleate (e.g. Fenistil®) or 2 mg clemastin (e.g.
Tavegil®),
will be given.
Short-term dexamethasone (40 mg / d for 4 days) will also be administered as stipulated in the
study schedule.
If after the first week of alemtuzumab treatment the study medication is well tolerated, then
pre-medication can be omitted.
7.5 Infection prophylaxis and treatment of infections
During treatment with alemtuzumab, lymphocyte deletion (T and B cells) occurs. This
conveys an elevated risk of opportunistic infections during and after therapy. For this reason,
all patients will receive mandatory infection prophylaxis with cotrimoxazol (e.g. Cotrim
forte®) against infection by Pneumocystis carinii and also an anti-viral (e.g. valaciclovir,
Valtrex®) against herpes infection. In cases of cytopenia caused by cotrimoxazol, this is
replaced by pentamidine inhalation (Pentacarinate®).
Prophylaxis (see Table 6 below) should be continued until at least four months after the end of
therapy with alemtuzumab.
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Table 6.
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Mandatory infection prophylaxis during and after treatment with alemtuzumab
Substance
Quantity
Cotrimoxazol (e.g. Cotrim forte®)
Route
1 tablet three times weekly
p.o.
®
250 mg (1-0-1) *
p.o.
®
Valaciclovir (e.g. Valtrex )
500 mg (1-1-1)
p.o.
Aciclovir
400 mg (1-1-1-1)
p.o.
Plus one of: Famciclovir (e.g. Famvir )
* Explanations for this table and the text below: 1-0-1, one tablet in the morning and early evening; 1-1-1, one
tablet in the morning, at midday and in the early evening; 1-1-1-1, one tablet in the morning, at midday, in the
early evening and in the late evening; ‘2’ two tablets etc.
Additionally, e.g. for patients who have frequently suffered from infections, the
administration of antifungal (e.g., AmphoMoronal® or Diflucan®) and antibacterial (e.g.,
Ciprobay® or Tavanic®) agents may be considered. In cases of neutropenia, prophylaxis with
quinolones (e.g. Tavanic®) and anti-fungals (e.g. Diflucan® or Ampho-Moronal®) is to be
instituted. CMV viremia monitoring will take place, with pre-emptive treatment with oral
valgancyclovir (Valcyte®) 450 mg (2-0-2) (see below).
Despite these measures, an increased infection rate must be expected. Therefore, the patient
must be informed in detail about possible symptoms of infection and, along with the
physician, be especially aware of this possibility. In cases of suspected infection, medical
treatment is to be initiated without delay.
Because of the strong suppression of immunity, infection can take an unusual course. For
example, fever as a main characteristic symptom can be absent. The spectrum and
appearance of infecting agents can be unusual. In cases where there is any doubt, immediate
and scrupulous differential diagnosis must be performed, including where necessary imaging,
cultures, serological and DNA-based detection. Any infections should be treated according to
the standard procedures at the investigation site. For severe cases and in cases of uncertainty,
admission to hospital is strongly advised.
7.6 CMV reactivation and CMV disease
Both CMV reactivation and symptomatic CMV disease during treatment with alemtuzumab
have been described. If fever of unclear origin arises, CMV viremia should always be tested
for (pp65-EA screening or CMV-DNA PCR). Anemia and/or thrombocytopenia can be early
signs of CMV reactivation during alemtuzumab treatment. Further examinations for signs of
affected organs (e.g. bronchoscopy, fundus ophthalmoscopy) are advisable. Before treatment,
and every week during treatment, tests for CMV viremia (pp65-EA screening or CMV-DNA
PCR) are mandatory in this protocol, in order to gain information about the rate of
asymptomatic CMV reactivation during alemtuzumab treatment.
Such reactivation appears to take a less aggressive course than after stem-cell transplantation,
and CMV viremia can disappear untreated. It is therefore not always necessary (depending on
the severity of the viremia) to institute antiviral therapy; an asymptomatic CMV reactivation
may not require therapeutic measures, if detailed quantitative monitoring (determination of
CMV-DNA copy number or counting of pp65-EA-positive cells) is performed.
However, it is recommended that anti-CMV treatment be instituted once CMV viremia is
detected, to prevent its aggravation or symptomatic CMV disease. During asymptomatic
CMV viremia treated with valgancyclovir (Valcyte® 450 mg, 2-0-2), the treatment with
alemtuzumab can be continued; detailed monitoring of CMV viremia must be performed. In
cases of increasing CMV viremia or symptomatic CMV disease (e.g. fever of unknown origin,
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pneumonitis), alemtuzumab therapy should be interrupted and antiviral therapy with
valganciclovir (Valcyte 450, 2-0-2) or equivalents (Cymeven®; 5 mg/kg/day, b.i.d.,
intravenous; or foscarnet (Foscavir®), or cidofovir (Vistide®)) should be instituted. After
resolution of the infection and repeated negative CMV testing, treatment with alemtuzumab
may be continued.
7.7 Hematopoietic insufficiency, growth factors, transfusions
Frequently, even before the commencement of therapy, hematopoietic insufficiency arises as a
result of extensive bone marrow infiltration and prior therapy resulting in the need for
transfusions. It appears to be precisely in cases where bone marrow infiltration is more
significant than lymphadenopathy and hepatosplenomegaly that lasting therapeutic success
can be achieved with alemtuzumab. However, at the beginning of treatment, an increase in
hematopoietic insufficiency – with the need for transfusion – can occur. In such cases, it is
still recommended to continue treatment, since therapeutic success indicated by recovering
blood counts may take 6–8 weeks to develop. Transfusions must be performed with irradiated
blood products. The use of hematopoietic growth factors to support recovery is to be as
follows:
A prophylactic dose of pegfilgrastin (Neulasta®) 6 mg s.c. is to be administered at 14-day
intervals from the start of therapy. This should be continued at 14-day intervals, even if the
alemtuzumab treatment is interrupted. If the neutrophil count rises to above 50,000 /µl the
administration of pegfilgrastin should be interrupted (however, owing to the self-limiting
mechanism of action, this is expected only rarely). The principal side effect is bone pain
caused by the stimulation of granulopoiesis. A sonographic check of spleen size should be
conducted at four-week intervals, as stipulated in this protocol (abdominal ultrasound
examination), or more often if indicated (e.g., by pain).
Since cases of hemolysis during the therapy have been described, further laboratory
diagnostic tests may be required. Since anemia and thrombocytopenia can be early signs of a
CMV reactivation, it may also be appropriate to perform CMV-viremia screening (pp65-EA
screening or CMV-DNA PCR). Hematopoietic insufficiency persisting after supportive
treatment calls for a bone marrow test, to find out whether its cause is persistent bone marrow
infiltration or delayed recovery of the hematopoiesis. A few cases of longer-term
pancytopenia, caused by bone marrow aplasia after alemtuzumab therapy, have been
described. In these instances, in addition to growth factors, short-term high doses of
corticosteroids and immunglobulins appear to be of therapeutic value. The infection
prophylaxis with cotrimoxazol can also be partly responsible for cytopenia. If there is
suspicion of this, cotrimoxazol should be replaced by inhaled pentamidin (Pentacarinat®).
Regarding the substitution of blood products and treatment interruption, see also the section
on interruption/termination of therapy below.
7.8 Duration and interruption of alemtuzumab therapy
According to the number of cycles and the duration of maintenance therapy, the duration of
treatment with alemtuzumab (subcutaneous administration only) will be as follows:
• 4, 8 or 12 weeks of treatment, 3 × 30 mg per week (12, 24 or 36 doses in all),
followed by
• Not more than 2 years of treatment 1 × 30 mg every 14 days (maximum of 52 doses).
If study treatment is interrupted temporarily, then all subsequent treatments will be postponed
correspondingly (“the clock will be stopped”) until resumption of study treatment; the total
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number of doses and study visits is thus unaffected, and the overall duration of treatment
prolonged.
According to experience to date, the average duration of therapy until remission is 6–8 weeks.
However, disease-related anemia or thrombocytopenia can persist even after a response of the
CLL to the treatment. The kinetics of response to alemtuzumab can vary according to the
manifestation of the disease observed. A regression of lymphocytosis in peripheral blood is
frequently seen already in the first phase of treatment, while bone marrow infiltration and
lymphadenopathy and hepatosplenomegaly respond more slowly. Furthermore, the quality of
the remission achieved by alemtuzumab treatment is related to the duration of remission and
survival. For this reason, the treatment should not be terminated too early, but should rather
be continued until CR has been documented according to the NCI criteria, as set out below
(see also flow diagram, Section 1.1).
7.9 Therapy after treatment failure (PD)
In cases of treatment failure (PD according to NCI criteria; see Appendix) the patient will be
withdrawn from the study and salvage therapy can be carried out (see also Section 1.1).
7.10 Therapy after remission or stable disease (CR, PR or SD)
In cases of complete or partial remission, or stable disease (CR, PR, SD), the patient may
continue treatment with alemtuzumab up to a maximum of two years' maintenance therapy
(see also Section 1.1). During the maintenance phase dexamethasone will not be
co-administered.
As an alternative treatment option, the possibility may be considered of stopping the
participation of the patient in the present study and enrolling him/her in a current DCLLSG
study involving allogeneic SCT. This possibility (Option B) is only to be offered to patients
who are under 65 years of age and for whom an HLA-identical donor who gives informed
consent to the transplantation are available. Patients for whom these prerequisites are not
fulfilled will continue with alemtuzumab treatment for as long as permitted by this protocol
(Section 7.8).
7.11 Interruption/termination of therapy
Study treatment can be interrupted or terminated at any time for any of the following reasons:
• The patient's decision.
• Adverse events associated with alemtuzumab.
• Unacceptable toxicity (e.g., non-hematological Grade IV toxicity)
• Severe infection (Grade III or higher)
• Progression of disease or lack of response, as stipulated by the treatment plan (cf.
Section 1.1)
• Pregnancy or inadequate contraception. (If pregnancy occurs despite adequate
contraception (oral contraceptives, intrauterine device or barrier method in conjunction
with spermicidal jelly), this is to be documented in the medical record and CRF (for both
male and female patients)
• Circumstances that prevent the administration of study treatment according to this protocol.
• Conspicuous hematotoxicity if not hematopoietic insufficiency due to CLL was present
before study entry. (Hematotoxicity is here understood as one or more of the following:
ANC <500 /µl, thrombocytes <25,000/µl, hemoglobin <6.5 g/dl; need for transfusion.)
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If hematotoxicity as defined above appears during therapy with alemtuzumab (i.e. was not
present before initiation of treatment), then this treatment is to be interrupted. After recovery
the treatment can be continued according to the following table. [Note: (i) Recovery is here
understood as all of the following: ANC > 500 /µl or initial value, thrombocytes > 25,000 /µl
or initial value, hemoglobin > 8 g/dl or initial value; no need for transfusion. (ii) This
requirement to interrupt treatment does not apply in cases where there was previous
hematopoietic insufficiency due to CLL, i.e. neutropenia, anemia, or thrombocytopenia before
the start of treatment.] For more details, see the product information in the Appendix.
Table 7.
Modification of alemtuzumab dose in cases of hematotoxicity (This does not apply
when hematopoietic insufficiency due to CLL, i.e. neutropenia, anemia,
thrombocytopenia, was present already before treatment with alemtuzumab)
Hematotoxicity (for definition see text)
Recommencement of alemtuzumab administration
First appearance
After recovery: Therapy with 30 mg*
Second appearance
After recovery: Therapy with 10 mg*
Third appearance
Withdrawal of patient from study
In case of fertile men and for women of childbearing potential: The patient has to be advised
that adequate contraception (oral contraceptives, intrauterine device or barrier method in
conjunction with spermicidal jelly) is required for at least 6 months after termination of
alemtuzumab therapy
8. STUDY ASSESSMENTS
Numbering of visits: Scheduled study visits will be numbered consecutively within each
treatment cycle, e.g. visit 1-1 will be the first study visit in cycle 1, visit 2-8 will be the eighth
study visit in cycle 2 etc. In the maintenance phase the visits will be numbered M-1, M-2 etc.
8.1 Screening
Procedures to be conducted at screening are as follows:
• Diagnosis of treated or untreated CLL that requires treatment (“active disease” according to
the NCI criteria; Appendices) and is either fludarabine-refractory or associated with 17p
deletion (confirmation of the 17p deletion must be obtained from the reference laboratory;
see Section 8.8.2). (N.B.: Within the framework of this trial, the term “fludarabinerefractory” is synonymous to a refractory status to any established purine analogue (i.e.
pentostatin, cladribine).)
• The patient's medical history will be recorded.
• A general clinical examination will be performed, including B-symptoms, infection,
familial CLL, WHO performance status, lymph nodes (bidimensional), liver and spleen.
• Disease staging (Binet system) and determination of the treatment required (NCI criteria)
will be performed.
• Blood samples will be taken for the following hematological, chemical and serological
tests:
– Routine hematological, chemical and serological testing (HBV, HCV, HIV, CMV) and
CMV viremia (pp65 or PCR) at local laboratory (10–20 ml).
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Pregnancy test (urine or blood)
Serum marker determination, at reference laboratory (10 ml).
Genetic analysis, at reference laboratory (40 ml).
MRD baseline analysis, at reference laboratory (10 ml).
Determination of the immunophenotype (CD5, CD19, CD23) if this has not already been
done, at local laboratory (10 ml).
• A bone marrow sample will be taken for cytological and histological analysis, if indicated
(e.g. cytopenia of unknown origin, suspected transformation).
• The following imaging procedures will be performed:
– Chest X-ray (plain radiograph of the chest), mandatory
– Ultrasound of abdomen, mandatory
– CT scan (if indicated, e.g. if lymphadenopathy suspected on chest X-ray / ultrasound, or
poor conditions for ultrasound (adipositas), etc.)
• Organ function tests (ECG, echocardiography, creatinine clearance, lung function) will be
performed, as indicated.
• The inclusion and exclusion criteria will be checked (Sections 6.1 and 6.2).
• If the patient is eligible to enter the study, then after completion of screening procedures a
report will be sent to the Central Study Office of the German CLL Study Group (GCLLSG)
for approval of enrolment. Further study procedures may not be conducted, and in
particular no study treatment may be administered, before the GCLLSG's Central
Study Office has confirmed in writing the enrolment of the patient in question.
8.2 Assessment in Cycle 1
For a survey of timings of visits 1-1 to 1-12, see Table 2.
Day 1 (Visit 1-1)
• The patient will be subjected to a general clinical examination as at screening
(B-symptoms, infection, WHO performance status, lymph nodes (bidimensional), liver and
spleen).
[Notes: (i) This may be omitted if the screening examination took place <14 days
previously. (ii) The WHO and ECOG performance scales are identical; see Appendix.]
• ECG is carried out
• Blood samples will be taken for hematological and chemical tests (10 ml) and for CMV
viremia (5 ml).
[Note: This may be omitted if the screening examination took place <14 days previously.]
• Any adverse events that have occurred since the previous visit will be recorded.
• The patient will receive 40 mg dexamethasone p.o. and be provided with a similar dose for
taking (off site) on the following and subsequent days (i.e. will receive a prescription).
• The patient will receive study treatment with alemtuzumab 30 mg s.c. (with appropriate
premedication and infection prophylaxis as described in this protocol, Sections 7.4 and 7.5).
• The patient will receive treatment with pegfilgrastim 6 mg s.c. on days 1 and 15.
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Day 3 (Visit 1-2)
If the patient is able and willing to administer the s.c. injection of alemtuzumab him/herself,
this visit can be omitted. In that case the recording of adverse events will be postponed until
the next actual visit.
• The patient will receive 40 mg dexamethasone p.o. and be provided with a similar dose for
taking (off site) on the following day.
• The patient will receive study treatment with alemtuzumab 30 mg s.c. (with premedication
and infection prophylaxis as appropriate).
Day 5 (Visit 1-3)
If the patient is able and willing to administer the s.c. injection of alemtuzumab him/herself,
this visit can be omitted. In that case the recording of adverse events will be postponed until
the next actual visit.
Note that dexamethasone will not be administered at this visit.
Days 8, 10, 12 (Visits 1-4 to 1-6)
As days 1, 3, 5, except that dexamethasone will not be administered at any of these visits.
[The general clinical examination and blood sampling on day 8 are mandatory.]
Days 15, 17, 19 (Visits 1-7 to 1-9)
As days 1, 3, 5.
[The general clinical examination and blood sampling on day 15 are mandatory.]
Day 22 (Visit 1-10)
• The patient will be subjected to a general clinical examination as at screening (Section 8.1).
• ECG is carried out
• Blood samples will be taken for hematological and chemical tests (10–20 ml) and for CMV
viremia (5 ml)
• Only if the result of the clinical examination is compatible with PR or CR:
– A blood sample will be taken for MRD determination at the reference laboratory (10 ml)
• Only if the result of the clinical examination is compatible with CR:
– A bone marrow sample will be taken for cytological and histological analysis.
– Chest X-ray (mandatory)
– Ultrasound of abdomen (mandatory)
– CT scan (if indicated; cf. screening visit)
• The patient will receive study treatment with alemtuzumab 30 mg s.c. (with infection
prophylaxis as appropriate; premedication should by this stage no longer be needed;
Section 7.4).
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Day 24 (Visit 1-11)
• Disease staging and response evaluation according to Binet and the NCI criteria (as at
screening) will be performed at any time from day 24 to day 26.
Day 26 (Visit 1-12)
• Disease staging according to Binet and the NCI criteria (as at screening) will be performed
at any time from day 24 to day 26 (inclusive).
• Overall assessment of remission will be done, and on the basis of this assessment and the
disease staging it will be decided whether the patient must be withdrawn (if there is PD) or
may continue in the study (entry to treatment cycle 2 if there PR or SD, entry to
maintenance if there is CR). If PD is found, a further peripheral blood or bone marrow
sample is to be sent for genetic analysis (Section 8.8.2).
All the visits (visits 2-1 to 2-12) and their respective procedures will be the same as in
cycle 1, with the exception of day 26, as follows:
Day 26 (Visit 2-12)
• Recording of adverse events, disease staging according to Binet and the NCI criteria and
study treatment will be performed as for day 26 of cycle 1.
• Overall assessment of remission will be done, and on the basis of this assessment and the
disease staging it will be decided whether the patient must be withdrawn (if there is PD) or
may continue in the study (entry to treatment cycle 3 if there PR or SD, entry to
maintenance if there is CR). If PD is found, a further peripheral blood or bone marrow
sample is to be sent for genetic analysis (Section 8.8.2).
All the visits (visits 3-1 to 3-12) and their respective procedures will be the same as in
cycle 2. After Cycle 3, a maintenance phase with alemtuzumab or withdrawal from the study
and stem cell transplantation will be instituted.
8.5 Treatment and assessment in the maintenance phase
Treatment with alemtuzumab will take place at 14-day intervals. Each of these treatment
visits (visits M-1, M-2 etc.) will be scheduled to take place 14 days after the previous one, and
must take place on the date scheduled or within the following seven days (i.e., 14–21 days
after the previous administration). Thus, the reference date for each administration is the
previous one, rather than the first one.
Assessment procedures will be performed at intervals of three calendar months; these
procedures will be conducted at a scheduled treatment visit as close as possible to three
months after the last assessment (i.e., the patient will not attend the investigation site
separately for assessment).
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Assessment procedures will also be performed if the patient is seen because of unexpected
events (i.e. PD) outside the scheduled 3-monthly intervals (see also the section on concluding
examination, below).
Maintenance treatment visits
• A general clinical examination will be performed, including B-symptoms, infection, lymph
nodes (bidimensional), liver and spleen.
• The patient's WHO performance status will be recorded.
• Blood samples will be taken for hematological and chemical tests (10–20 ml) and for CMV
viremia (5 ml).
prophylaxis as appropriate).
