The following protocol information is provided solely to describe how... research underlying the published report associated with the following article:

Transcription

The following protocol information is provided solely to describe how the authors conducted the
research underlying the published report associated with the following article:
Abagovomab as Maintenance Therapy in Patients with Epithelial Ovarian Cancer
(MIMOSA Study): A Phase III Trial of the AGO OVAR, COGI, GINECO, and GEICO on
behalf of the MIMOSA Investigators
Sabbatini, et al
DOI: 10.1200/JCO.2012.46.4057
The information provided may not reflect the complete protocol or any previous amendments or
modifications. As described in the Information for Contributors
(http://jco.ascopubs.org/site/ifc/protocol.xhtml) only specific elements of the most recent version
of the protocol are requested by JCO. The protocol information is not intended to replace good
clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and
dose modifications. The treating physician or other health care provider is responsible for
determining the best treatment for the patient. ASCO and JCO assume no responsibility for any
injury or damage to persons or property arising out of the use of these protocol materials or due
to any errors or omissions. Individuals seeking additional information about the protocol are
encouraged to consult with the corresponding author directly.
MENARINI RICERCHE S.p.A.
CLINICAL TRIAL PROTOCOL
Sponsor Study Code: ABA-01
AGO Study Code: AGO-OVAR 10
BB-IND 10724
EuDRACT n°: 2006-002801-30
Phase of Clinical Research: II/III
A RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED,
MULTICENTRE TRIAL OF ABAGOVOMAB MAINTENANCE
THERAPY IN PATIENTS WITH EPITHELIAL OVARIAN CANCER
AFTER COMPLETE RESPONSE TO FIRST LINE CHEMOTHERAPY
COORDINATING
INVESTIGATOR:
Prof. Jacobus Pfisterer
Frauenklinik
Universitätsklinikum
D - 68167 Mannheim
Germany
Phone: +49 621 383 2386
Fax: +49 621 383 3814
USA CHAIR:
Prof. Paul Sabbatini
Memorial Sloan-Kettering Cancer
Center
New York, NY 10021
USA
Phone: +1 212 639 6423
Fax: +1 212 639 8865
CONTRACT RESEARCH ORGANIZATION:
Pharmaceutical Research Associates España, S.A.U.
Avenida de Europa, 19 Edificio 1, 2ª Planta
28224 Pozuelo de Alarcón - Madrid (Spain)
Phone: +34 91 708 1110
Fax: +34 91 708 1111
AGO-OVAR:
Ovarian Cancer Study Group
Wiesbaden Office
Ludwig-Erhard Str. 100
D-65199 Wiesbaden
Germany
Phone: +49 611 433203
Fax: +49 611 433205
USA CO-CHAIR:
Prof. Jonathan Berek
Chair, COGI
Department of Obstetrics and
Gynecology
Stanford, CA 94305-5317
USA
Phone: +1 650 723 5533
Fax: +1 650 723 7737
SPONSOR:
Menarini Ricerche S.p.A.
Clinical Research Department
Via Sette Santi 1
50131 Florence
Italy
Phone: +39 055 5680 9990
Fax: +39 055 5680 597
CONFIDENTIAL
This document is a confidential communication of the sponsor. Acceptance of this document represents an agreement
by the recipient that no unpublished information contained here will be published or disclosed without the Sponsor’s
written authorisation, except that this document may be disclosed to appropriate Institutional Review Boards or Ethics
Committees as long as they are requested to keep it confidential.
Study Protocol ABA-01, Version 1.0, 4 August 2006
Page 1 of 66
SIGNATURE PAGE
The signatories have read the protocol (ABA-01, version 1.0, dated 04 August 2006) carefully
and agree to adhere to its provisions. Any changes to the protocol may only be made after
consultation with Menarini Ricerche S.p.A and must be submitted to the appropriate Ethics
Committee(s) or Institutional Review Board in the form of an Amendment.