Assessment visits (including treatment)
viremia (5 ml).
• Only if the result of the clinical examination is compatible with PR or CR:
– A blood sample will be taken for MRD determination at the reference laboratory (10 ml)
• Only if the result of the clinical examination is compatible with CR:
– A bone marrow sample will be taken for cytological and histological analysis (may be
omitted, if a bone-marrow sample for cytological and histological analysis
(documentation of CR) was already performed within the staging of the main study
treatment). (CR confirmation only once).
– CT scan (if indicated)
• Disease staging according to Binet and the NCI criteria (as at screening) will be performed.
prophylaxis as appropriate).
• On the basis of the disease staging it will be decided whether the patient must be withdrawn
(if there is PD) or may continue maintenance treatment (if there is CR, PR or SD).
• If PD is found, a further peripheral blood or bone marrow sample is to be sent for genetic
analysis (Section 8.8.2).
8.6 Concluding examination
When a patient is withdrawn from the study, for whatever reason, a concluding visit will take
place. The following procedures will be conducted (however, any procedure that has been
performed within the past two weeks need not be repeated):
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viremia (5 ml).
• Only if the result of the clinical examination is compatible with PR or CR or if PD is
suspected:
– A blood sample will be taken for MRD determination at the reference laboratory
(10 ml), and
– A bone marrow sample will be taken for cytological and histological analysis (CR
confirmation only once).
• The following imaging procedures will be performed, as appropriate:
If PD is found, a further peripheral blood or bone marrow sample is to be sent for genetic
8.7 Follow-up contact
After conclusion of study treatment, the patient will visit the study center at three-month
intervals. The following procedures will be performed:
viremia (5 ml).
• Only if the result of the clinical examination is compatible with PR or CR or if PD is
suspected:
– A blood sample will be taken for MRD determination at the reference laboratory
(10 ml), and
– A bone marrow sample will be taken for cytological and histological analysis (CR
confirmation only once).
• The following imaging procedures will be performed, as appropriate:
If PD is found, a further peripheral blood or bone marrow sample is to be sent for genetic
The study center will contact the patient shortly beforehand to remind him/her of the
forthcoming visit. Documentation of the disease status during the follow-up period is
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performed until closure of the study. If it is established that the patient has died, the date of
death will be recorded.
8.8 Laboratory tests
8.8.1
Locally conducted laboratory tests
The following tests will be carried out at the investigator's local laboratory:
Hematological tests
– Erythrocyte count
– Hemoglobin
– Hematocrit
– Thrombocytes (platelets)
– Leukocyte count (total)
– Leukocyte count (differential) including lymphocytes, basophils, neutrophils, eosinophils,
monocytes
– ESR (1-hour and 2-hour) (only at screening)
– Immunophenotyping (only at screening)
– Coombs test (only at screening and at concluding visit)
Chemical tests
– Lactate dehydrogenase (LDH)
– ASAT
– ALAT
– Serum alkaline phosphatase (AP)
– γ-glutamyl transferase (γ-GT)
– Serum bilirubin
– Total protein (only at screening and at concluding visit)
– Albumin (only at screening and at concluding visit)
– Immunoglobulins IgG, IgA, IgM (only at screening and at concluding visit)
– Creatinine
– Creatinine clearance
Serological screening and routine testing for CMV viremia
– Standard detection tests: HBV, HCV, HIV and CMV (only at screening visit)
– Detection of CMV viremia by pp65 antigen or by CMV-DNA PCR.
8.8.2
Centrally conducted laboratory tests
The following tests will be carried out at the reference laboratories stated below. The samples
used for these tests will be destroyed after completion of the study.
8.8.2.1 Serum markers thymidine kinase, β-2-microglobulin
This will be performed at the Institute of clinical chemistry, Ludwig Maximilian University of
Munich. Along with the appropriate documentation form, 5 ml of freshly centrifuged serum
will be sent to:
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(dispatch Monday–Thursday only)
CLL Study
CLL Studien
Marchioninistr. 15
D–81377 München
Tel.: +49 / 89 / 7095-3213 or -3220
8.8.2.2 Genetic tests
The reference laboratory for genetic testing (genomic aberrations, SNP chip, mutation status
of p53, ATM, and IgVH, miR and mRNA-expression analyses, ZAP-70 and CD38) is at the
University of Ulm (Prof. Dr. S. Stilgenbauer, Prof. H. Döhner). A volume of 40 ml peripheral
blood or 5–10 ml bone marrow (in cases of low CLL cell count in peripheral blood) are to be
treated with heparin (volume of blood or bone marrow to volume of heparin = 10:1), mixed
and sent, along with the appropriate documentation form (see Appendix) to the following
address:
Zytogenetisches Labor
Monday–Thursday by express post
Friday by express courier (e.g., TNT)
Universitätsklinikum Ulm
Robert-Koch-Str. 8
D-89081 Ulm
Tel.: +49 / 731 / 500-45810 or -45501; Fax: +49 / 731 / 500-45505
To allow monitoring of disease progress, a further sample is to be sent if PD is established.
8.8.2.3 MRD diagnosis (quantitative CDR3 PCR, FACS)
Patients who experience PR or CR are to be tested for MRD by quantitative CDR3 PCR and
FACS. This presupposes that the original genetic reference diagnosis (see Section 8.8.2.2)
has been carried out to determine the clonal IgVH sequence.
If PR or CR is achieved (for timing see tables in Section 1.2), 10 ml peripheral blood and 5 ml
bone marrow are treated with EDTA (volume of blood or bone marrow to volume of EDTA =
10:1) and sent, along with the appropriate documentation form (see Appendix) to the
following address:
Dr. S. Böttcher / Dr. M. Ritgen / Prof. M. Kneba
Wiss. Labor / Molekulargenetik
II. Medizinische Klinik
Chemnitzstraße 33
D-24116 Kiel
Tel.: 0431-1697- 1265 /-5231; Fax: 0431-1697-1287
8.8.3 Dispatch of samples to the central laboratories
The following table summarizes the quantities, study dates and destinations of the various
samples for central laboratory diagnostic testing.
At screening:
• 5 ml serum to Munich
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• 40 ml blood (heparinised) or 5–10 ml bone marrow (heparinised) to Ulm
• 10 ml peripheral blood (in EDTA) or 5 ml bone marrow (in EDTA) to Kiel.
In the four treatment cycles, if there is evidence of PR or CR:
• 10 ml peripheral blood (in EDTA) and 5 ml bone marrow (in EDTA) to Kiel.
In the maintenance phase, if there is evidence of PR or CR:
In the follow-up phase, if there is evidence of PR or CR:
In case of progressive disease (PD):
• 40 ml blood (heparinised) or 5–10 ml bone marrow (heparinised) to Ulm
9. CHARACTERISTICS OF ALEMTUZUMAB
9.1 Composition of alemtuzumab
Alemtuzumab is sold under the trade name MabCAMPATH® in glass vials, each containing
1 ml of a colorless solution of 30 mg alemtuzumab and, in addition, disodium ethylene
diamine tetraacetate, polysorbate 80 and phosphate-buffered saline comprising potassium
chloride, sodium chloride, disodium phosphate, potassium dihydrogen phosphate and water
for injection. The ampoules have a rubber septum for withdrawal of the contents by
hypodermic needle.
9.2
Method of administration
Before use, the contents of the ampoule should be checked to ensure that no precipitation or
discoloration has occurred; if this is the case, then the ampoule should not be used.
For subcutaneous administration (as used in this study), the content of an ampoule of
alemtuzumab (1 ml., containing 30 mg alemtuzumab) is taken up into a 2-ml syringe. As
alemtuzumab solution contains no preservatives, attention must be paid to maintaining
sterility in handling and administration. One syringe full of 1 ml alemtuzumab solution
(containing 30 mg alemtuzumab) is injected into the left or right thigh, with care being taken
to avoid repeated use of exactly the same injection site (i.e. alternating left/right sides at
successive visits). Before administration of the injection, the skin should be disinfected. At
the start of subcutaneous treatment, local reactions can be experienced, such as mild swelling
and reddening of the skin, sometimes painful; such reactions decrease during continued
therapy.
9.3 Storage
Alemtuzumab ampoules must be kept refrigerated at 2–8 °C. They must be protected from
light and must not be frozen.
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10. SAFETY ASPECTS OF THE STUDY
10.1 Monitoring the progress of the trial and the safety of patients
The coordinating investigator (CI) will arrange for monitoring of the trial progress by an
appropriate organization (WiSP Wissenschaftlicher Service Pharma GmbH, Langenfeld).
Information about the progress of the trial will be communicated at regular intervals to a Data
Safety Monitoring Board (DSMB, members: R. Busch, H. Döhner, P. Dreger, U. Dührsen, M.
Hallek, U. Jäger, M. Kneba, S. Stilgenbauer). It will review the data on safety, tolerability, and
efficacy. The DSMB is authorized to recommend early termination of the study. In addition,
information about the progress of the trial will be communicated at monthly intervals to the
coordinating investigator (CI), the Central Study Office of the German CLL Study Group
(GCLLSG), and the central biometry (R. Busch).
Patients will be observed at study visits – and daily, if they are in-patients – for signs and
symptoms of toxicity or other complications. Any findings will be documented in the
patient's records and the CRFs. Additionally, the keeping of a “patients diary” is mandatory
for this study. All applications of study medication, other medications as well as hematological tests and transfusions will be recorded in the “patients diary”.Toxicity will be graded
according to the National Cancer Institute Common Terminology Criteria for Adverse Events
(CTCAE), version 3.0.
Serious adverse events are to be reported without delay to the Central Study Office of the
German CLL Study Group (GCLLSG) according to procedures laid down in this protocol
(Section 10.3) and the corresponding SOP of the Central Study Office.
The study design (Section 5.1) includes frequent assessment of the patients' disease and the
potential toxicity of the treatment, in order to avoid unnecessary continuation of the study if
the treatment is found to be inefficacious or to have unacceptable toxicity. The DSMB will
evaluate the risk/benefit ratio for the patients at regular intervals, based on summary data
reported by the Data Management Office.
10.2 Reporting of adverse events
Investigators are to complete the “Adverse event” section of the CRF. This information will
be communicated to the Monitors at WiSP along will all other data and subjected to regular
review as stipulated in Section 10.1.
10.3 Reporting of serious adverse events
10.3.1 Definition
A serious adverse event (SAE) is classified as any untoward medical occurrence that:
– results in death, or
– is life-threatening, or
– requires the patient's hospitalization or prolongation of existing hospitalization, or
– results in persistent or significant disability/ incapacity, or
– is a congenital anomaly/ birth defect.
The following events are not considered as SAEs within the framework of this study,
even if the fulfill one or more of the criteria given above:
– events that are unequivocally caused by the underlying disease (CLL) and/or its progression
– elective hospitalizations, not related to actual adverse drug reactions
– events that are clearly related to / caused by salvage therapies
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Medical and scientific judgment should be exercised in deciding whether expedited reporting
is appropriate in other situations, such as important medical events that may not be
immediately life-threatening or result in death or hospitalization but may jeopardize the
patient or may require intervention to prevent one of the other outcomes listed in the
definition above. These should also usually be considered serious. Examples of such events
are intensive treatment in an emergency room or at home for allergic bronchospasm; blood
dyscrasias or convulsions that do not result in hospitalization; or development of drug
dependency or drug abuse. The investigator should take appropriate diagnostic and
therapeutic measures to minimize the risk to the patient. Where appropriate he/she should
take diagnostic measures to collect evidence for clarification of the relationship between the
SAE and the investigational product. The investigator must submit a complete SAE Report
for all serious adverse events. Once an investigator becomes aware that an SAE has occurred,
the event will be reported to the Central Study Office of the German CLL Study Group
(GCLLSG) within one working day.
The SAE Report Form will always be completed as thoroughly as possible with all available
details of the event, signed by the investigator (or designate). If not all information regarding
an SAE is available within the required time frame, the report will be up-dated when
additional information is received. For reported deaths, the investigator is required to supply
any additional available information (e.g. autopsy reports or terminal medical reports). As all
adverse events will be treated in this manner, no separate rules are laid down for
theinvestigator’s reporting of SUSARs. The report is to be sent to:
Central Study Office of the German CLL Study Group (GCLLSG)
Cologne University Hospital
Klinikum der Universität zu Köln
Klinik I für Innere Medizin
D–50924 Köln
Tel.: +49 / 221 / 478-3988
Fax: +49 / 221 / 478-86886
http://www.dcllsg.de
The Central Study Office of the GCLLSG will forward the SAE report to the monitoring
organization and to the coordinating investigator within one working-day.
A SAE not listed in the SmPC and for which a causal relationship to the study drug cannot be
excluded is defined as a SUSAR (suspected unexpected serious adverse reaction). The
coordinating investigator will decide, whether a SAE fulfills the criteria of a SUSAR.
The monitoring organization will ensure timely reporting to regulatory authorities or ethics
committees according to applicable law and, in parallel with this, to the study drug's
manufacturer Bayer Schering AG (e-mail [email protected]; fax +49 – 30
– 468 96765). These notifications shall include the investigator’s assessment concerning
causality.
Furthermore, the coordinating investigator through the monitoring organization will inform
Bayer Schering AG immediately of any communication concerning safety-related information
to regulatory authorities or ethics committees including, but not limited to:
– Annual safety reports for the study
– Any other safety-related reports, issues and queries that are either raised by or
communicated to regulatory authorities or ethics committees.
Relevant safety issues from all ongoing clinical trials will be communicated by Bayer
Schering AG to the coordinating investigator.
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All SAEs occurring after signature of the informed consent must be documented.
In addition, SAEs will also briefly be recorded on the ‘Baseline Findings’ CRF page if they
occur before administration of the study treatment and on the “Adverse Event Form” of the
CRF if they occur after administration of study treatment.
10.4 Termination of the study
Any decision to prematurely terminate the study as a whole will be made by the DSMB
and/or the sponsor. Criteria for termination of the study as a whole are:
• An unacceptable profile, or incidence rate, of adverse events revealed in this or any other
study in which alemtuzumab is administered.
• Demonstration that the study treatment is ineffective or only insufficiently active.
• Excessive frequency or severity of local reactions.
• Excessive frequency of Grade III/IV adverse events.
• Significant number of cases of death associated with the study treatment.
• Any other factor that in the view of the DSMB and/or the sponsor constitutes an
adequate reason for terminating the study as a whole.
11. DATA MANAGEMENT, EVALUATION UND STATISTICS
11.1 Data Management
Case record forms (CRFs) will be provided to investigation sites by the monitoring
organization (cf. Section 12.1). Sites will receive instructions on when to detach and return
CRF pages. Investigators will be required to keep CRFs up to date, so that pages can be
detached and returned at short notice.
Data entry will be performed twice, by at least two persons independently. The double entry
will be validated and cross-checked by a computer program.
Patients will be informed that data on their disease and its course will be stored electronically
in an anonymous way. Each patient has the right to know, which information has been stored
electronically.
The statistical evaluation will be performed at the Institut für Medizinische Statistik und
Epidemiologie (IMSE) of the Technical University, Munich (Dipl. Math. R. Busch).
11.2 Statistical aspects
11.2.1 General design
The present trial is designed as a phase II study which aims at estimating the anti-tumor
effect of alemtuzumab treatment in combination with dexamethasone in two selected highrisk populations of patients, who were shown (cohort 1) to be resistant against or are expected
(cohort 2) to be insufficiently effectively treated by fludarabine-based treatment. As the two
cohorts are clearly different in respect of their disease status and their chance of response, a
separate estimation of efficacy in the groups is required.
11.2.2 Sample-size estimate
The result of this study is intended to be compared with those of the earlier CAM211,
CLL2H, and CLL4 studies. The anticipated number of patients and rate of recruitment in this
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study are based on experience from multi-center trials of the DCLLSG, particularly in
connection with the earlier trials CLL4 and CLL2H. Enrollment of 95 patients with
fludarabine-refractory CLL or 17p deletion should be possible over less than three years, as
follows:
~65 patients with fludarabine-refractory CLL (irrespective of whether they have 17p deletion
or not),
~15 patients with 17p deletion for first-line therapy (i.e., patients who have received no
therapy for CLL),
~15 patients with 17p deletion for second- or higher-line treatment who are not (yet)
fludarabine-refractory.
Recruitment will be tracked by GCLLSG Central Study Office, so that if necessary
recruitment in one or two of the above categories can be stopped selectively, when enough
patients in that category have been recruited.
Cohort 1:
The objective response rate (ORR = number of (CR+PR) / number of evaluable subjects)
according to the NCI working-group criteria is chosen as primary efficacy endpoint for both
cohorts. In cohort 1, consisting of cases refractory to fludarabine, an alemtuzumab treatment
for twelve weeks achieved an ORR of 33 to 37% (CAM211, CLL2H). Thus, the primary
objective of this study for cohort 1 is to show a clinically meaningful improvement of this
response rate (i.e. an increase of at least 15%).
Since alemtuzumab single-drug therapy has already shown sufficient activity in the salvage
treatment of patients with fludarabine-resistant disease in the CAM211 and CLL2H trials, the
application of a two-stage design, allowing for early termination in case of inefficacy, is not
necessary. Thus, a single-stage design according to the method of Fleming (1982) is selected,
based on the following assumptions:
• The experimental treatment under study in this trial would be considered as not
sufficiently effective (i.e. no relevant additional effect of intensification) if the true
response rate is lower than 35%.
• The intensified therapy would be regarded as a very promising candidate for further
investigation (e.g. in a phase III comparative trial) if the true ORR exceeds 50%.
• The probability of erroneously declaring the alemtuzumab/dexamethasone combination as
sufficiently active for further investigation in spite of a true response rate of less than 35%
(type I error), is set at 5%.
• The probability of erroneously rejecting the new combination therapy as not sufficiently
active (<35%) in the case of a true promising response rate (>50%) is 20% (type II error),
corresponding to a power of 80%.
According to these parameters n = 65 evaluable patients are required in this part of the phase
II trial. (This number is only marginally influenced in case of a general shift of the
assumptions, e.g. to 40% vs. 55%, which leads to n = 67. However, narrowing the gap
between futility and success rate to 10%, e.g. between 35% and 45% would distinctly increase
the sample size to 107, even if the type one error is raised to 10%.)
The precision of the estimation of the response rate in the study is provided by confidence
intervals in the following table, for different actual response rate findings:
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V. 1.1 / 25.04.2007
overall response rate
exact 90% confidence interval
23/65 (≈ 35%)
24 ... 48 %
26/65 (= 40%)
28 ... 53 %
33/65 (≈ 50%)
38 ... 63 %
Page 47 of 60
Cohort 2:
In cohort 2, consisting of cases with 17p deletion, standard chemotherapy including
fludarabine achieved a comparatively low response rate of only 54% in the CLL4 study in
patients without fludarabine pre-treatment. As pre-treated patients are allowed to be recruited
into this cohort, 50% may be considered as an appropriate estimate for baseline ORR. As a
response rate of approx. 50% was observed for this high risk mutation subgroup in the
CLL2H protocol with s.c. alemtuzumab, albeit all of these patients were refractory to
fludarabine, an increase to 70% or more seems to be a realistic goal with
alemtuzumab/dexamethasone therapy.
Again, as alemtuzumab single drug therapy has already shown sufficient activity in this high
risk population, and as there is no established standard treatment with high long-term efficacy
in this subgroup, the application of a two-stage design, allowing for early termination in case
of inefficacy, is not necessary. The single-stage design according to Fleming (1982) for cohort
2 is based on the following assumptions:
•
The experimental treatment under study in this trial would be considered as not
sufficiently effective (i.e. no benefit compared to fludarabine-based chemotherapy), if
the true response rate is lower than 50%.
•
The alemtuzumab/dexamethasone therapy would be regarded as a very promising
candidate for further investigation (e.g. in a phase III comparative trial), if the true ORR
exceeds 70%.
•
The probability of erroneously declaring the alemtuzumab/dexamethasone combination
as sufficiently active for further investigation in spite of a true response rate of less than
50% (type I error), is set at 5%.
•
The probability of erroneously rejecting the antibody combination therapy as not
sufficiently active (<50%) in case of a true promising response rate (>70%) is 30%
(type II error), corresponding to a power of 70%.
According to these parameters n = 29 evaluable patients are required in the second cohort. (If
a more optimistic upper margin of 75% is chosen against the futility rate of 50%, n = 18 have
to be recruited.)
The precision of the estimation of the response rate in the experimental arm is provided by
confidence intervals in the following table, for different actual response rate findings:
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V. 1.1 / 25.04.2007
overall response rate
exact 90% confidence interval
15/29 (≈ 50%)
35 … 68%
18/29 (≈ 60%)
45 … 77%
21/29 (≈ 70%)
55 … 86%
Page 48 of 60
Separately in both cohorts, the final conclusion of the phase II trial will depend on the definite
overall response rate (and its confidence interval), the comparison with patient population and
efficacy findings in the CLL4 and CLL2H studies as well as the information on type,
frequency and severity of toxicities.
According to the recruitment assumptions provided at the beginning of this section, two to
three years are necessary to recruit these patient numbers.
11.2.3 Evaluation categories of patients
Patients unequivocally not fulfilling the selection criteria of the trial a priori ("non-eligible")
will be excluded from the statistical analysis. Only casuistic reports will be provided for this
group.
All other patients recruited to the study will primarily be evaluated in an intent-to-treat
analysis of the primary endpoint (including all early drop-outs with insufficient restaging
information) if they received at least one dose of treatment. A second analysis ("per
protocol") will include only patients with at least one fully completed treatment cycle of 4
weeks (12 x 30 mg alemtuzumab, and 2 x 4 days of 40 mg dexamethasone) according to the
study plan (except for cases of unequivocal early progression during therapy).
All patients having received at least one application of study therapy are evaluable for
toxicity.
11.2.4 Definition and assessment of efficacy endpoints
The efficacy endpoints will be assessed according to the NCI guidelines (Cheson et al., 1996;
Appendix).
The methods for assessment of the efficacy of the treatment (efficacy variables) will be:
• Clinical examination to assess state of disease (CR, PR, SD, PD according to the NCI
criteria; these are given in the Appendix)
• Imaging (ultrasound and chest X-ray), mandatory
• Bone marrow histology (only in case of possible CR)
• MRD testing (bone marrow and peripheral blood) (for molecular response rate only)
• CT scans (if indicated).
Time points for response evaluation according to NCI criteria will be:
• The end of each treatment cycle: after 12 doses (4 weeks actual treatment), 24 doses (8
weeks actual treatment), and 36 doses (12 weeks actual treatment) of alemtuzumab
• During maintenance therapy, every three months
• During follow-up, every three months
• A final response assessment will be made at the end of study treatment if the patient's
participation is ended at a point other than one of those specified above.
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Time-to-event endpoints are defined as follows:
• Progression-free survival: time from study entry to the detection of progressive disease
according to NCI criteria or death of any cause, whichever occurs first.
• Failure-free survival: time from study entry until next treatment, detection of progressive
disease according to NCI criteria or death of any cause, whichever occurs first.
• Overall survival: Time from study entry to death of any cause.
11.2.5 Statistical methods
All parameters will be evaluated in an explorative or descriptive manner, providing means,
medians, ranges, standard deviations and/or confidence intervals. If p values are calculated
(e.g. in subgroup comparisons or when comparing the results with defined subpopulations of
the CLL4 and CLL2H trials), they will be presented explicitly without referring to hypotheses
or a significance level. Usually, no error adjustment for multiple testing will be performed.
Thus the p values will reflect the comparison-wise error and not the experiment-wise error.
All p values will be two-sided if not stated otherwise. The statistical methods described in
this section are suited for the data and distributions usually expected in this type of trials. The
suitability will be checked after data entry. If necessary, the statistical method will be
modified accordingly.
Toxicity, response and progression or survival rates at specific time points will be calculated
and confidence intervals will be provided. For comparison between patient subgroups, these
rates will be analyzed by Fisher's exact test, the χ² test or the Mantel-Haenszel test (or trend
test according to Cochran/Armitage).
Event-related data (e.g. overall or progression-free survival, time to response) will be
estimated by the product limit method (Kaplan et al., 1958). Prognostic subgroups or
historical patient groups will, if appropriate, be compared by using the logrank test. If the
Peto logrank test (Peto et al., 1972; Peto et al., 1976) is not appropriate because of violation
of the proportional hazard assumption (Haybittle, 1988), then Gehan's generalization of the
Wilcoxon rank sum test for censored data (Gehan, 1965) may be applied, preferably in its
modification by Peto (Peto et al., 1972) and Prentice (Prentice, 1978).
Multivariate analyses will be performed by suitable regression models (logistic regression,
proportional hazard regression model (Cox, 1972)).
11.2.6 Interim and final analyses
As described and justified in Section 11.2.2, no formal interim analysis at pre-specified time
points is planned. Nevertheless, a DSMB will be allowed to retrieve descriptive analytical
data (especially concerning adverse events) during the course of the trial (cf. Section 10.1).
Exploratory interim analyses are allowed.
The final biometrical evaluation of the study and the compilation of the statistical report as
part of the integrated clinical/biometrical report will be performed after termination of the last
patient’s maintenance phase as well as after completion and/or correction of all case report
forms. An additional analysis report on long-term results may be written, if further data on the
patients’ relapse/survival status are retrieved beyond this time point.
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12. STUDY DOCUMENTATION, ARCHIVING AND QUALITY
ASSURANCE
12.1 Documentation and information flow
All patient-related data will be recorded in a pseudonomized way. Each patient will be
unequivocally identified by a trial subject number, attributed at recruitment into the study.
The investigator is required to keep a patient identification log, including the full name and
address of the subject and eventually additional relevant personal data such as hospital record
number, home physician etc.
All the data retrieved during the conduct of the study are to be entered into the appropriate
case record forms (CRF) by the investigator or another person authorized by the investigator
(co-investigator). The CRFs will be provided by the monitoring organization and explained to
the investigators/documentation personnel during a study group meeting.
All recorded data are to be plausible and complete. The following technical instructions are
to be adhered to when the CRFs are used:
• Use black or blue ballpoint pens only in order to insure that all copies are legible.
• Write only one letter or numeral in each of the open boxes of the data fields. Closed boxes
are to be crossed only (“check-boxes”).
• All data fields have to be filled, except for those referring to open questions. If a specific
test was not performed or an information item is definitely not available or applicable,
information on this should be provided (not done= ND, not applicable, not available = NA,
unknown= UK).
• If a date is not known exactly, please fill in the respective field according to the following
example: – – 08 05.
• If any corrections have to be performed in the CRF by the investigator or co-investigator,
they have to be performed according to GCP principles, i.e. the original entry has to be
crossed out but remain legible. The correct version is then written legibly beside or above
the original one. The correction (or addition) is to be dated and signed or initialed.
Version to be corrected:
Corrected version:
2 date, initials
1
2
day
1
3
month
0
3
1
year
2
day
1
3
month
0
3
year
• Please write legibly and use block letters.
The investigator is obliged to complete the case report forms within a reasonable time period
after retrieval of the data (i.e. usually within 2 weeks). The completed forms are signed by
the investigator, where necessary. The original has to be sent to the data management office
or handed over to the monitor in case of on-site visits. A copy remains with the investigator.
The study office or monitor checks the forms for completeness and plausibility. In case of
queries, the form or a photocopy of it will be sent or given back to the investigator for
clarification, correction or completion as required.
After finalization of the data checks by the monitor the originals or fair copies are sent to data
management. If additional queries arise there during computer data entry, they will be
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handled by the investigator through the monitor or study office contacts. After finalization of
computer data entry and cleaning of the data, the raw data are sent to the biometrical center.
12.2 Data archiving
The trial master file will be archived by the coordinating investigator for at least 10 years after
termination of all study-related procedures. The original forms of all data-related documents
including CRFs are to be stored at the data management office for at least 10 years after
completion of the final study report.
The investigators at the participating centers are to archive major administrative documents
(investigator site file) with correspondence with ethics committee, authorities, sponsor etc.,
the patient identification log, the signed informed consent forms, and the main study
documents (protocol, amendments), for the same period. The original patient records have to
be archived according to the standard procedures of the respective institution, but at least for
10 years.
12.3 Quality assurance
12.3.1 Standardization
The evaluation criteria are similar for all participating centers. Each center has to report its
normal ranges for hematology and blood chemistry to the monitoring organization. The
respective laboratory institutions have to participate in an appropriate quality assurance
program. Toxicity will be recorded in a standardized way according to the NCI CTCAE
criteria for categorization and grading. Evaluation of efficacy will be performed according to
standards resulting from an NCI workshop (Cheson et al., 1996).
12.3.2 Monitoring / source data verification
The study will be monitored externally by regular site visits and telephone calls to the
investigator by personnel authorized by the coordinating investigator (WiSP
Wissenschaftlicher Service Pharma GmbH). Queries or monitoring visits may take place
before, during and after recruitment of patients into the study. The number of contacts will
depend on the characteristics of the respective center, e.g. the number of recruited patients.
According to the investigator's agreement, the monitor is allowed to access the trial
documentation and the patients' personal medical records in the participating center.
In order to ensure the quality of the data, all entries into the CRFs are formally inspected for
completeness and plausibility. During site visits, an additional control with respect to identity
of the data recorded in the personal patient records and in the CRF (Source Data Verification)
may be performed. The latter will proceed according to a random sample plan, while key
information of the trial such as major selection criteria, as well as data concerning the primary
endpoint, will be checked on a 100% basis.
The list of points to be observed and source-data-verified in a random sample, respectively,
(below) is intended to assist the monitors in their assessment of items that affect significantly
the evaluation of the clinical effectiveness of the treatment or of its toxicity. It is not intended
to be exhaustive.
12.3.2.1.1 Registration
• Correct registration of the patient with the GCLLSG Central Study Office and receipt of
approval for inclusion in the study before the patient was treated.
• It must be checked that the information given at registration and the data in the patient's
medical records (stage, active disease, immunophenotype, F-refractory disease, etc.) are
identical.
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12.3.2.1.2 Informed Consent / IRB approval
• Signature of the Informed Consent and Transfer of Property forms before registration.
• IRB approval of the study protocol and relevant associated documents (e.g. Patient
Information) after appropriate review, before inclusion of the first patient at the site.
• IRB approval of any protocol amendments.
12.3.2.1.3 Patient eligibility
• Correspondence of the patients recruited with all inclusion and exclusion criteria.
• Adherence to the study protocol in respect of screening procedures.
12.3.2.1.4 Study tests/evaluation
•
•
•
•
•
Availability of results of protocol-specified laboratory tests and diagnostic examinations.
Administration of all study medication(s) according to protocol.
Accurate and complete documentation of administration of study medication(s).
Appropriate record of examinations, procedures and treatments stipulated in the protocol.
Correct and timely filling-in of the CRF, and timely return of filled-in CRF pages to the
Central Study Office of the GCLLSG.
12.3.2.1.5 Adverse events
• Recording of adverse events, and reporting of serious adverse events, according to
protocol.
Moreover, the monitor should observe study procedures, review document retention and will
discuss any problems with the investigator.
In case the monitors observes inadequate performance of a participating centers, in a way
which may jeopardize the ethical and/or scientific integrity of the study (e.g. a sequence of
major protocol violations, fraud, major documentation gaps), he/she will inform the
coordinating investigator and the sponsor. The coordinating investigator and the sponsor will
jointly decide on appropriate consequences in the best interest of the patients and the validity
of the trial.
12.3.3 Audits
In case of an audit by the sponsor or an appropriate authority the investigator will make
available all relevant documents. If an audit visit by a regional or federal authority is
announced, the respective center should inform the sponsor/co-ordinating investigator and the
monitoring organization (WiSP) as early as possible in order to allow for an appropriate
preparation and support. The inspected investigator or organizational institution of the study
will be informed on the result of the audit.
13. PROTOCOL AMENDMENTS
Any modifications to the protocol which may have an impact on the conduct of the study or
the potential benefit of the study, or which may affect patient safety – including changes of
study objectives, study design, patient population, sample sizes, study procedures, or
significant administrative aspects (cf. § 10, Abs. 1 GCP-V for the decision criteria) – will
require a formal written amendment to the protocol. Such an amendment will be agreed upon
by the investigators and the sponsor. It requires a new application to the responsible authority
and to the responsible ethics committee before implementation, according to §10, Abs. 2 to 4
GCP-V.
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Administrative or technical changes of the protocol such as minor corrections and/or
clarifications that have no effect on the way the study is to be conducted, nor on the risk–
benefit ratio, will be agreed upon by the sponsor and the investigator(s) and will be
documented in a memorandum to the protocol. The ethics committee responsible may be
notified of such changes at the discretion of the sponsor/co-ordinating investigator.
The monitoring organization on behalf of the sponsor has to assure, that all amendments have
been added to the study documents at any site involved in the trial.
14. ETHICAL AND LEGAL REQUIREMENTS
14.1 General requirements and agreements
The study will be performed according to current legal standards. The ICH E6 Harmonized
Tripartite Guideline for Good Clinical Practice, dating from 1997, will be taken into account.
In Germany, the requirements according to the following documents will be fulfilled:
Deutsches Arzneimittelgesetz (AMG, 12. Novelle, 2004), Grundsätze für die ordnungsgemäße
Durchführung der klinischen Prüfung von Arzneimitteln (Bundesanzeiger Nr. 243 vom
30.12.1987) and Verordnung über die Anwendung der Guten Klinischen Praxis bei der
Durchführung von klinischen Prüfungen mit Arzneimitteln zur Anwendung am Menschen from
9th August 2004. The co-ordinating investigator has at least two years of experience in
clinical trials on medicinal products. Universitätsklinikum Ulm (Ulm University Hospital,
Ulm, Germany), represented by the chairman of the board, is the sponsor of the study with
respect to GCP regulations (according to article 7 of the EC Commission Directive
2005/28/EC), since the trial at hand is a non-commercial or investigator-initiated clinical trial.
The sponsor is responsible for the trial master file according to chapter 4 of the EC Directive
2005/28/EC. The sponsor may delegate this function (or other requirements mentioned in the
previous or following sections) to another individual, a company, an institution or an
organization.
The participating institutions are selected by the coordinating investigator, based on the
proven qualification in the framework of previous trials in the cooperative groups. The
clinical centers will document their appropriate qualification and capacities for taking part in
the trial, in order to allow for a qualified decision of the (local) ethical committee on the
participation.
Country-specific regulatory aspects for France and Germany are to be found in
Appendix S and T.
14.2 Declaration of Helsinki
The trial will be performed in accordance with the Declaration of Helsinki, as decided upon
by the 18th World Medical Assembly, Helsinki, Finland, June 1964 (amended by subsequent
World Medical Assemblies in Tokyo, Japan, October 1975, Venice, Italy, October 1983, Hong
Kong, September 1989, Somerset West, South Africa, October 1996, and Edinburgh,
Scotland, 2000, including the Note of Clarification on Paragraph 29 added by the General
Assembly of the World Medical Association, Washington 2002).) The declaration is included
as an appendix.
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14.3 Informed consent of the patient
Before recruitment into this clinical trial, each patient will be informed that participation in
the study is completely voluntary, and that he or she may withdraw the participation in the
trial at any time without any declaration of reasons. This will not lead to any disadvantage for
the patient. If the withdrawal is caused by any adverse drug events, the patient should inform
the investigator about this fact. All data collected before the time point of withdrawal remain
within the study database (according to AMG § 40 (2a) 3). Consent will be sought from the
patient, in order to be allowed to report further major outcome information.
The treating physician will inform the patient about the drugs to be used and their possible
adverse effects. At the same time he/she will be informed on the nature and objectives of the
study, expected advantages of the participation, possible hazards of the study and alternatives
of treatment. The patient will also receive the necessary information on the trial-specific
insurance and his/her obligations in this connection. The patient will have sufficient time for
his/her decision and opportunity to ask additional questions. Moreover, the patient will
receive a written “patient information” (Appendix), containing all relevant information for the
patient's decision and the course of the study.
The consent of the patient to participate must be obtained in writing before recruitment into
the study. The informed consent form (Appendix) must be dated and signed by the patient.
Thereby, he/she declares his/her voluntary consent to participate in the study and his/her
willingness to comply with the requirements of the trial and the instructions of the treating
investigator during the course of the study.
There are two copies of the informed consent form: one for the patient and one to be kept by
the investigator in his study documents. The informed consent is only valid after receiving
the patient's signature. Thereafter, the patient can be entered into the study if he/she fulfils the
selection criteria.
With the declaration of consent the patient agrees to the recording of data on his/her disease
within the framework of the clinical trial and to their transfer to the sponsor and/or data center
in an pseudonymized way. Moreover, the patient agrees that delegates from the responsible
authorities or the sponsor (or his delegates) may have direct access to his/her original medical
records for trial related monitoring, audit, review and regulatory inspection. For these
purposes, the members of the study team are dispensed from their professional discretion.
In addition, the patient is asked to allow the usage and distribution of specimens obtained
during the study for scientific purpose via the Transfer of Ownership form (Appendix).
No compensation will be paid to the patients. The study subject may receive additional advice
from the competent authority
Paul-Ehrlich-Institut (PEI)
Paul-Ehrlich-Str. 51-59
D-63225 Langen
Tel. 06103 / 77 1811
14.4 Protection of data confidentiality
Most of the data retrieved in the course of the trial will be stored on electronic devices. These
data will be treated as confidential, and organizational procedures will be established in order
to prevent access to the data by unauthorized persons. In general, all data are reported and
stored in a pseudonymized way only, without the patient’s name and identified via a unique
patient number. The data protection laws of the respective federal states will be adhered to.
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The patient has the right to know, where his/her data are stored and who has access to these
data.
14.5 Registration and request for authorization of the trial
Before the start of the trial the sponsor/co-ordinating investigator has to issue a request for
authorization according to § 7, Abs. 1,2,4-6 GCP-V of the Bundesinstitut für Arzneimittel und
Medizinprodukte (BfArM) and/or to the Paul-Ehrlich-Institut, respectively. At the same time
he will issue a request for opinion to his ethics committee according to § 7, Abs. 1, 2, 3, 5 and
6 GCP-V. In addition, the request for opinion will be sent in parallel to the appropriate local
ethics committees in Germany, formed according to the law of the respective federal states
(§ 7, Abs. 1 GCP-V). On behalf of the individual investigators, the sponsor will also
announce all individual trial centers to the respective regional authority, according to § 67 of
the Arzneimittelgesetz and § 12, Abs. 1 GCP-V.
The respective federal authority will be informed on the course of the study (in parallel to the
Ethics Committee; Section 14.6), with respect to safety aspects to be announced (according to
§ 13 GCP-V, Abs. 1-6) as well as with respect to the termination of the trial and its results
(according to § 13 GCP-V, Abs. 8 and 9).
14.6 Ethics committee
Before the start of the trial the study protocol and all other requested documents (cf.
Section 14.5) will be sent to the responsible ethics committee of the sponsor/co-ordinating
investigator in order to receive its opinion. The trial is only allowed to start when a positive
vote of the ethics committee has been received. A copy of the letter of approval from the
Ethics Committee will be added as an appendix to this protocol. During the course of the
study the monitoring organization on behalf of the sponsor/ co-ordinating investigator will
inform the ethics committee about all study protocol amendments (cf. Section 13) as well as
all SUSARs from the trial according to § 13, Abs. 2 and 3 GCP-V. In addition, the ethics
committee will receive a report on all SAEs, and/or a statement on the safety of the study
subjects once a year or on request during the course of the study (according to § 13, Abs. 6
GCP-V). If need be, recommendations of the ethics committee will be included in the study
protocol.