Signature
Date
COORDINATING
INVESTIGATOR:
_____________________
______________
Prof. Jacobus Pfisterer, MD
MENARINI RICERCHE S.p.A.:
Corporate Director Clinical Research
and Sponsor Representative
_____________________
Angela Capriati, MD PhD
______________
Page 2 of 66
INVESTIGATOR STATEMENT
“My signature below verifies my agreement with the contents of this protocol (ABA-01, version
1.0, 18 July 2006) with regard to the execution of the study and the required documentation of
data. I agree to comply with the protocol in its entirety and with the ICH guidelines for Good
Clinical Practice.”
Signature
Date
Principal Investigator:
Please print name:
Page 3 of 66
ABBREVIATIONS
Ab1
Ab2
Ab3
ADCC
ADR
AE
AGO OVAR
ALT
ANC
AP
ASCO
AST
BUN
CA125
CEAC
CHMP/EWP
CI
COGI
CR
CRF
CRO
CT
CTC
CV
DBO
DHHS
DLT
DMAP
DSMB
DSU
EC
ECG
ECOG
EU
FDA
FIGO
GCP
GMP
GMSS
Antibody that binds to a given TAA
Anti-idiotypic antibody
Anti-anti-idiotypic antibody
Antibody-Dependent Cell-mediated Cytotoxicity
Adverse Drug Reaction
Adverse Event
Arbeitsgemeinschaft Gynaekologische Onkologie studiengruppevarialkarzinom
Alanine Transaminase
Absolute Neutrophil Count
Alkaline Phosphatase
American Society of Clinical Oncology
Aspartate Aminotransferase
Blood Urea Nitrogen
Cancer Antigen 125
Clinical event Adjudication Committee
Committee for Medicinal Products for Human Use/Efficacy Working Party
Confidence Intervals
Cooperative Ovarian Cancer Group for Immunotherapy
Complete Response
Case Report Form
Contract Research Organization
Computerized Tomography
Common Toxicity Criteria
Curricula Vitae
Double Blind Observation
Department of Health and Human Services
Dose Limiting Toxicity
Data Monitoring Analysis Plan
Data and Safety Monitoring Board
Drug Safety Unit
Ethics Committee
Electrocardiogram
Eastern Cooperative Oncology Group
European Union
Food and Drug Administration
International Federation of Gynecology and Obstetrics
Good Clinical Practice
Good Manufacturing Practice
Global Medical and Safety Service (PRA International)
Page 4 of 66
GP
γ-GT
HAMA
Hb
HIPAA
HIV
HR
IB
ICH
IM
IND
IP
IRB
ITT
IV
IVRS
LDH
Mab
MITO
NCI-CTC
NMR
NYHA
OC125
OS
PFS
POC
PR
PS
RFS
SAE
SAP
SC
SOP
SUSAR
TAA
ULN
WBC
WMA
General Practitioner
γ-Glutamyl Transferase
Human Anti Mouse Antibody
Haemoglobin
Health Insurance Portability and Accountability Act
Human Immunodeficiency Virus
Hazard Ratio
Investigator’s Brochure
International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use
Intramuscular
Investigational New Drug
Intraperitoneal
Institutional Review Board
Intent To Treat
Intravenous
Interactive Voice Recognition System
Lactate Dehydrogenase
Monoclonal antibody
Multicenter Italian Trials in Ovarian cancer
National Cancer Institute-Common Toxicity Criteria
Nuclear Magnetic Resonance
New York Heart Association
Monoclonal antibody that binds to CA125
Overall Survival
Progression Free Survival
Proof-Of-Concept
Partial Response
Performance Status
Recurrence Free Survival
Serious Adverse Event
Statistical Analysis Plan
Subcutaneous
Standard Operating Procedure
Suspected Unexpected Serious Adverse Reaction
Tumor associated antigen
Upper Limit of Normal
White Blood Cells
World Medical Association
Page 5 of 66
TABLE OF CONTENTS
ABBREVIATIONS ..................................................................................................................................................... 4
1
PROTOCOL SYNOPSIS ................................................................................................................................ 9
2
INTRODUCTION ......................................................................................................................................... 19
3
2.1
THE INVESTIGATIONAL PRODUCT: ABAGOVOMAB......................................................................................20
2.2
CLINICAL EXPERIENCE WITH ABAGOVOMAB ..............................................................................................20
2.2.1
Phase Ib/II study - Proof of concept for specific immune response induced by Abagovomab and
tolerability of repeated doses ............................................................................................................... 21
2.2.2
Phase I studies: influence of dose, route of administration and duration of treatment on the specific
immune response induced by Abagovomab and its tolerability............................................................ 22
2.2.3
Summary of clinical experience with Abagovomab .............................................................................. 25
ETHICAL AND LEGAL ASPECTS ........................................................................................................... 26
3.1
GENERAL ASPECTS ......................................................................................................................................26
3.2
INDEPENDENT ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................................26
3.3
SUBJECT INFORMATION AND INFORMED CONSENT ......................................................................................26
3.4
SUBJECT INSURANCE ...................................................................................................................................27
3.5
RECORD RETENTION ...................................................................................................................................28
3.6
CONFIDENTIALITY .......................................................................................................................................28
3.7
PROTOCOL ADHERENCE AND STUDY PROTOCOL AMENDMENTS .................................................................29
3.8
STUDY COMMENCEMENT ............................................................................................................................29
3.9