In addition, the ethics committee will be informed by the sponsor/co-ordinating investigator
on the course of the study with respect to the termination of the study and its results
(according to § 13, Abs. 8 and 9 GCP-V).
Investigators participating in the trial are not allowed to take part in the decision of the ethics
committee. A list of the committee members as well as its statutes are included in the trial
master file.
14.7 Subject insurance
An indemnity insurance against any impairment the patient’s health occurring as a result of
participation in the study will be contracted for the trial subjects, in accordance with § 40,
Abs. 1, Nr.8 and Abs. 3 AMG. The patient will receive all the respective information of
relevance to him/her.
In order not to jeopardize insurance protection, any health damage occurring in connection
with participation in the clinical trial has to be immediately reported by the subject to the
insurance company. The patient has to take all appropriate measures to identify the cause and
extent of the damage as well as to limit its extent, if possible. Especially he/she is obliged to
• report any adverse event or additional medication to the treating investigator
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• consult the treating investigator before applying additional medication or other clinical
treatment.
In Germany, the insurance is provided by Gerling Allgemeine Versicherungs AG, Düsseldorf,
policy number („Versicherungsnummer“) 70-005627793-0 (Contact: Ecclesia Mildenberger
Hospital GmbH, Klingenbergstrasse 4, D-32758 Detmold. Mrs. Henrike Biedermann, Tel.
++49 (0)5231 6036 377).
14.8 Information on study drugs to trial investigators
The investigators will receive all relevant and up-to-date clinical and pre-clinical information
on the study drugs (investigator's brochure; or SmPC/Fachinformation in case of registered
drugs). When additional data of relevance for the conduct of the study become known, they
will be distributed to the investigators via an amendment to or an up-dated version of the
existing IB/SmPC.
14.9 Financing
The CI and the sponsor will take care of the financing/funding of the study. The study will be
funded in part by a non-restricted grant from Bayer Schering AG and Amgen GmbH.
Alemtuzumab will be provided by Bayer Schering AG free of charge as a grant for the study
for patients in cohort 2 (not fludarabine-refractory) and for the maintenance treatment.
15. PUBLICATION POLICY
The results of the study will be evaluated by the coordinating investigator and, where
appropriate, by members of the protocol committee. All publications resulting from this study
will be the responsibility of the coordinating investigator, and the authorship will reflect the
contribution of each collaborating center and organization.
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16. REFERENCES
Bellosillo B, Villamor N, López-Guillermo A, Marcé S, Bosch F, Campo E, Eili Montserrat E, Colomer D
(2002). Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in Bcell chronic lymphocytic leukemia. Blood 100(5): 1810–6.
Binet JL, Auquier A, Dighiero G et al. (1981). A new prognostic classification of chronic lymphocytic leukemia
derived from a multivariate survival analysis. Cancer 48: 198–206.
Bowen AL, Zomas A, Emmett E et al. (1997). Subcutaneous Campath-1H in fludarabine-resistant/relapsed
chronic lymphocytic and B-prolymphocytic leukaemia. Br J Hematol 96: 617–619.
Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR (1996). National Cancer Institutesponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and
treatment. Blood 87(12): 4990–7.
Cox DR (1972). Regression models and life tables. J Roy Stat Soc (B) 34: 187–202.
Crespo M, Bosch F, Villamor N, et al. (2003). ZAP-70 expression as a surrogate for immunoglobulin-variableregion mutations in chronic lymphocytic leukemia. N Engl J Med 348: 1764–1775.
Damle RN, Wasil T, Fais F, et al. (1999). IgV gene mutation status and CD38 expression as novel prognostic
indicators in chronic lymphocytic leukemia. Blood 94(6): 1840–7.
Döhner H, Fischer K, Bentz M, et al. (1995). p53 gene deletion predicts for poor survival and non-response to
therapy with purine analogs in chronic B-cell leukemias. Blood 85: 1580–1589.
Döhner H, Stilgenbauer S, Benner A, et al. (2000). Genomic aberrations and survival in chronic lymphocytic
leukemia. N Engl J Med 343(26): 1910–1916.
Dreger P, Stilgenbauer S Böttcher S, Bunjes D, Ottinger H, Beelen D, Cohen S, Schubert J, Hertenstein B,
Basara N, Humpe A, Ritgen M, Zeis M, Schmitz N, Hallek M, Kneba M, Döhner H and the German CLL Study
Group (2005). Long-term disease control of poor-risk chronic lymphocytic leukemia (CLL) by allogeneic stem
cell transplantation with nonmyeloablative conditioning (NST): Interim results of a prospective study. Ann
Oncol 16 (Suppl 5), abstract no. 42.
Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M,
Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M; German CLL
Study Group (2006). Fludarabine plus cyclophosphamide versus fludarabine alone in first line therapy of
younger patients with chronic lymphocytic leukemia. Blood 107(3): 885–91.
El Rouby S, Thomas A, Costin D, et al. (1993). p53 gene mutation in B-cell chronic lymphocytic leukemia is
associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 82: 3452–3459.
Fleming TR (1982): One-sample multiple testing procedure for phase II clinical trials. Biometrics 38: 143–151.
Flinn IW, Byrd JC, Morrison C, et al. (2000). Fludarabine and cyclophosphamide: a highly active and well
tolerated regimen for patients with previously untreated chronic lymphocytic leukemia (CLL). Blood 96(1): 71–
75.
Gehan E (1965): A generalized Wilcoxon test for comparing arbitrarily single censored samples. Biometrika 52:
203–223.
Geisler CH, Philip P, Egelund Christensen B, et al. (1997). In B-cell chronic lymphocytic leukaemia
chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the
prognosis: A cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients. Leuk Res
21: 1011–1023.
Haybittle JL (1988): Significance testing in the comparison of survival curves from clinical trials of cancer
treatment. Rec Res Cancer Res 111: 75–81.
Hallek M, Schmitt B, Wilhelm M, et al. (2001). Fludarabine plus cyclophosphamide is an efficient treatment for
advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group.
Br J Hematol 114(2): 342–348.
Hallek M, Langenmayer I, Nerl C et al. (1999). Elevated serum thymidine kinase levels identify a subgroup at
high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood 93(5): 1732–7.
57
V. 1.1 / 25.04.2007
Page 58 of 60
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999). Unmutated Ig V(H) genes are associated
with a more aggressive form of chronic lymphocytic leukemia. Blood 94(6): 1848–54.
Kaplan EL, Meier P (1958): Nonparametric estimation from incomplete observations. J Am Stat Ass 53: 457–
481.
Keating M, Rai K, Flinn I et al. (2002). Therapeutic role of alemtuzumab (Campath-1H) in patients who have
failed fludarabine: results of a large international study. Blood 99(10): 3554–61.
Keating MJ, O'Brien S, Kontoyiannis DP, Plunkett W, Koller C, Beran M, Lerner S, Kantarjian H (2002a).
Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia.
Leukemia and Lymphoma 43: 1755–1762.
Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai
KR (2002b). Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of
a large international study. Blood 99(10): 3554–61.
Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D,
Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H (2005). Early results of a chemoimmunotherapy regimen
of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin
Oncol. 23: 4079–4088.
Kennedy B, Rawstron AC, Evans P et al. (2002). Campath-1H and fludarabine in combination are highly active
in refractory chronic lymphocytic leukemia. Blood 99(6): 2245–7.
Kröber A, Seiler T, Benner A, Bullinger L, Brückle E, Lichter P, Döhner H, Stilgenbauer S. (2002). VH mutation
status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:
1410–1418.
Kröber A, Bloehdorn J, Hafner S, Bühler A, Seiler T, Kienle D, Winkler D, Bangerter M, Schlenk RF, Benner A,
Lichter P, Döhner H, Stilgenbauer S. (2006). Additional genetic high-risk features such as 11q deletion, 17p
deletion, and V3-21 usage classify discordance of ZAP-70 and VH mutation status in chronic lymphocyic
leukemia. J Clin Oncol 24(6): 969–975.
Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML,
Proffitt JH, Lucas D, Grever MR, Byrd JC (2004). Alemtuzumab is an effective therapy for chronic lymphocytic
leukemia with p53 mutations and deletions. Blood 103: 3278–81.
Lundin J, Kimby E, Björkholm M et al. (2001). Phase II study of subcutaneous alemtuzumab (Campath-1H)
therapy of patients with previously untreated chronic lymphocytic leukaemia (CLL). Blood 98(11): 772a,
Abstract no. 3215.
Lundin J, Kimby E, Björkholm M, Broliden P-A, Celsing F, Hjalmar V, Möllgård, Rebello P, Hale G, Waldmann
H, Mellstedt H, Österborg A (2002). Phase II trial of subcutaneous anti-CD52 monoclonal antibody
alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (BCLL). Blood 100(3); 768–773.
Lundin J, Celsing F, Karlsson C, et al. (2005). Treatment of refractory autoimmune hemolytic anemia in B-CLL
with alemtuzumab (humanized CD52 MAb). Blood 106(11), Abstract no. 2967.
Marsh JCW, Gordon-Smith EC (2001).
Cytotherapy 3(3): 189–95.
CAMPATH-1H in the treatment of autoimmune cytopenias.
Meinhardt G, Wendtner CM, Hallek M (1999). Molecular pathogenesis of chronic lymphocytic leukemia:
factors and signaling pathways regulating cell growth and survival. J Mol Med. 77(2): 282–93.
O'Brien SM, Kantarjian HM, Cortes J, et al. (2001). Results of the fludarabine and cyclophosphamide
combination regimen in chronic lymphocytic leukemia. J Clin Oncol 19(5): 1414–1420.
Österborg A, Fassas AS, Anagnostopoulos A, et al. (1996). Humanized CD52 monoclonal antibody Campath1H as first-line treatment in chronic lymphocytic leukaemia. Br J Haematol. 93(1): 151–153.
Peto R, Peto J (1972): Asymptotically efficient rank invariation test procedures (with discussion). J R Stat Soc
A135: 185–206.
Peto R, Pike MC, Armitage P, et al. (1976): Design and analysis of clinical trials requiring prolonged observation
of each patient. Br J Cancer (Part I) 34: 585–612; (Part II) 35: 1–39.
Pettitt AR, Matutes E, Oscier D (2006): Alemtuzumab in combination with high-dose methylprednisolone is a
logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53
defects. Leukemia. 20(8):1441–5. Epub 2006 June 1.
58
V. 1.1 / 25.04.2007
Page 59 of 60
Prentice RL (1978): Linear rank tests with right censored data. Biometrika 65: 167–179.
Rai KR, Sawitsky A, Cronkite EP et al. (1975). Clinical staging of chronic lymphocytic leukemia. Blood 46:
219–234.
Rai KR, Peterson BL, Appelbaum FR, et al. (2000). Fludarabine compared with chlorambucil as primary
therapy for chronic lymphocytic leukemia. N Engl J Med 343(24): 1750–1757.
Rai KR, Freter CE, Mercier RJ, Cooper MR, Mitchell BS, Stadtmauer EA, Santábarbara P, Wacker B, Brettman
L (2002). Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received
fludarabine. J Clin Oncol 20: 3891–3897.
Rassenti LZ, Huynh L, Toy TL, et al. (2004). ZAP-70 compared with immunoglobulin heavy-chain gene
mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 351: 893–
901.
Rozman C, Montserrat E (1995). Chronic lymphocytic leukemia. N Engl J Med 333: 1052.
Stilgenbauer S, Döhner H (2002). Campath-1H induced complete remission of chronic lymphocytic leukemia
despite p53 gene mutation and resistance to chemotherapy. N Engl J Med 347: 452–453 (letter).
Stilgenbauer S, Winkler D, Kröber A, Kienle D, Busch R, Hallek M, Hensel M, Lengfelder E, Trümper L,
Dreger P, Jäger U, Döhner H, for the GCLLSG (2004). Subcutaneous Campath-1H (alemtuzumab) in
fludarabine-refractory CLL: interim analysis of the CLL2H study of the German CLL study group (GCLLSG).
Blood 104 suppl 1, abstract 478.
Stilgenbauer S, Kröber A, Busch R, Eichhorst B, Kienle D, Winkler D, Hopfinger G, Lichter P, Emmerich B,
Hallek M, Döhner H, for the GCLLSG (2005a). 17p deletion predicts for inferior overall survival after
fludarabine-based first line therapy in chronic lymphocytic leukemia: First analysis of genetics in the CLL4 trial
of the GCLLSG. Blood 106(11), Abstract no. 715.
Stilgenbauer S, Kröber A, Winkler D, Kienle D, Busch R, Hallek M, Hensel M, Lengfelder E, Trümper L,
Dreger P, Jäger U, Döhner H, for the GCLLSG (2005b). Efficacy of subcutaneous alemtuzumab (Campath-1H)
in genetic high-risk, fludarabine-refractory CLL: CLL2H study of the German CLL Study Group (GCLLSG).
9th International Conference on Malignant Lymphoma, Lugano, 2005. Ann Oncol 16 (Suppl 5), abstract no. 41.
Thieblemont C, Bouafia F, Hornez E, Dumontet C, Tartas S, Antal D, Lemieux B, TRAULLÉ C, Espinouse D,
Salles G and Coiffier B. Maintenance therapy with a monthly injection of alemtuzumab prolongs response
duration in patients with refractory B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma (BCLL/SLL) (2004). Leukemia & Lymphoma 45(4): 711–714.
Thornton PD, Matutes E, Bosanquet AG, Lakhani AK, Grech H, Ropner JE, Joshi ·R, Mackie PH, Douglas IDC,
Bowcock SJ, Catovsky D (2003). High dose methylprednisolone can induce remissions in CLL patients with
p53 abnormalities. Ann Hematol 82: 759–65.
Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jäger G, Eichhorst B, Busch R,
Diem H, Engert A, Stilgenbauer S, Döhner H, Kneba M, Emmerich B, Hallek M; German CLL Study Group
(GCLLSG) (2004). Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in
first remission-experience on safety and efficacy within a randomized multicenter phase III trial of the German
CLL Study Group (GCLLSG). Leukemia 18(6): 1093–101.
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17. APPENDICES
Appendix A: Patient's Information Sheet
Appendix B: Informed Consent Form
Appendix C: Transference agreement
Appendix D: Binet staging
(Binet et al., 1981)
Appendix E: NCI criteria for active disease requiring therapy
(Cheson et al., 1996)
Appendix F: NCI criteria for remission
(Cheson et al., 1996)
Appendix G: WHO/ECOG Performance Status
Appendix H: NCI Common Terminology Criteria for Adverse Events
Version 3.0, 12th. December 2003.
Appendix I: SAE reporting form
Appendix J: Vote of the Ethics Committee
Appendix K: Certificate of insurance
Appendix L: Form for registration of patients
(DCLLSG Studienzentrale)
Appendix M: Serum reference diagnostics form, München
Appendix N: Genetic reference diagnostics form, Ulm
Appendix O: MRD reference diagnostics form, Kiel
Appendix P: Product information for MabCampath®
Appendix Q: List of centers planning to participate in the study
Appendix R: Declaration of Helsinki
Appendix S: Specific regulatory aspects in France
Appendix T: Specific regulatory aspects in Austria
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CLL2O Protocol / Appendices
V. 1.3 / 29.10.2007
Appendix A
Patient’s Information Sheet (German version)
1
Page 1 of 40
V. 1.3 / 29.10.2007
Page 2 of 40
Universität Ulm
Medizinische Fakultät
Medizinische Universitätsklinik, D-89070 Ulm
Hämatologie, Onkologie, Rheumatologie
und Infektionskrankheiten
Ärztlicher Direktor: Prof. Dr. H. Döhner
Robert-Koch-Straße 8, D-89081 Ulm
Telefon:
0731/500-45501
Telefax:
0731/500-45505
Telefonzentrale: 0731/5000
http://www.uni-ulm.de/onkologie/
PATIENTENINFORMATION ZU STUDIE
„Prospektive, multizentrische Phase II-Studie zur subkutanen Anwendung von
Alemtuzumab in Kombination mit oraler Dexamethason-Gabe und anschließender
Erhaltungstherapie mit Alemtuzumab oder Stammzellentransplantation bei chronischer
lymphatischer Leukämie, die mit einer 17p-Deletion assoziiert oder gegenüber
Fludarabin-haltiger Therapie refraktär ist“ (CLL2O Protokoll der Deutschen CLL
Studiengruppe)
Sehr geehrte Patientin, sehr geehrter Patient,
durch Forschung und Entwicklung neuer Behandlungsmöglichkeiten wird in der modernen
Medizin kontinuierlich der Versuch unternommen, die Therapie bösartiger Erkrankungen zu
verbessern. Nur durch die Erprobung am Patienten selbst ist es möglich, Erkenntnisse zu
gewinnen, die eine Beurteilung der Wirksamkeit, Sicherheit und Verträglichkeit neuer
Therapien erlauben.
Dieses Merkblatt soll als Basis zum Aufklärungsgespräch über die Behandlung der
chronischen lymphatischen Leukämie (CLL) mit Alemtuzumab dienen. Hierbei handelt es
sich speziell um solche Fälle von CLL, die entweder durch einen genetischen Defekt („17pDeletion“) oder durch mangelndes Ansprechen auf Fludarabin-haltige Chemotherapie
gekennzeichnet sind. Wir möchten Sie um Ihre Einwilligung zur Teilnahme an der oben
genannten klinischen Studie bitten.
Bitte lesen Sie diese Patientenformation sorgfältig durch. Ihr Arzt wird mit Ihnen auch direkt
über die Studie sprechen. Bitte fragen Sie Ihren Arzt, wenn Sie etwas nicht verstehen oder
wenn Sie zusätzlich etwas wissen möchten.
Bitte unterschreiben Sie die Einwilligungserklärung nur
- wenn Sie Art und Ablauf der klinischen Prüfung vollständig verstanden haben,
- wenn Sie bereit sind, der Teilnahme zuzustimmen und
- wenn Sie sich über Ihre Rechte als Teilnehmer an dieser klinischen Prüfung im Klaren sind.
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Natürlicher Verlauf der CLL
Im frühen Stadium macht die CLL häufig keine Beschwerden, mit Fortschreiten der
Erkrankung kann es zu Problemen kommen, beispielsweise Störungen der Blutbildung,
Infektneigung, Vergrößerungen von Lymphknoten, Leber oder Milz mit Verdrängung anderer
Organe oder zu Allgemeinsymptomen wie Fieber, Gewichtsverlust und Abgeschlagenheit.
Zwar kann die bisher übliche Behandlung die Krankheitserscheinungen vorübergehend
zurückdrängen, eine Heilung ist dadurch jedoch nicht möglich. Es ist deshalb dringend
notwendig, nach besseren Behandlungsmöglichkeiten für die CLL im fortgeschrittenen
Stadium zu suchen.
Behandlungsmöglichkeiten bei der CLL
Die derzeit wirksamste Behandlung der CLL ist eine Chemotherapie mit Fludarabin
(Fludara®). Fludarabin kann auch mit anderen Substanzen – Chemotherapeutika oder
Antikörpern – kombiniert werden. Durch eine derartige Behandlung kann die CLL bei der
Mehrzahl der Patienten zurückgedrängt werden (sogenannte „Remission“). Allerdings kann
es nach einer Fludarabin-haltigen Chemotherapie zum Versagen dieser kommen; man spricht
dann von „Fludarabin-refraktärer“ CLL. Die Prognose der Fludarabin-refraktären CLL ist
ungünstig, und daher wird intensiv an der Entwicklung neuer Medikamente zur Behandlungen
der Fludarabin-refraktären CLL gearbeitet. Eine weitere Form der CLL, die ebenfalls mit
einer schlechten Prognose einhergeht, ist durch einen bestimmten genetischen Defekt in den
CLL Zellen, die „17p-Deletion“ (17p–) gekennzeichnet. In die vorliegende Studie werden
zwei Gruppen von Patienten aufgenommen: 1) Patienten mit „Fludarabin-refraktärer“ CLL
und 2) Patienten deren CLL durch eine „17p-Deletion“ (17p–) gekennzeichnet ist. Die
Zuordnung zu den beiden Kohorten erfolgt durch die genannten Charakteristika („Fludarabinrefraktärer“ oder „17p-Deletion). Die Behandlung der beiden Kohorten verläuft gleich, die
Unterscheidung der beiden Gruppen ist nur aus Gründen der Studienauswertung erforderlich.
Behandlung der Fludarabin-refraktären CLL mit Alemtuzumab
Ein Medikament zur Behandlung der Fludarabin-refraktären CLL ist Alemtuzumab (auch
Campath-1H oder MabCampath® genannt). Dies stellt eine Art der „Immuntherapie“ gegen
menschliche Lymphozyten (spezielle Typen von weißen Blutkörperchen), also auch gegen die
CLL dar. Im Gegensatz zu normaler Chemotherapie wirkt Alemtuzumab dadurch, dass es
sich gezielt an die Leukämiezellen anhaftet und sie zerstört. Alemtuzumab wurde weltweit
bereits bei mehreren tausend Patienten mit CLL eingesetzt. Dabei zeigte sich, dass mit
Alemtuzumab auch in Fällen, bei denen eine konventionelle Chemotherapie, wie z.B.
Fludarabin, nicht mehr wirkt, häufig noch eine Remission erzielt werden kann. Alemtuzumab
wurde daher im Mai 2001 zur Behandlung der Fludarabin-refraktären CLL in den USA und
wenig später auch in Europa zugelassen. Bisher wurde Alemtuzumab normalerweise als
intravenöse Infusion über 2 Stunden dreimal wöchentlich über eine Behandlungsdauer von 12
Wochen verabreicht. Durch neuere Studien wurde jedoch entdeckt, dass subkutan (d.h. unter
die Haut) verabreichtes Alemtuzumab mit weniger unangenehmen Nebenwirkungen
verbunden ist und eine ebenso gute Wirkung zeigt. Daher wird mit dieser Studie beabsichtigt,
diese viel versprechenden Möglichkeiten genauer zu untersuchen.
Ablauf der Behandlung mit Alemtuzumab subkutan in der vorliegenden Studie
Erste Studien zeigen, dass Alemtuzumab auch als Injektion („Spritze“) subkutan gegeben
wirksam ist, darunter auch zwei laufende bzw. kürzlich abgeschlossene bundesweite klinische
Therapiestudien der Deutschen CLL Studiengruppe (DCLLSG). Im Rahmen des vorliegenden
Projekts sollen in zahlreichen Kliniken und Arztpraxen (auch in Frankreich und Österreich)
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im Verlauf von 3 Jahren etwa 100 CLL Patienten behandelt werden, um möglichst rasch
Rückschlüsse auf die Verträglichkeit und Wirksamkeit ziehen zu können.
Der Behandlungsablauf gliedert sich in die folgenden Abschnitte:
(1) In einer Voruntersuchung (beinhaltet z.B. ein Gespräch, körperliche Untersuchung,
Blutentnahme [Umfang und Verwendungszweck aller Blutentnahmen sind weiter unten
ausführlich beschrieben], Ultraschall und Röntgenuntersuchung) wird entschieden, ob Sie an
dieser Studie teilnehmen können. Patienten mit einer CLL, die weder Fludarabin-refraktär ist
noch mit 17p– verbunden ist, sowie Patienten, deren Gesundheitszustand durch die
Behandlung in nicht vertretbarem Ausmaß gefährdet werden könnte, dürfen nicht teilnehmen.
Zu Beginn wird als Bestandteil der Studie auch ein HIV Test durchgeführt. Falls dieser positiv
ausfällt, wird Ihnen dies mitgeteilt.
(2) Vor Beginn und im Verlauf der Behandlung werden Untersuchungen (beinhaltet z.B. ein
Gespräch, körperliche Untersuchung, Blutentnahme, evtl. Knochenmarkuntersuchung,
Ultraschall und Röntgenuntersuchung, EKG) durchgeführt, um die Ausbreitung der CLL
sowie den Krankheitsverlauf unter der Therapie zu erfassen und um mögliche
Komplikationen zu vermeiden. Über Notwendigkeit, Nutzen und Risiken der Maßnahmen
werden Sie im Einzelnen von Ihrem behandelnden Arzt informiert.
(3) Die Behandlung wird mit einer Dosis von 30 mg als Spritze unter die Haut 3 mal pro
Woche durchgeführt. Dies kann in der Klinik oder Arztpraxis, aber auch nach entsprechender
Schulung (durch schriftliches Informationsmaterial, mündliche Unterweisung und praktische
Anleitung) durch Sie selbst durchgeführt werden. Zu Beginn der Behandlung kann es zu
Hautausschlägen an der Injektionsstelle kommen, die z.T. leicht schmerzhaft sein können,
aber nach einigen Behandlungen nicht mehr auftreten. Um diese möglichst gering zu halten,
wird es auch eine Begleittherapie geben (siehe Pkt. (4)).
(4) Begleittherapie: Vor der ersten Alemtuzumab-Dosis, und falls erforderlich auch vor den
weiteren Gaben, erfolgt die Gabe („Prämedikation“) von Medikamenten zur Milderung der
Nebenwirkungen. Hierdurch kann es zu Einschränkungen z.B. der Fahrtüchtigkeit kommen.
Zusätzlich werden Medikamente gegeben, die einer Infektion vorbeugen. Details zu
Begleittherapie und zusätzlichen Maßnahmen sind unten im Abschnitt über die Risiken der
Behandlung geschildert.
Begleitend zur Behandlung mit Alemtuzumab erhalten Sie alle 2 Wochen an 4
aufeinanderfolgenden Tagen Dexamethason-Tabletten (40 mg täglich). Dieses
Kortisonpräparat soll die Wirksamkeit der Immuntherapie erhöhen.
Von Beginn der Behandlung an erfolgt die Gabe von Pegfilgrastim (Neulasta®) 6 mg
subkutan in 2-wöchigen Abständen. Dadurch wird die Bildung gesunder Abwehrzellen
(“Granulozyten”) gefördert, die bei der CLL vor allem nach der Therapie in der Regel
vermindert sind.
(5) Die Dauer der Behandlung ist zunächst für 12 Wochen geplant.
Bei den
Verlaufsuntersuchungen nach 4 und 8 Wochen kann die Behandlung vorzeitig beendet
werden; hierüber wird Sie Ihr Arzt ggf. aufklären. Bei Ansprechen auf die Therapie stehen
folgende weitere Behandlungsmöglichkeiten zur Verfügung:
1. Im Rahmen einer längerfristigen Therapie („Erhaltungstherapie“) kann die Behandlung
mit Alemtuzumab verlängert werden. Dabei wird die Gabe von Alemtuzumab alle zwei
Wochen wiederholt. Dies kann maximal zwei Jahre fortgesetzt werden, vorausgesetzt,
dass Sie weiterhin auf diese Therapie ansprechen.
2. Als weitere Möglichkeit kann statt der Alemtuzumab-Erhaltungstherapie eine sog.
Stammzellentransplantation angeboten werden. Dies setzt jedoch voraus, i) dass Sie
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unter 65 Jahre alt sind, sowie ii) dass ein geeigneter Spender gefunden werden kann.
Die Stammzellentransplantation ist nicht Gegenstand der vorliegenden Studie. Sie
werden dazu in eine andere Studie aufgenommen und separat über diese informiert.
Über diese beiden Möglichkeiten wird Sie Ihr Arzt näher informieren.
Um über die langfristige Wirkung der Therapie Aufschluss zu erhalten, sind nach Beendigung
der Behandlung Verlaufsuntersuchungen erforderlich. Hierfür ist ein Abstand von 3 Monaten
vorgesehen über einen Zeitraum von maximal drei Jahren. Ihr Arzt wird Sie über Einzelheiten
zu Art und Zeitpunkten dieser Untersuchungen informieren.
Risiken der Behandlung mit Alemtuzumab
Die Nebenwirkungen der subkutanen Gabe von Alemtuzumab bestehen hauptsächlich in einer
Reaktion nach der Injektion, welche vor allem bei Behandlungsbeginn auftritt. Hierbei kann
es u.a. zu lokalen Reaktionen an der Injektionsstelle wie Rötung, Schwellung oder Schmerz
kommen; weniger häufig wird Steifheit oder Müdigkeit erlebt. Diese Symptome treten vor
allem am Anfang der Therapie auf und sind nur selten von schwerer Ausprägung.
Lebensbedrohliche Nebenwirkungen dieser Art sind extrem selten.
Bei der alternativ möglichen, hier aber nicht angewendeten Verabreichungsmethode von
Alemtuzumab (intravenös, d.h. direkt in die Blutbahn) sind hingegen zahlreiche andere, z.T.
schwere bzw. selten auch lebensbedrohliche Nebenwirkungen beschrieben. Sehr häufig sind
darunter Beeinträchtigungen des Blutbilds, die gelegentlich auch mit Symptomen verbunden
sind. Darüber hinaus werden häufig beobachtet: Stoffwechsel- und Ernährungsstörungen,
psychische
Störungen,
Störungen
des
Nervensystems,
Augenerkrankungen,
Gefäßerkrankungen, Erkrankungen der Atemwege und des Brustraums, Übelkeit, Erbrechen,
Diarrhoe sowie andere Störungen des Ernährungstrakts, eine gestörte Leberfunktion,
Hautveränderungen, Skelett- bzw. Muskelschmerzen oder –steife, Ödeme. Erkrankungen der
Niere und Harnwege wurden gelegentlich beschrieben. Ebenso wurden gelegentlich (d.h. bei
weniger als 1 von 100 Patienten) bei Patienten, die begleitend zur Therapie mit Alemtuzumab
Antihypertensiva (Mittel gegen Bluthochdruck) erhielten, oder die mit herzschädigenden
Wirkstoffen vorbehandelt waren, z.T. tödlich verlaufende Herzerkrankungen beobachtet. Alle
Angaben in diesem Absatz beziehen sich allerdings auf die intravenöse Verabreichung.
Studien zur subkutanen Gabe von Alemtuzumab mit erheblich mehr als 100 Patienten
ergaben, dass die genannten Nebenwirkungen bei dieser Verabreichungsform in wesentlich
geringerer Häufigkeit und zum Teil gar nicht mehr auftreten. Es kann dennoch nicht mit
Sicherheit ausgeschlossen werden, dass diese Nebenwirkungen bei einer breiteren
Anwendung der subkutanen Gabe nicht auftreten können. Daher wird ihr behandelnder Arzt
auch zu Beginn der Studie zu Ihrer Sicherheit ein EKG durchführen, um eine evtl.
vorbestehende Herzfunktionsstörung erkennen zu können.
Durch die CLL selbst und die Behandlung mit Alemtuzumab wird das Immunsystem
geschwächt, daher ist mit einer erhöhten Infektanfälligkeit zu rechnen. Sollte es zu
Infektionen kommen, ist eine unverzügliche ärztliche Behandlung erforderlich. Zur
Vermeidung von Infektionen während und in den ersten Monaten nach der Behandlung sollten
Sie besondere Vorsichtsmaßnahmen einhalten, über die Sie im persönlichen Gespräch
informiert werden. Es ist die vorsorgliche Gabe von Antibiotika erforderlich. Eventuell kann
es während der ersten Behandlungswochen zu einem Abfall des Blutbildes kommen und es
können Transfusionen notwendig werden. Über Notwendigkeit, Nutzen und Risiken von
Transfusionen werden Sie gesondert informiert.
Zur Beurteilung des Behandlungserfolges sind vor, während und regelmäßig nach der
Therapie Blut- und Knochenmarksanalysen sowie Ultraschall- und Röntgenuntersuchungen
vorgesehen, über deren Notwendigkeit, Nutzen und Risiken Sie gesondert informiert werden.
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Diese Untersuchungen würden aber auch durchgeführt, wenn Sie anstatt in der Studie mit
einer anderen Therapie behandelt würden.
Risiken der Behandlung mit Pegfilgrastim (Neulasta®)
Hauptnebenwirkung von Pegfilgrastim sind Knochenschmerzen von leichter bis mäßiger
Ausprägung, die vorübergehend sind und durch ein Schmerzmittel (z.B. Paracetamol) bei den
meisten Patienten beherrscht werden können. Die Knochenschmerzen treten als Zeichen der
Bildung gesunder Abwehrzellen (“Granulozyten”) auf und sind kein krankhaftes Zeichen.
Risiken der Behandlung mit Dexamethason
Dexamethason ist ein Kortison-ähnliches Medikament, das schon seit langer Zeit eingesetzt
wird. Es wird auch in dieser Therapieoptimierung verwandt und hat typische
Nebenwirkungen: der Zuckerstoffwechsel kann sich verschlechtern, manchmal wird
vorübergehend Insulin nötig; Magen- oder Zwölffingerdarmgeschwüre können auftreten. Es
kann zu Unruhezuständen kommen, eine Abwehrschwäche gegenüber Infektionen kann
verstärkt werden. Unter dem hier verwandten Therapieschema kommen andere
Nebenwirkungen selten zustande: Vollmondgesicht, Stammfettsucht, Knochenentkalkung
(Osteoporose), selten auch Knochennekrosen, Wassereinlagerungen (Ödeme), Erhöhung des
Risikos für Blutgerinnsel (Thrombosen), erhöhter Augeninnendruck (Glaukom).
Mögliche Nutzen der Behandlung mit Alemtuzumab subkutan
Alemtuzumab als intravenöse Infusion ist als eine wirksame Behandlung der Fludarabinrefraktären CLL bereits zugelassen. Die subkutane Gabe von Alemtuzumab scheint nach
Daten aus ersten Studien ebenfalls wirksam zu sein und bietet daneben Vorteile, die vor allem
in der einfacheren und besser verträglichen Gabe liegen. Es ist keine Anlage einer Kanüle in
eine Vene erforderlich. Die subkutane Injektion erfordert kürzere Aufenthalte in der Klinik
bzw. Arztpraxis. Die subkutane Gabe scheint mit weniger Nebenwirkungen behaftet zu sein
und kann einen Gewinn an Lebensqualität bei erhaltener Wirksamkeit ermöglichen.
Andere therapeutische Möglichkeiten
Für Ihre Erkrankung stehen auch andere Therapiemöglichkeiten zur Verfügung. Diese können
sein: Eine andere Form der Chemotherapie, eine Chemo-Immuntherapie oder eine
ausschließliche Behandlung der durch den Tumor hervorgerufenen Beschwerden. Ihr Arzt
wird die für Sie am besten geeignete Therapiemöglichkeit mit Ihnen besprechen.
Blutentnahmen und Probenweitergabe an Tumorzellbanken und Serumbanken
Bei Studieneinschluss und im Verlauf der Behandlung ist vorgesehen, Blutentnahmen (bei
Aufnahme bis zu 80 – 90 ml, bei den Verlaufsuntersuchungen je 15 - 35 ml Blut, zusätzlich
jeweils evtl. 5-10 ml Knochenmark) von Patienten vorzunehmen. Anzahl und Umfang der
Proben hängen stark vom Verlauf der Erkrankung und der Therapiedauer ab. In der Regel
sind dies 15 – 35 ml Blut in 4 -12 wöchigen Abständen. Es handelt sich hierbei um
Routineblutabnahmen, die nur zum Teil etwas umfangreicher ausfallen, da es vorgesehen ist,
auch Proben an die zentralen Referenzlabors der Deutschen CLL Studiengruppe in München,
Kiel und Ulm zu verschicken.
An diesen Proben werden Untersuchungen von
Serumparametern sowie zu genetischen Merkmalen der Tumorzellen (erworbene
Veränderungen der Leukämioezellen)
und Eiweißmolekülen im wissenschaftlichen
Programm der Studie durchgeführt, um ihre individuelle Erkrankung in Bezug auf den
möglichen Verlauf besser beurteilen zu können und auch das tatsächliche Ansprechen auf Ihre
Behandlung genauer bewerten zu können. Die Proben dienen aber auch dazu, um generell
weiteren Aufschluss über die Entstehung der CLL und eine Verbesserung der Behandlung zu
6
V. 1.3 / 29.10.2007
Page 7 of 40
erhalten. Die Proben werden eingefroren und aufbewahrt, um wissenschaftliche
Untersuchungen durchzuführen. Dabei werden Informationen zu Ihrer Person nur in
pseudonymisierter Form (ohne Ihren Namen) gespeichert.
Ihr Einverständnis für den Umgang mit diesen Proben wird auf einem gesonderten Formular
eingeholt. Der Probenversand nach Ulm für die Diagnose krankheitsbezogener genetischer
Veränderungen (17p-Deletion) ist für Ihre korrekte Behandlung im Rahmen der Studie
erforderlich. Die Probenweitergabe und Nutzung für darüber hinaus gehende Untersuchungen
wie Serummarker und Eiweißmoluküle in Ulm, München und Kiel dient hingegen dem
wissenschaftlichen Begleitprogramm, so dass Sie auch an der Studie teilnehmen können,
wenn Sie sich gegen diese Probenweitergabe entscheiden.
Es ist für Sie auch von Vorteil, dass diese diagnostischen Verfahren an den jeweiligen
Empfängerorten zentral von hierauf spezialisierten Institutionen durchgeführt werden, um die
Qualität der Analysen zu gewährleisten. Die Forschung zu erworbenen genetischen
Veränderungen der Leukämiezellen in Ulm, und die im wissenschaftlichen Begleitprogramm
(München, Kiel) kann unter strenger Kontrolle bzgl. Verwendung und Vertraulichkeit mit
Industriepartnern durchgeführt werden. Die Proben bleiben hierbei jedoch Eigentum der
Klinik. Um eventuelle Entdeckungen möglichst effektiv für Patienten einsetzen zu können,
kann eine kommerzielle Nutzung der Ergebnisse erforderlich werden. Sofern dies rechtlich
zulässig ist, wird die Universität Schutzrechte (Patente) begründen und industriellen Partnern
Nutzungsrechte einräumen. Seitens des Patienten können hieraus keine finanziellen
Ansprüche abgeleitet werden. Sie haben jederzeit – auch nachträglich – das Recht, Ihr
Einverständnis zu widerrufen und den Übereignungsvertrag zu kündigen. Dies wird keinen
Einfluss auf Ihre weitere Behandlung haben. Die gewonnenen Körpermaterialien werden in
diesem Fall vernichtet. Die bereits gewonnenen Daten können jedoch unter strenger
Pseudonymisierung weiter verwendet werden.
Freiwilligkeit, Recht auf Behandlungsablehnung und auf Widerruf der
Einverständniserklärung
Die Teilnahme an dieser klinischen Studie ist freiwillig. Ihr Einverständnis kann jederzeit und
ohne Angabe von Gründen widerrufen werden. Dieser eventuelle Widerruf hat keine
Auswirkungen auf Ihre weitere medizinische Betreuung.
Die Verwendung bereits vor dem Ausscheiden erhobener pseudonymisierter Daten kann nicht
widerrufen werden, um die Korrektheit der Studienauswertung nicht zu gefährden. Es wird
jedoch geprüft, welche Daten hierzu erforderlich sind. Die übrigen im Rahmen der Studie
über Ihre Erkrankung gesammelten Daten werden umgehend gelöscht.
Ihre Teilnahme kann auch von Ihrem behandelnden Arzt, durch den Auftraggeber der Studie
(Studienleitung/Sponsor bzw. Protokollkomitee) oder eine Aufsichtsbehörde (z.B. das PaulEhrlich-Institut) beendet werden. So kann die Studie insgesamt aus Sicherheitsgründen
abgebrochen werden, bzw. beim einzelnen Patienten kann es aufgrund Nichtbefolgen der
Anweisungen des Arztes, oder zum Schutz des Patienten zum Abbruch kommen. Dies kann
ohne Ihre Einwilligung geschehen.
Erreichbarkeit des Prüfarztes
Sollten während des Verlaufes der klinischen Prüfung Fragen auftauchen, so können Sie
jederzeit folgende(n) Ansprechpartner (bitte Namen einsetzen) ................................................
unter der Telefonnummer .................................................... erreichen. In Notfällen gilt folgende Nummer: .................................................
Bei Fragen können Sie sich jederzeit an den Leiter der Studie (Prof. Dr. St. Stilgenbauer,
Klinik für Innere Medizin III, Universitätsklinikum Ulm, Tel: 0731/500-45901) wenden (in
7
V. 1.3 / 29.10.2007
Page 8 of 40
Notfällen: Tel. 0731-5000, Telefonzentrale des Universitätsklinikums Ulm). Sponsor der
Studie ist der Vorsitzende des Klinikumsvorstandes des Universitätsklinikums Ulm.
Versicherung
Für Schäden, die aus dieser klinischen Prüfung resultieren können, ist zu Ihren Gunsten eine
Probandenversicherung abgeschlossen worden. Der Versicherer ist: Gerling Allgemeine
Versicherungs- AG, Düsseldorf, Versicherungsnummer 70-005627793-0 (Kontakt: HDI
Gerling-Industrieversicherungs-AG, Am Schönenkamp 45, 40599 Düsseldorf, Herr Bernhard
Hoppe, Tel. 0211/7482-5404). Die Versicherungssumme beträgt bis zu 500.000 Euro im
Einzelfall. Der Versicherungsschutz ist an folgende Bedingungen (Obliegenheiten) geknüpft:
1. Während der Dauer der Studie dürfen Sie sich einer anderen medizinischen Behandlung
nur im Einvernehmen mit Ihrem behandelnden Prüfarzt unterziehen (ausgenommen davon
sind natürlich Notfälle)
2. Eine Gesundheitsschädigung, die als Folge der klinischen Prüfung eingetreten sein könnte,
ist dem behandelnden Arzt bzw. dem Versicherer unverzüglich zu melden.
3. Im möglichen Schadensfall sind alle zweckmäßigen Maßnahmen zu treffen, die der
Aufklärung der Ursache und des Umfangs des eingetretenen Schadens und der Minderung
dieses Schadens dienen.
4. Im möglichen Schadensfall sind alle Ihre behandelnden Ärzte, Sozialversicherungsträger
und anderen Versicherer zu ermächtigen, dass sie dem Versicherer auf Verlangen Auskunft
erteilen.
Für die Versicherung ist es auch relevant, dass nicht wissentlich Krankheiten, die den
Einschluss in die Studie beeinflussen könnten, bzw. Konsum von Alkohol oder Drogen
verschwiegen werden dürfen.
Ein Ausdruck der vollständigen Versicherungsbedingungen wird Ihnen im Rahmen des
Informationsgesprächs von Ihrem Arzt/ Ihrer Ärztin ausgehändigt.
Vertraulichkeit, Datenschutz und Weitergabe von Daten
Alle Personen, die Sie im Rahmen dieser klinischen Prüfung betreuen, unterliegen der
ärztlichen Schweigepflicht und sind auf das Datengeheimnis/Datenschutzgesetz verpflichtet.
Die studienbezogenen Untersuchungsergebnisse werden in der Krankenakte festgehalten. Sie
sollen in sogenannter pseudonymisierter Form (d.h. nur unter Angabe von Initialen wie Monat
und Jahr der Geburt) für wissenschaftliche Veröffentlichungen verwendet werden. Zu diesem
Zweck können die erhobenen Daten auch an die Auftraggeber der klinischen Prüfung
und/oder von diesem autorisierte Personen weitergegeben werden. Soweit es zur Kontrolle
der korrekten Datenerhebung erforderlich ist, dürfen autorisierte Personen (z.B.: des
Auftraggebers, der Universität, von Aufsichtsbehörden) auch Einsicht in die studienrelevanten
Teile der Krankenakte nehmen. Deutsche und andere Aufsichtsbehörden dürfen zu Überwachungszwecken kraft Gesetzes Kopien von den Unterlagen der klinischen Prüfung (außer
personenbezogene Daten) fertigen. Die zuständige Bundesoberbehörde darf bei Bedarf die
Daten an die Europäische Datenbank weiterleiten. Sofern autorisierte Personen des
Auftraggebers der klinischen Prüfung nicht der obengenannten ärztlichen Schweigepflicht
unterliegen, stellen personenbezogene Daten, von denen sie bei der Kontrolle Kenntnis
erlangen, Betriebsgeheimnisse dar, die geheim zu halten sind.
8
V. 1.3 / 29.10.2007
Page 9 of 40
Falls die Daten im Rahmen eines Zulassungsantrags für ein Medikament Verwendung finden
sollen, können sie pseudonymisiert an den Anragsteller und die für die Zulassung zuständige
Behörde weitergegeben werden. Zu diesem Punkt ist die Einwilligung nicht widerrufbar. Im
Falle eines Widerrufs bezüglich der anderen Punkte zur Weitergabe pseudonymisierter Daten
können die bereits erhobenen Daten weiter verwendet werden, soweit dies erforderlich ist, um
•
Wirkungen des zu prüfenden Arzneimittels festzustellen
•
sicherzustellen, dass Ihre schutzwürdige Interessen nicht beeinträchtigt werden,
•
der Pflicht zur Vorlage vollständiger Zulassungsunterlagen zu genügen.
Die genannten Daten werden für die gesetzlich vorgeschriebene Dauer gespeichert.
Hinweis
Diese klinische Studie wurde durch die zuständige Ethikkommission ethisch geprüft und
positiv bewertet. Es ist keine Zahlung einer Aufwandsentschädigung an die Studienteilnehmer
vorgesehen.
Wir möchten um Ihr Einverständnis bitten, dass Daten Ihrer Behandlung dokumentiert und
wissenschaftlich ausgewertet werden. Die Daten werden im Prüfzentrum 10 Jahre aufbewahrt.
Ihre Krankenunterlagen sind vertraulich. Weder Ihr Name noch persönliche Informationen
werden in wissenschaftlichen Veröffentlichungen verwendet, die auf den Daten Ihrer
Erkrankung und Behandlung basieren.
Sie können sich auch vor und während der Teilnahme an der Studie mit Fragen auch an die
zuständige Stelle der Bundesoberbehörde wenden:
Paul-Ehrlich-Institut (PEI)
Paul-Ehrlich-Str. 51-59
D-63225 Langen
Tel. 06103 / 77 1811
Hinweis für zeugungsfähige Männer und gebärfähige Frauen:
Zu Beginn wird als Bestandteil der Studie ein Schwangerschaftstest (mittels Blut oder Urin)
durchgeführt um mögliche Schäden zu vermeiden. Ab Beginn der Studienteilnahme, während
der Behandlung mit Alemtuzumab sowie 6 Monate nach deren Beendigung sind als
hochwirksam anerkannte Methoden zur Verhinderung der Zeugung eines Kindes (männliche
Studienteilnehmer) bzw. einer Schwangerschaft (weibliche Studienteilnehmer) anzuwenden.
Unter hocheffektiven Methoden zur Verhütung sind zu verstehen: orale Verhütungsmethoden
(„Antibabypille“) (Kombinationspräparate), Implantate, injizierbare kontrazeptive
Substanzen, hormonelle IUDs („Hormon-Spirale“), Vasektomie des Partners oder auch
Abstinenz. Ihr Arzt wird Sie ggf. über diesbezügliche Details beraten. Sollte dennoch ein
Kind gezeugt werden bzw. eine Schwangerschaft eintreten ist dies dem Prüfarzt unbedingt
sofort mitzuteilen.
9
V. 1.3 / 29.10.2007
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Falls Sie noch weitere Fragen zur sicheren Empfängnisverhütung haben, wenden Sie sich
bitte an Ihren Studienarzt.
Stillende Mütter dürfen an dieser Arzneimittelstudie nicht teilnehmen!
................................
Ort, Datum
...............................................................
Unterschrift des/der aufklärenden Arztes/Ärztin
................................
Ort, Datum
...............................................................
Unterschrift des Patienten / der Patientin
10
V. 1.3 / 29.10.2007
Appendix B
Informed Consent Form (German version)
11
Page 11 of 40
V. 1.3 / 29.10.2007
Page 12 of 40
Universität Ulm
Medizinische Universitätsklinik u. Poliklinik, D-89070 Ulm
Hämatologie, Onkologie,
Rheumatologie und
Infektionskrankheiten,
Ärztlicher Direktor
Prof. Dr. H. Döhner
Telefon:
0731/500-45501
Telefax:
0731/500-45505
EINWILLIGUNGSERKLÄRUNG
Name der Studie:
„Prospektive, multizentrische Phase II-Studie zur subkutanen Anwendung von Alemtuzumab in
Kombination mit oraler Dexamethason-Gabe und anschließender Erhaltungstherapie mit
Alemtuzumab oder Stammzellentransplantation bei chronischer lymphatischer Leukämie, die
mit einer 17p-Deletion assoziiert oder gegenüber Fludarabin-haltiger Therapie refraktär ist“
(CLL2O Protokoll der Deutschen CLL Studiengruppe)
Inhalt, Vorgehensweise, Risiken und Ziel des oben genannten Forschungsprojektes sowie die Befugnis
zur Einsichtnahme in die erhobenen Daten hat mir Dr. ...................................... ausreichend erklärt.
Die Informationen beinhalteten insbesondere folgende Bereiche:
•
Sinn und Zweck einer klinischen Studie
•
Natürlicher Verlauf der CLL
•
Behandlungsmöglichkeiten bei der CLL
•
Behandlung der Fludarabin-refraktären CLL mit Alemtuzumab
•
Ablauf der Behandlung mit Alemtuzumab subkutan in der Studie
•
Risiken der Behandlung mit Alemtuzumab, Pegfilgrastim und Dexamethason
•
Mögliche Nutzen der Behandlung mit Alemtuzumab subkutan
•
Andere therapeutische Möglichkeiten
•
Blutentnahmen und Probenweitergabe an Tumorzellbanken und Serumbanken
•
Freiwilligkeit, Recht auf Behandlungsablehnung und auf Widerruf der
Einverständniserklärung
•
Erreichbarkeit des Prüfarztes
•
Versicherung und Versicherungsbedingungen
•
Vertraulichkeit, Datenschutz und Weitergabe von Daten
•
Hinweis für zeugungsfähige Männer und gebärfähige Frauen
12
V. 1.3 / 29.10.2007
Page 13 of 40
Ich hatte Gelegenheit Fragen zu stellen und habe hierauf Antwort erhalten.
Ich hatte ausreichend Zeit, mich für oder gegen die Teilnahme am Projekt zu entscheiden.
Eine Kopie der Patienteninformation und Einwilligungserklärung habe ich erhalten.
Ich willige in die Teilnahme am Forschungsprojekt ein.
.............................................................
(Name des Patienten)
.....................................................................
Ort, Datum
....................................................................
(Unterschrift des Patienten)
Information und Einwilligungserklärung zum Datenschutz
Bei wissenschaftlichen Studien werden persönliche Daten und medizinische Befunde über Sie erhoben. Die
Speicherung, Auswertung und Weitergabe dieser studienbezogenen Daten erfolgt nach gesetzlichen Bestimmungen
und setzt vor Teilnahme an der Studie folgende freiwillige Einwilligung voraus:
1) Ich erkläre mich damit einverstanden, dass im Rahmen dieser Studie erhobene Daten/Krankheitsdaten auf
Fragebögen und elektronischen Datenträgern aufgezeichnet und ohne Namensnennung weitergegeben werden
an:
a) den Auftraggeber (Universitätsklinikum Ulm, Robert-Koch-Str. 8, 89081 Ulm) der Studie zur
wissenschaftlichen Auswertung bzw. von ihm beauftragte Wissenschaftler/wissenschaftliche Institutionen;
b) die zuständige Überwachungsbehörde (Landesamt oder Bezirksregierung) oder Bundesoberbehörde (PaulEhrlich-Institut) zur Überprüfung der ordnungsgemäßen Durchführung der Studie. Die zuständige
Bundesoberbehörde darf bei Bedarf die Daten an die Europäische Datenbank weiterleiten.
2) Außerdem erkläre ich mich damit einverstanden, dass ein autorisierter und zur Verschwiegenheit verpflichteter
Beauftragter des Auftraggebers, der zuständigen deutschen und ausländischen Überwachungsbehörde oder der
zuständigen Bundesoberbehörde in meine beim Prüfarzt vorhandenen personenbezogenen Daten Einsicht
nimmt, soweit dies für die Überprüfung der Studie notwendig ist. Für diese Maßnahme entbinde ich den
Prüfarzt von der ärztlichen Schweigepflicht.
......................................
Ort, Datum
..................................................
Name
.....................................................................
Unterschrift des Patienten/der Patientin)
Ich versichere hiermit, die/den o.g. Patientin/Patienten über Wesen, Zweck sowie vorhersehbare
Auswirkungen der Studie aufgeklärt zu haben. Sie/Er hat durch Unterschrift einer freiwilligen
Teilnahme an der Studie zugestimmt.
......................................
Ort, Datum
..................................................
Name
13
.....................................................................
Unterschrift der/des aufklärenden Ärztin/Artztes
V. 1.3 / 29.10.2007
Appendix C
Transference Agreement (German version)
14
Page 14 of 40
V. 1.3 / 29.10.2007
Page 15 of 40
Universität Ulm
Medizinische Universitätsklinik u. Poliklinik, D-89070 Ulm
Hämatologie, Onkologie,
Rheumatologie und
Infektionskrankheiten,
Ärztlicher Direktor
Prof. Dr. H. Döhner
Telefon:
0731/500-45501
Telefax:
0731/500-45505
Übereignungsvertrag
Dieser Übereignungsvertrag betrifft Patientenproben, die im Rahmen der multizentrischen
Therapiestudien der Deutschen CLL Studiengruppe (DCLLSG) entnommen werden.
Zwischen der Universität Ulm, handelnd für die Klinik für Innere Medizin III, vertreten durch
Herrn/Frau Dr.
und
(Patientin/Patient)
wird folgendes vereinbart:
Name der Patientin / des Patienten) wird der Universität
1. Frau/Herr
Ulm das Eigentum an folgendem Körpermaterial unentgeltlich übertragen:
Bei der Einschlußuntersuchung:
• Eine Blutprobe (ca. 60 ml)
• Eine Knochenmarkprobe (ca. 10–15 ml)
Bei Studienabschluß:
• Eine Blutprobe (ca. 15–35 ml)
• falls notwendig eine Knochenmarkprobe (ca. 5–10 ml)
Bei den Verlaufsuntersuchungen (Die Abstände der Probenentnahmen betragen während
der Hauptbehandlungszeit 4 Wochen, während der Erhaltungstherapie 3 Monate. Dieser
Abstand und die Entnahmemenge können u.a. abhängig vom klinischen Verlauf der
Erkrankung sein) jeweils:
• Blutprobe (ca. 15–35 ml)
• Evtl. (abhängig vom klinischen Verlauf) Knochenmarkprobe (ca. 5–10 ml)
2. Die o.g. Patientenproben werden zur Untersuchung und Anlage von Tumorzell- bzw.
Serumbanken an die zentralen Labors der DCLLSG in München, Kiel, und Ulm versandt.
An diesen Proben werden Untersuchungen von Serumparametern, zu erworbenen
Veränderungen von genetischen Merkmalen an den Tumorzellen (Tumorgenetik) sowie
Eiweißmolekülen (Proteinen) im Rahmen des studienbegleitenden wissenschaftlichen
Programms durchgeführt. Diese Forschung wird unter Umständen in Zusammenarbeit mit
Industriepartnern durchgeführt. Es gehen jedoch keine Proben in das Eigentum der
industriellen Partner über.
15
V. 1.3 / 29.10.2007
Page 16 of 40
3. Die o.g. Patientenproben können von den zentralen Forschungslabors der DCLLSG zu
wissenschaftlichen Untersuchungen gemeinsam genutzt werden.
4. Informationen zu Ihrer Person werden nur in pseudonymisierter Form gespeichert.
5. An den Arbeiten können industrielle Kooperationspartner beteiligt sein. Patentierung und
Lizenzvergabe können, soweit rechtlich möglich, durch die Universität verfolgt werden.
6. Die Proben werden nach Abschluss der Studie vernichtet.
7. Alle anhand dieser Proben gewonnenen Daten können in pseudonymisierter Form
elektronisch gespeichert und an autorisierte Institutionen weitergegeben werden. Hier
gelten die entsprechenden Textpassagen der Ihnen bereits ausgehändigten
„Patienteninformation zur Studie“ sowie der „Einverständniserklärung“ in gleicher Weise.
8. Die Probenweitergabe an Ulm (krankheitsbezogene genetische Daten) ist für die
Teilnahme an der Therapiestudie erforderlich. Hingegen können Sie sich bezüglich der
Probenversendung nach München und Ulm (wissenschaftliches Begleitprogramm)
entscheiden:
Ich stimme dem Probenversand an die zentralen diagnostischen Institute in München
und Kiel zu:
ja
nein
Inhalt, Vorgehensweise, Risiken und Ziele des Übereignungsvertrag wurden mir ausreichend
erklärt. Ich hatte Gelegenheit Fragen zu stellen und habe hierauf Antwort erhalten. Ich hatte
ausreichend Zeit, mich für oder gegen die Teilnahme am Projekt zu entscheiden. Eine Kopie
der Patienteninformation und Einwilligungserklärung habe ich erhalten.
Ich willige in die Teilnahme am Forschungsprojekt ein.
...................................... ..................................................
Ort, Datum
Name
.....................................................................
Unterschrift des Patienten/der Patientin
Ich versichere hiermit, die/den o.g. Patientin/Patienten über Wesen, Zweck sowie
vorhersehbare Auswirkungen dieses Übereignungsvertrages aufgeklärt zu haben. Sie/Er
hat durch Unterschrift einer freiwilligen Teilnahme zugestimmt.
...................................... ..................................................
Ort, Datum
Name
.....................................................................
Unterschrift der/des aufklärenden Ärztin/Arztes
16
V. 1.3 / 29.10.2007
Page 17 of 40
Appendix D
Binet staging system (Binet et al., 1981)
Stage
Definition
____________________________________________________________
A
hemoglobin >10g/dl
and
platelets >100 x109/l
and
less than three palpable enlarged lymphatic areas*
B
hemoglobin >10g/dl
and
platelets >100 x109/l
and
three or more palpable enlarged lymphatic areas*
C
hemoglobin <10g/dl
or
platelets <100 x109/l
____________________________________________________________
* Adenopathy >1cm in diameter is required. Lymphatic areas are:
1
2
3
4
5
Head and neck (uni- or bilateral) including the Waldeyer ring
Axillary nodes (uni- or bilateral)
Inguinal nodes (uni- or bilateral)
Liver
Spleen
Each of these counts as one area even if more than one group of lymph nodes is enlarged
within one area.
Thoracic, abdominal and other lymph nodes or masses as found by imaging techniques (CT or
ultrasound etc.) are not relevant for the Binet stage.
17
V. 1.3 / 29.10.2007
Page 18 of 40
Appendix E
NCI Criteria for „active disease“ requiring therapy (Cheson et al., 1996)
(1)
A minimum of any one of the following disease-related symptoms must be present:
(a)
(b)
(c)
(d)
Weight loss ≥ 10% within the previous 6 months.
Extreme fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to
perform usual activities).
Fevers of greater than 100.5°F for ≥ 2 weeks without evidence of infection.
Night sweats without evidence of infection.
(2)
Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia and/or thrombocytopenia
(3)
Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid
therapy
(4)
Massive (i.e., > 6 cm below the left costal margin) or progressive splenomegaly
(5)
Massive nodes or clusters (i.e., > 10cm in longest diameter) or progressive
lymphadenopathy
(6)
Progressive lymphocytosis with an increase of > 50% over a 2-month period, or an
anticipated doubling time of less than 6 months
(7)
Marked hypogammaglobulinemia or the development of a monoclonal protein in the
absence of any of the above criteria for active disease is not sufficient for protocol therapy
18
V. 1.3 / 29.10.2007
Page 19 of 40
Appendix F
NCI Response Criteria (modified from Cheson et al., 1996)
A.1.
Complete remission (CR) requires all of the following for a period of at least 2
months:
A.1.1. Absence of lymphadenopathy by physical examination and appropriate radiographic
techniques.
A.1.2. No hepatomegaly or splenomegaly by physical examination, and appropriate
radiographic techniques.
A.1.3. Absence of constitutional symptoms.
A.1.4. Normal CBC as exhibited by:
A.1.4.1.
Polymorphonuclear leukocytes ≥ 1,500/µL.
A.1.4.2.
Platelets > 100,000/µL.
A.1.4.3.
Hemoglobin > 11.0 g/dL (untransfused).
A.1.5. Bone marrow aspirate and biopsy should be performed 2 months after clinical and
laboratory results demonstrate that all of the requirements listed in A.1.1 to A.1.4 have
been met to demonstrate that a CR has been achieved. The marrow sample must be at
least normocellular for age, with less than 30% of nucleated cells being lymphocytes.
Lymphoid nodules should be absent. If the bone marrow is hypocellular, a repeat
determination should be made in 4 weeks. Samples should be re-reviewed in
conjunction with the prior pathology.
A.1.6. For patients who fulfill all of the previous criteria for a CR, an abdominal CT scan
may be performed to confirm this clinical and hematologic impression if clinically
indicated or if required testing for a clinical research study.
A.2.
A.2.1.
A.2.2.
A.2.3.
A.2.4.
A.2.5.
A.2.6.
A.2.7.
Partial remission (PR) is considered in a broad sense to enable the detection of agents
with biological effect. To be considered a PR, the patient must exhibit A.2.1 and A.2.2
and/or A.2.3 (if abnormal prior to therapy), as well as one or more of the remaining
features for at least 2 months. In addition, the presence or absence of constitutional
symptoms will also be recorded.
≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline
value.
≥ 50% reduction in lymphadenopathy.
≥ 50% reduction in the size of the liver and/or spleen.
Polymorphonuclear leukocytes ≥ 1,500/µL or 50% improvement over baseline.
Platelets > 100,000/µL or 50% improvement over baseline.
Hemoglobin > 11.0 g/dL or 50% improvement over baseline without transfusions.
In a subset of patients who are otherwise in a complete remission, bone marrow
nodules can be identified histologically. It is, unfortunately, difficult with current
available techniques to determine the clonality of these nodules. The original NCIWG guidelines suggested that patients with a CR and persistent nodules should be
analyzed carefully to compare their outcome relative to others who are more
conventionally classified as a CR or PR. Robertson et al have since demonstrated that
patients with a nodular CR had a shorter time to disease progression compared with
patients with a CR. Therefore, nodular CRs should be reported separately from CRs,
and should not be used to inflate the percentage of CRs. We recommend that they be
referred to as nodular PRs (nPR) and included with the PRs.
19
V. 1.3 / 29.10.2007
Page 20 of 40
A.2.8. A controversial issue is how best to categorize the response of patients who fulfill all
the criteria for a CR, but who have a persistent anemia or thrombocytopenia
apparently unrelated to disease activity and more likely the consequence of persistent
drug toxicity. The long-term outcome of these patients may differ from the more
routine complete responders. Therefore, these patients should not be considered CRs
or a separate response category, but should be considered PRs. However, they should
be monitored prospectively to better characterize their outcome, and may be described
within the context of results of clinical trials.
A.3. Progressive disease (PD) will be characterized by at least one of the following:
A.3.1. ≥ 50% increase in the sum of the products of at least two lymph nodes on two
consecutive determinations 2 weeks apart (at least one node must be ≥ 2 cm);
appearance of new palpable lymph nodes.
A.3.2. ≥ 50% increase in the size of the liver and/or spleen as determined by measurement
below the respective costal margin; appearance of palpable hepatomegaly or
splenomegaly, which was not previously present.
A.3.3. ≥ 50% increase in the absolute number of circulating lymphocytes to at least
5,000/µL.
A.3.4. Transformation to a more aggressive histology (eg, Richter’s syndrome or PLL with
> 55% prolymphocytes).
A.3.5. In the absence of progression, as defined earlier, the presence of a ≥ 2 g/dL decrease in
Hb, or ≥ 50% decrease in platelet count, and/or absolute granulocyte count will not
exclude a patient from continuing the study. Each protocol will define the amount of
drug(s) to be administered with such hematological parameters. Bone marrow aspirate
and biopsy are strongly encouraged to better define the cause of the suppressed counts.
A.4.
Patients who have not achieved a CR or a PR, or who have not exhibited PD, will be
considered to have stable disease (SD).
A.5.
Responses that should be considered clinically beneficial include CR, nPR and PR; all
others, eg, stable disease, nonresponse, progressive disease, and death from any cause,
should be rated as a treatment failure.
A.6.
Because current criteria for response are arbitrary and often not validated by
prospective studies, alternative criteria may also be evaluated; however, to ensure
comparability with other studies, these should be studied within the framework of the
current schema and be well defined, with adequate rationale. Should such a schema
be determined to have important clinical relevance following prospective evaluation, it
will be considered for incorporation into criteria for future studies.
A.7
Duration of response should be measured from the time the patient has exhibited the
features of maximum response until evidence of progressive disease. Survival duration
should be measured from the time of entry onto the clinical trial.
20
V. 1.3 / 29.10.2007
Page 21 of 40
Appendix G
WHO/ECOG Performance status
Grade
Definition
0
Fully active, able to carry on all pre-disease activities without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry
out work of a light or sedentary nature e.g. light house work, office work.
2
Ambulatory and capable of all self care but unable to carry out any work
activities. Up and about more than 50% of waking hours.
3
Capable of only limited self care, confirmed to bed or chair more than 50%
of waking hours.
4
Completely disabled. Cannot carry on any self care. Totally confined to bed
or chair.
German translation:
0
Volle Belastbarkeit, kann ohne Einschränkung allen vor der Erkrankung möglichen
Aktivitäten nachgehen
1
Anstrengende Tätigkeiten nur mit Einschränkung möglich, kann aber leichten Hausoder Büroarbeiten nachgehen
2
Arbeitsaktivitäten nicht möglich, ist aber ambulant und zur vollständigen
Selbstversorgung in der Lage. Weniger als 50% der Wachzeit bettlägerig
3
Teilweise pflegebedürftig, mehr als 50% der Wachzeit bettlägerig
4
Komplett pflegebedürftig, permanent bettlägerig
21
V. 1.3 / 29.10.2007
Appendix H
Common Terminology Criteria for Adverse Events v3.0 (CTCAE)
(Publish Date: August 9, 2006)
To be downloaded from: http://ctep.cancer.gov/reporting/ctc_v30.html
22
Page 22 of 40
V. 1.3 / 29.10.2007
Appendix I
SAE Reporting Form (German version)
23
Page 23 of 40
V. 1.3 / 29.10.2007
Bericht über schwerwiegende
unerwünschte Ereignisse (SAE)
Page 24 of 40
Studie: _______________
Zentrums-Nr.:
(Bitte ankreuzen)
Meldung an:
❍ Stationäre Behandlung oder Verlängerung einer
❍
❍
❍
❍
❍
Pat.-Nr.:
Studienzentrale der DCLLSG
D-50924 Köln
Tel.: 0221- 478- 3988
Fax: 0221- 478- 86886
stationären Behandlung
lebensbedrohlich
tödlich
bleibende oder signifikante Schäden / Behinderung
angeborene Missbildung / Geburtsfehler
anderweitig medizinisch relevant
I. PATIENTENDATEN
Initialen
______ ______
Vor- Nachname
Geburtsdatum
___ ___
Tag
___ ___
Monat
___ ___
Jahr
Geschlecht
männlich
weiblich
Grundkrankheit:
Größe
__ __ __ cm
Gewicht
__ __ __ kg
II. UNERWÜNSCHTES EREIGNIS
SAE (Symptome, Lokalisation, Labor-und Messwerte, Diagnostik, Dauer, Therapie und Verlauf) Auftreten des SAE:
Ausgang der SAE: wiederhergestellt
Besserung, aber noch nicht wiederhergestellt gleichbleibend
Verschlechterung noch nicht wiederhergestellt
bleibende Schäden
nicht bekannt Exitus, Datum .....................Todesursache:...........................
III. VERDÄCHTIGE PRÄPARATE
Verdächtige Präparate
(incl. Oberbegriff)
Tagesdosis
Applikationsart
Therapiedaten
(von/bis)
Indikation
Kausalität *
(1,2,3,4,
5,6,7)
1.
2.
3.
4.
* Beurteilung des Kausalzusammenhanges:
1 gesichert
5 ungeklärt
Abklingen der Reaktion nach Absetzen
des Medikamentes/der Medikamente?
❑ Ja
❑ Nein ❑ unbekannt
2 wahrscheinlich 3 möglich 4 unwahrscheinlich
6 kein Zusammenhang
7 nicht beurteilbar
Wiedereintreten der Reaktion nach erneuter Gabe?
❑ Ja
❑ Nein
❑ unbekannt
IV. WEITERE MEDIKAMENTE, VORGESCHICHTE, ZUSÄTZLICHE DATEN
Begleitmedikamente mit Applikationsdaten (excl. Medikamente zur Behandlung der Nebenwirkung)
Anamnese / weitere Erläuterungen (z.B. Allergien, Schwangerschaft), Begleiterkrankungen
Allergien:
Alkohol:
Nikotin:
Implantate:
Meldung an weitere Stellen erfolgt?
❑ BfarM
❑ PEI
❑ Andere Stellen
Arzt/Apotheker (Name in Druckbuchstaben):
Telefon:
Datum/Unterschrift:
Falls der Platz nicht ausreicht, bitte formlose Bögen hinzufügen
24
❑
❑
❑
❑
V. 1.3 / 29.10.2007
Appendix J
Votes of Ethical Committees
------------- to be included ---------------------
25
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V. 1.3 / 29.10.2007
Appendix K
Certificates of Insurance
------------- to be included ---------------------
26
Page 26 of 40
V. 1.3 / 29.10.2007
Page 27 of 40
Appendix L
Form for Registration of Patients (DCLLSG Studienzentrale)
CLL2O PROTOCOL
REGISTRATION FORM
SEND OR FAX TO:
Tel: +49-221-478-3988
Fax: +49-221-478-86886
E mail: [email protected]
GCLLSG Study Office
CLL-Studiensekretariat
50924 Köln
Corresponding physician .................................................................. Phone/Fax ..........................
Center ..................................................................................................
.............................................................................................................................
.............................................................................................................................
Patient initials
|__|
Date of birth
|__||__| |__||__| |__||__|
day
Date of diagnosis
|__|
month
|__||__| |__||__| |__||__|
day
Binet stage
month
year
|__| A; B; C
Patient meets all inclusion/exclusion criteria
|__|
Date |__||__| |__||__| |__||__|
day
year
month
1 = yes
0 = no
Signature...............................................
year
27
R
V. 1.3 / 29.10.2007
Page 28 of 40
Appendix M
Serum reference diagnostics form, München
CLL2O PROTOCOL
STK/ß2M FORM
SF
SEND OR FAX TO:
CLL Studien
Marchioninistr. 15
D-81377 München
Montag-Donnerstag mit Postversand
Center ..................................................................................................
.............................................................................................................................
.............................................................................................................................
Patient initials / date of birth
|__|
|__|
|__||__| |__||__| |__||__|
day
Leukocyte count (x109/l)
|__||__||__|
Binet stage
|__| A; B; C
Date |__||__| |__||__| |__||__|
day
month
month
year
Signature...............................................
year
28
V. 1.3 / 29.10.2007
Page 29 of 40
Appendix N
Genetic reference diagnostics form, Ulm
CLL2O PROTOCOL
Genetics FORM
CF
SEND OR FAX TO:
Zytogenetisches Labor (Prof. Dr. H. Döhner)
Medizinische Universitätsklinik und Poliklinik
Universität Ulm
Robert-Koch-Str. 8
D-89081 Ulm
Tel.: +49 / 731 / 500-45810 or –45888
Fax: +49 / 731 / 500-45905 or –45915
Center ..................................................................................................
.............................................................................................................................
.............................................................................................................................
|__|
|__|
|__||__| |__||__| |__||__|
day
month
year
Occasion
|__|
1
2
Study entry
Clinical relapse
Material
|__|
1
2
Blood (+Heparine, 10:1)
BM (+Heparine, 10:1)
Leukocytes (x109/l) / % lymphocytes
|__||__||__| x109/l
Binet stage
|__| A; B; C
Date |__||__| |__||__| |__||__|
day
month
|__||__|%
Signature...............................................
year
29
V. 1.3 / 29.10.2007
Page 30 of 40
Appendix O
MRD reference diagnostics form, Kiel
CLL2O PROTOCOL
MRD FORM
MF
SEND OR FAX TO:
Prof. Dr. Dr. M. Kneba / Dr. M. Ritgen
Wiss. Labor / Molekulargenetik
II. Medizinische Klinik
Chemnitzstraße 33
D-24116 Kiel
Tel:
Fax:
0431-1697- 1265 /-5231
0431-1697-1264
Center ..................................................................................................
.............................................................................................................................
.............................................................................................................................
|__|
|__|
|__||__| |__||__| |__||__|
day
month
year
Occasion
|__|
1
2
Study entry
at clinical remission
Material
|__|
1
2
Blood (10ml EDTA)
BM (3ml EDTA)
Leukocytes (x109/l)
|__||__||__|
Binet stage
|__| A; B; C
Date |__||__| |__||__| |__||__|
day
month
Signature...............................................
year
30
V. 1.3 / 29.10.2007
Appendix P
Product information for MabCampath® (SPC)
31
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V. 1.3 / 29.10.2007
Page 32 of 40
Appendix Q
List of centers planning to participate in the study
LISTE GEPLANTER TEILNEHMENDER ZENTREN (DEUTSCHLAND, ÖSTERREICH)
Klinik für Innere Med. Klinik III
Universitätsklinikum Ulm
Robert Koch-Str. 8
89081 Ulm
Prof. Dr. L. Uharek
Charité - Universitätsmedizin Berlin
Campus Benjamin Franklin
Hindenburgdamm 30
12200 Berlin
PD Dr. J. Schetelig
Universitätsklinikum Carl Gustav Carus
Fetscherstr. 74
01307 Dresden
Prof. Dr. U. Dührsen
Universitätsklinikum Essen
Hufelandstr. 55
45147 Essen
Prof. Dr. J. Finke
Universitätsklinikum Freiburg
Hugstetterstr. 55
79106 Freiburg
PD Dr. M. Rummel
Universitätsklinikum Gießen
Klinikstr. 36
35392 Gießen
Prof. Dr. L. Trümper
Universität Göttingen
Robert-Koch-Str. 40
37075 Göttingen
Prof. Dr. N. Schmitz
Allgemeines KH St. Georg
Lohmühlenstr. 5
20099 Hamburg
Prof. Dr. A. Ganser
Medizinische Hochschule Hannover
Carl-Neuberg-Str. 1
30625 Hannover
PD Dr. M. Hensel
Universitätsklinik Heidelberg
Im Neuenheimer Feld 410
69120 Heidelberg
Prof. Dr. M. Pfreundschuh
Universitätskliniken des Saarlandes
Kirrberger Straße
66421 Homburg/Saar
Prof. Dr. M. Kneba
Universitätsklinikum Schleswig-Holstein, Campus
Kiel
Chemnitzstr. 33
24116 Kiel
PD Dr. G. Heß
Johannes-Gutenberg-Universität
Langenbeckstr. 1
55131 Mainz
PD Dr. Eva Lengfelder
Universitätsklinikum Mannheim
Wiesbadener Str. 7-11
68305 Mannheim
Prof. Dr. Chr. Peschel
Klinikum rechts der Isar
Ismaninger Str. 22
81675 München
Prof. Dr. M. Wilhelm
Klinikum Nürnberg Nord
Prof.-Ernst-Nathan-Str. 1
90419 Nürnberg
Prof. Dr. L. Kanz
Universitätsklinikum Tübingen
Otfried-Müller-Str. 10
72076 Tübingen
Prof. Dr. H. Einsele
Universitätsklinikum Würzburg
Klinikstr. 6-8
97070 Würzburg
Dr. R. Schlag
Internistische Praxis
Bleicherkirchplatz 15
97070 Würzburg
Prof. Dr. U. Jäger
Universitätsklinik für Innere Medizin I
Klinische Abtlg. für Hämatologie u.
Hämostaseologie
Währinger Gürtel 18-20
1090 Wien / Österreich
Dr. G. Hopfinger
Hanusch Krankenhaus
Medizinische Klinik III
Heinrich Collinstr. 30
1140 Wien / Österreich
Dr. Ulrike Söling
Internistische Gemeinschaftspraxis
Jordanstr. 6
34117 Kassel
32
V. 1.3 / 29.10.2007
Liste des centres participants (France)
Etablissement
Investigateur
Hôpital Avicenne -APHP
125 route de Stalingrad
93009 BOBIGNY Cedex
Pr Florence CYMBALISTA
Hôpital Henri Mondor -APHP
51 av du Maréchal de Tassigny
94010 CRETEIL Cedex
Pr Corinne HAIOUN
Hôpital Saint-Louis -APHP
10 avenue Claude Vellefaux
75010 PARIS
Dr Vincent LEVY
Hôpital Pitié Salpêtrière -APHP
47-83 bd de l'Hôpital
75013 PARIS
Pr Véronique LEBLOND
CHU de Reims
23 rue des Moulins
51092 REIMS Cedex
Pr Alain DELMER
CHU de Toulouse
2 rue de la Viguerie
TSA 80035
31059 TOULOUSE Cedex9
Dr Loïc YSEBAERT
Hôpital Edouard Herriot
Place d'Arsonval
69437 LYON Cedex 3
Pr Mauricette MICHALLET
Tél. 04 72 11 73 92
Tél. 04 72 11 74 02
Centre François Baclesse
Pr Xavier TROUSSARD
14000 CAEN
Tél. 02 31 06 50 14
CHU de Nantes
5 allée de l'île Gloriette
44093 NANTES Cedex 01
Dr Béatrice MAHE
CHU Clermont-Ferrand - Hôtel Dieu
Pavillon Villemin Pasteur
11 bd Léon Malfreyt BP 69
63058 CLERMONT-FERRAND
Dr Olivier TOURNILHAC
CHU Claude Huriez
Rue Michel Polonovski
59037 LILLE Cedex
Dr Bruno CAZIN
Tél. 01 48 95 56 41
Tél. 01 49 81 20 51
Tél. 01 42 49 47 87
Tél. 01 42 16 28 24
Tél. 03 26 78 36 44
Tél. 05 61 77 24 67
Tél. 02 40 08 32 71
Tél. 04 73 75 00 65
Tél. 03 20 44 42 90
CHU de Grenoble
BP 217
38043 GRENOBLE Cedex 9
Dr Brigitte PEGOURIE
CHU de Poitiers
2 rue de la Milétrie BP 577
86021 POITIERS Cedex
Dr Brigitte DREYFUS
Tél. 04 76 76 55 90
Tél. 05 49 44 43 07
33
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V. 1.3 / 29.10.2007
Etablissement
Investigateur
Centre Henri Becquerel
Rue d'Amiens
76038 ROUEN Cedex
Dr Stéphane LEPRETRE
CHU d'Angers
4 rue Larrey
49033 ANGERS Cedex
Dr TRUCHAN
CHU de Tours
2 Bd Tonnellé
37000 TOURS
Centre Hospitalier de la Côte
Basque
13 avenue de l'Interne Jacques
Loëb
64109 BAYONNE
Dr Caroline DARTIGEAS
Tél.02 32 08 22 23 / 22 22
Tél.
Tél. 02 47 47 32 12
Dr BAUDUER
Tél. 05 59 44 35 35
Hôpital Saint-Jean
Dr Laurence SANHES
20 avenue du Languedoc BP 49954
66046 PERPIGNAN Cedex 9
Tél. 04 68 61 64 48
CHU d'Amiens
Place Victor Pauchet
80054 AMIENS Cedex
CHU de Nancy
C.O. 34
54035 NANCY Cedex
Dr Bruno ROYER
Tél. 03 22 45 59 14
Pr Pierre FEUGIER
Tél. 03 83 15 37 05
34
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V. 1.3 / 29.10.2007
Page 35 of 40
Appendix R
Declaration of Helsinki (German version)
Original: Englisch
WELTÄRZTEBUND
Deklaration des Weltärztebundes
von Helsinki
Ethische Grundsätze
für
die medizinische Forschung am Menschen
verabschiedet von der
18 Generalversammlung des Weltarztebundes
Helsinki, Finnland, Juni 1964
revidiert von der
29 Generalversammlung des Weltärztebundes
Tokio, Japan, Oktober 1975
von der
Venedig, Italien, Oktober 1983,
von der
Hong Kong, September 1989
von der
Somerset West, Republik Südafrika, Oktober 1996
und von der
Edinburgh, Schottland, Oktober 2000
und von der
54 Generalversammlung des Weltarztebundes,
Washington 2002
Klarstellender Kommentar zu Punkt 30,
hinzugefügt von der 56. Generalversammlung des Weltärztebundes,
Tokio 2004
A. Einleitung
1. Mit der Deklaration von Helsinki hat der Weltärztebund eine Erklärung ethischer Grundsätze als Leitlinie für
Arzte und andere Personen entwickelt, die in der medizinischen Forschung am Menschen tätig sind.
Medizinische Forschung am Menschen schließt die Forschung an identifizierbarem menschlichen Material oder
identifizierbaren Daten ein.
2. Es ist die Pflicht des Arztes, die Gesundheit der Menschen zu fordern und zu erhalten. Der Erfüllung dieser
Pflicht dient der Arzt mit seinem Wissen und Gewissen.
3. Die Genfer Deklaration des Weltärztebundes verpflichtet den Arzt mit den Worten: "Die Gesundheit meines
Patienten soll mein vornehmstes Anliegen sein", und der internationale Kodex für ärztliche Ethik legt fest: "Der
Arzt soll bei der Ausübung seiner ärztlichen Tätigkeit ausschließlich im Interesse des Patienten handeln, wenn
die Therapie eine Schwächung des physischen und psychischen Zustandes des Patienten zur Folge haben kann".
35
V. 1.3 / 29.10.2007
Page 36 of 40
4. Medizinischer Fortschritt beruht auf' Forschung, die sich letztlich zum Teil auch auf Versuche am Menschen
stützen muss.
5. In der medizinischen Forschung am Menschen haben Überlegungen, die das Wohlergehen der Versuchsperson
(die von der Forschung betroffene Person) betreffen, Vorrang vor den Interessen der Wissenschaft und der
Gesellschaft.
6. Oberstes Ziel der medizinischen Forschung am Menschen muss es sein, prophylaktische, diagnostische und
therapeutische Verfahren sowie das Verständnis für die Aetiologie und Pathogenese der Krankheit zu verbessern.
Selbst die am besten erprobten prophylaktischen, diagnostischen und therapeutischen Methoden müssen
fortwährend durch Forschung auf ihre Effektivität, Effizienz, Verfügbarkeit und Qualität geprüft werden.
7. In der medizinischen Praxis und in der medizinischen Forschung sind die meisten prophylaktischen, diagnostischen und therapeutischen Verfahren mit Risiken und Belastungen verbunden.
8. Medizinische Forschung unterliegt ethischen Standards, die die Achtung vor den Menschen fördern und ihre
Gesundheit und Rechte schützen. Einige Forschungspopulationen sind vulnerabel und benötigen besonderen
Schutz. Die besonderen Schutzbedürfnisse der wirtschaftlich und gesundheitlich Benachteiligten müssen
gewahrt werden. Besondere Aufmerksamkeit muss außerdem denjenigen entgegengebracht werden, die nicht in
der Lage sind, ihre Zustimmung zu erteilen oder zu verweigern, denjenigen, die ihre Zustimmung möglicherweise unter Ausübung von Zwang abgegeben haben, denjenigen, die keinen persönlichen Vorteil von dem Forschungsvorhaben haben und denjenigen, bei denen das Forschungsvorhaben mit einer Behandlung verbunden ist.
9. Forscher sollten sich der in ihren eigenen Ländern sowie der auf internationaler Ebene für die Forschung am
Menschen geltenden ethischen, gesetzlichen und verwaltungstechnischen Vorschriften bewusst sein. Landesspezifische, ethische, gesetzliche oder verwaltungstechnische Vorschriften dürfen jedoch die in der vorliegenden
Deklaration genannten Bestimmungen zum Schutz der Menschen in keiner Weise abschwächen oder aufheben.
B. Allgemeine Grundsatze für jede Art von medizinischer Forschung
10. Bei der medizinischen Forschung am Menschen ist es die Pflicht des Arztes, das Leben, die Gesundheit, die
Privatsphäre und die Wurde der Versuchsperson zu schützen.
11. Medizinische Forschung am Menschen muss den allgemein anerkannten wissenschaftlichen Grundsätzen
entsprechen, auf' einer umfassenden Kenntnis der wissenschaftlichen Literatur, auf anderen relevanten Informationsquellen sowie auf ausreichenden Laborversuchen und gegebenenfalls Tierversuchen basieren.
12. Besondere Sorgfalt muss bei der Durchführung von Versuchen walten, die die Umwelt in Mitleidenschaft
ziehen können. Auf' das Wohl der Versuchstiere muss Rücksicht genommen werden.
13. Die Planung und Durchführung eines jeden Versuches am Menschen ist eindeutig in einem Versuchsprotokoll niederzulegen. Dieses Protokoll ist einer besonders berufenen Ethikkommission zur Beratung, Stellungnahme, Orientierung und gegebenenfalls zur Genehmigung vorzulegen, die unabhängig vom Forschungsteam,
vom Sponsor oder von anderen unangemessenen Einflussfaktoren sein muss. Diese unabhängige Kommission
muss mit den Gesetzen und Bestimmungen des Landes, in dem das Forschungsvorhaben durchgeführt wird, im
Einklang sein. Die Kommission hat das Recht, laufende Versuche zu überwachen. Der Forscher hat die Pflicht,
die Kommission über den Versuchsablauf zu informieren, insbesondere über alle während des Versuchs auftretenden ernsten Zwischenfalle. Der Forscher hat der Kornmission außerdem zur Prüfung Informationen über
Finanzierung, Sponsoren, institutionelle Verbindungen, potentielle Interessenkonflikte und Anreize für die
Versuchspersonen vorzulegen.
14. Das Forschungsprotokoll muss stets die ethischen Überlegungen im Zusammenhang mit der Durchführung
des Versuchs darlegen und aufzeigen, dass die Einhaltung der in dieser Deklaration genannten Grundsätze gewährleistet ist.
15. Medizinische Forschung am Menschen darf nur von wissenschaftlich qualifizierten Personen und unter Aufsicht einer klinisch kompetenten, medizinisch ausgebildeten Person durchgeführt werden. Die Verantwortung für
die Versuchsperson trägt stets eine medizinisch qualifizierte Person und nie die Versuchsperson selbst, auch dann
nicht, wenn sie ihr Einverständnis gegeben hat.
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Page 37 of 40
16. Jedem medizinischen Forschungsvorhaben am Menschen hat eine sorgfaltige Abschätzung der voraussehbaren Risiken und Belastungen im Vergleich zu dem voraussichtlichen Nutzen für die Versuchsperson oder andere
vorauszugehen. Dies schließt nicht die Mitwirkung von gesunden Freiwilligen in der medizinischen Forschung
aus. Die Plane aller Studien sind der Öffentlichkeit zugänglich zu machen.
17. Ärzte dürfen nicht bei Versuchen am Menschen tätig werden, wenn sie nicht überzeugt sind, dass die mit
dem Versuch verbundenen Risiken entsprechend eingeschätzt worden sind und in zufriedenstellender Weise
beherrscht werden können.. Ärzte müssen den Versuch abbrechen, sobald sich herausstellt, dass das Risiko den
möglichen Nutzen übersteigt oder wenn es einen schlüssigen Beweis für positive und günstige Ergebnisse gibt.
18. Medizinische Forschung am Menschen darf nur durchgeführt werden, wenn die Bedeutung des Versuchsziels
die Risiken und Belastungen für die Versuchsperson überwiegt. Dies ist besonders wichtig, wenn es sich bei den
Versuchspersonen um gesunde Freiwillige handelt.
19. Medizinische Forschung ist nu. gerechtfertigt, wenn es eine große Wahrscheinlichkeit gibt, dass die
Populationen, an denen die Forschung durchgeführt wird, von den Ergebnissen der Forschung profitieren.
20. Die Versuchspersonen müssen Freiwillige sein und über das Forschungsvorhaben aufgeklärt sein.
21. Das Recht der Versuchspersonen auf Wahrung ihrer Unversehrtheit muss stets geachtet werden. Es müssen
alle Vorsichtsmaßnahmen getroffen werden, um die Privatsphäre der Versuchsperson und die Vertraulichkeit der
Informationen über den Patienten zu wahren und die Auswirkungen des Versuchs auf die körperliche und
geistige Unversehrtheit sowie die Persönlichkeit der Versuchsperson so gering wie möglich zu halten.
22. Bei jeder Forschung am Menschen muss jede Versuchsperson ausreichend über die Ziele, Methoden,
Geldquellen, eventuelle Interessenkonflikte, institutionelle Verbindungen des Forschers, erwarteten Nutzen und
Risiken des Versuchs sowie über möglicherweise damit verbundene Störungen des Wohlbefindens unterrichtet
werden. Die Versuchsperson ist darauf hinzuweisen, dass sie das Recht hat, die Teilnahme am Versuch zu
verweigern oder eine einmal gegebene Einwilligung jederzeit zu widerrufen, ohne dass ihr irgendwelche
Nachteile entstehen., Nachdem er sich vergewissert hat, dass die Versuchsperson diese Informationen verstanden
hat, hat der Arzt die freiwillige Einwilligung nach Aufklärung ("informed consent") der Versuchsperson einzuholen; die Erklärung sollte vorzugsweise schriftlich abgegeben werden. Falls die Einwilligung nicht in schriftlicher
Form eingeholt werden kann, muss die nichtschriftliche Einwilligung formell dokumentiert und bezeugt werden.
23. Beim Einholen der Einwilligung nach Aufklärung für das Forschungsvorhaben muss der Arzt besonders
zurückhaltend sein, wenn die Person in einem Abhängigkeitsverhältnis zu dem Arzt steht oder die Einwilligung
möglicherweise unter Druck erfolgt.. In einem solchen Fall muss die Einwilligung nach Aufklärung durch einen
gutunterrichteten Arzt eingeholt werden, der mit diesem Forschungsvorhaben nicht befasst ist und der keine
Beziehung zu den Personen hat, die in diesem Abhängigkeitsverhältnis zueinander stehen.
24. Im Falle einer Versuchsperson, die nicht voll geschäftsfähig ist, infolge körperlicher oder geistiger Behinderung ihre Einwilligung nicht erteilen kann oder minderjährig ist, muss die Einwilligung nach Aufklärung vom
gesetzlich ermächtigten Vertreter entsprechend dem geltenden Recht eingeholt werden. Diese Personengruppen
sollten nicht in die Forschung einbezogen werden, es sei denn, die Forschung ist für die Förderung der Gesundheit der Population, der sie angehören, erforderlich und kann nicht mit voll geschäftsfähigen Personen durchgeführt werden.
25. Wenn die nicht voll geschäftsfähige Person, wie beispielsweise ein minderjähriges Kind, fähig ist, seine
Zustimmung zur Mitwirkung an einem Forschungsvorhaben zu erteilen, so muss neben der Einwilligung des
gesetzlich ermächtigten Vertreters auch die Zustimmung des Minderjährigen eingeholt werden.
26. Forschung an Menschen, bei denen die Einwilligung, einschließlich der Einwilligung des ermächtigten
Vertreters oder der vorherigen Einwilligung, nicht eingeholt werden kann, darf nur dann erfolgen, wenn der
physische/geistige Zustand, der die Einholung der Einwilligung nach Aufklärung verhindert, ein notwendiger
charakteristischer Faktor f* die Forschungspopulation ist. Die konkreten Gründe für die Einbeziehung von Versuchspersonen, deren Zustand die Einholung der Einwilligung nach Aufklärung nicht erlaubt, ist in dem Forschungsprotokoll festzuhalten und der Ethikkommission zur Prüfung und Genehmigung vorzulegen. In dem
Protokoll ist festzuhalten, dass die Einwilligung zur weiteren Teilnahme an dem Forschungsvorhaben so bald
wie möglich von der Versuchsperson oder dem gesetzlich ermächtigten Vertreter eingeholt werden muss.
27. Sowohl die Verfasser als auch die Herausgeber von Veröffentlichungen haben ethische Verpflichtungen. Der
Forscher ist bei der Veröffentlichung der Forschungsergebnisse verpflichtet, die Ergebnisse genau wiederzugeben. Positive, aber auch negative Ergebnisse müssen veröffentlicht oder der Öffentlichkeit anderweitig zugäng-
37
V. 1.3 / 29.10.2007
Page 38 of 40
lich gemacht werden.. In der Veröffentlichung müssen die Finanzierungsquellen, institutionelle Verbindungen
und eventuelle Interessenkonflikte dargelegt werden. Berichte über Versuche, die nicht in Übereinstimmung mit
den in dieser Deklaration niedergelegten Grundsätzen durchgeführt wurden, sollten nicht zur Veröffentlichung
angenommen werden.
C. Weitere Grundsätze für die medizinische Forschung in Verbindung mit ärztlicherVersorgung
28. Der Arzt darf medizinische Forschung mit der ärztlichen Betreuung nur soweit verbinden, als dies durch den
möglichen prophylaktischen, diagnostischen oder therapeutischen Wert der Forschung gerechtfertigt ist.. Wenn
medizinische Forschung mit ärztlicher Versorgung verbunden ist, dann sind für den Schutz der Patienten, die
gleichzeitig Versuchspersonen sind, zusätzliche Standards anzuwenden.
29. Vorteile, Risiken Belastungen und die Effektivität eines neuen Verfahrens sind gegenüber denjenigen der
gegenwärtig besten prophylaktischen, diagnostischen und therapeutischen Methoden abzuwägen.. Dies schließt
nicht die Verwendung von Placebos, oder die Nichtbehandlung, bei Versuchen aus, für die es kein erprobtes
prophylaktisches, diagnostisches oder therapeutisches Verfahren gibt. 1
30. Am Ende des Versuchs sollten alle Patienten, die an dem Versuch teilgenommen haben, die sich in der Erprobung als am wirksamsten erwiesenen prophylaktischen, diagnostischen und therapeutischen Verfahren erhalten. 2
31. Der Arzt hat den Patienten ausführlich über die forschungsbezogenen Aspekte der Behandlung zu informieren, Die Weigerung eines Patienten, an einem Versuch teilzunehmen, darf niemals die Beziehung zwischen
Patient und Arzt beeinträchtigen.
32. Bei der Behandlung eines Patienten, für die es keine erwiesene prophylaktische, diagnostische und therapeutische Methoden gibt oder diese keine Wirkung zeigten, muss der Arzt mit der Einwilligung des Patienten
nach Aufklärung die Freiheit haben, nicht erprobte neue prophylaktische, diagnostische und therapeutische
Maßnahmen anzuwenden, wenn sie nach dem Urteil des Arztes die Hoffnung bieten, das Leben des Patienten zu
retten, seine Gesundheit wiederherzustellen oder seine Leiden zu lindern. Gegebenenfalls sollten diese Maßnahmen zur Evaluierung ihrer Sicherheit und Wirksamkeit zum Gegenstand von Forschungsvorhaben gemacht
werden. In allen Fällen sollten neue Informationen aufgezeichnet und gegebenenfalls veröffentlicht werden.. Die
anderen relevanten Leitlinien dieser Deklaration sollten befolgt werden.
1
Klarstellender Kommentar zu Punkt 29 der Deklaration des Weltärztebundes von
Helsinki
Der Weltärztebund bekräftigt hiermit seine Position, dass bei der Verwendung von placebokontrollierten Versuchen mit extremer Sorgfalt vorgegangen werden muss und dass diese Methode generell nur angewendet werden
sollte, wenn es keine erprobte Therapie gibt. Selbst wenn es eine erprobte Therapie gibt, kann ein placebokontrollierter Versuch unter den folgenden Bedingungen ethisch vertretbar sein:
-
wenn seine Verwendung aus zwingenden und wissenschaftlich begründeten methodischen Gründen erforderlich ist, um die Wirksamkeit und Sicherheit einer prophylaktischen, diagnostischen oder therapeutischen
Methode festzustellen; oder
-
wenn eine prophylaktische, diagnostische oder therapeutische Methode bei einer nicht schwerwiegenden
Krankheit erprobt wird und die Patienten, die die Placebos erhalten, nicht der zusätzlichen Gefahr eines
ernsten oder irreversiblen Schadens ausgesetzt werden.
Alle anderen Bestimmungen der Deklaration von Helsinki müssen befolgt werden, insbesondere die Notwendigkeit einer entsprechenden ethischen und wissenschaftlichen Überprüfung.
2
Klarstellender Kommentar zu Punkt 30 der Deklaration des Weltärztebundes von Helsinki
Der Weltärztebund bekräftigt hiermit seine Position, dass es bei dem Versuchsplanungsprozess von Bedeutung
ist, dafür Sorge zu tragen, dass die Versuchsteilnehmer nach dem Versuch die prophylaktischen, diagnostischen
und therapeutischen Verfahren, die sich in der Studie als vorteilhaft erwiesen haben, oder eine andere geeignete
Behandlung erhalten. Vereinbarungen darüber, dass die Versuchsteilnehmer nach dem Versuch die im Versuch
erprobten Verfahren bzw.. eine andere geeignete Behandlung erhalten, sollten im Versuchsprotokoll festgehalten
werden, damit der Ethikausschuss diese Vereinbarungen bei seiner Prüfung berücksichtigen kann.
38
V. 1.3 / 29.10.2007
Appendix S
Specific regulatory aspects in France
------------- to be included ---------------------
39
Page 39 of 40
V. 1.3 / 29.10.2007
Appendix T
Specific regulatory aspects in Austria
------------- to be included ---------------------
40
Page 40 of 40

CLL2O Protokoll der DCLLSG

Transcription

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