USE OF INFORMATION AND PUBLICATION ....................................................................................................30
4
QUALITY ASSURANCE ............................................................................................................................. 31
5
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURES................................................ 32
6
STUDY OBJECTIVES.................................................................................................................................. 34
7
INVESTIGATIONAL PLAN ....................................................................................................................... 35
7.1
OVERALL STUDY DESIGN AND PLAN DESCRIPTION ....................................................................................35
7.2
DISCUSSION OF STUDY DESIGN AND PLAN DESCRIPTION ............................................................................38
7.3
RANDOMIZATION ........................................................................................................................................39
7.4
STUDY POPULATION ....................................................................................................................................39
7.4.1
Number of subjects/centers................................................................................................................... 39
7.4.2
Inclusion Criteria ................................................................................................................................. 40
7.4.3
Exclusion criteria ................................................................................................................................. 40
7.4.4
Removal of subjects from therapy or assessment ................................................................................. 41
Page 6 of 66
7.5
7.5.1
Identity of Investigational Drugs .......................................................................................................... 41
7.5.2
Packaging............................................................................................................................................. 42
7.5.3
Labeling................................................................................................................................................ 42
7.5.4
Storage of Study Medication, Accountability and Dispensing.............................................................. 42
7.5.5
Schedule of Administration................................................................................................................... 43
7.5.6
Dose Adjustment and Modification ...................................................................................................... 43
7.5.7
Discontinuation of Treatment............................................................................................................... 43
7.5.8
Concomitant Treatments ...................................................................................................................... 44
7.6
STUDY PROCEDURES ...................................................................................................................................44
7.6.1
Efficacy and Safety Measurement Flowchart ....................................................................................... 44
7.6.2
Screening/Randomization..................................................................................................................... 46
7.6.3
Treatment and Double Blind Observation Period ................................................................................ 46
7.6.4
End of treatment and double blind observation period ........................................................................ 48
7.6.5
Overall survival follow-up.................................................................................................................... 48
7.7
EFFICACY AND SAFETY ASSESSMENT ..........................................................................................................48
7.7.1
Primary efficacy endpoint .................................................................................................................... 48
7.7.2
Secondary efficacy endpoints ............................................................................................................... 49
7.7.3
Safety Assessment ................................................................................................................................. 50
7.7.4
Monitoring of Adverse Events .............................................................................................................. 50
7.7.5
Breaking of Treatment Code................................................................................................................. 52
7.7.6
SAE Reporting ...................................................................................................................................... 52
7.7.7
24 - hour Medical Monitoring and SAE fax receipt ............................................................................. 53
7.8
8
TREATMENT ................................................................................................................................................41
STUDY COMMITTEES ...................................................................................................................................53
7.8.1
Steering Committee .............................................................................................................................. 54
7.8.2
Independent Clinical event Adjudication Committee (CEAC).............................................................. 54
7.8.3
Data and Safety Monitoring Board (DSMB) ........................................................................................ 54
7.8.4
Data Quality Management ................................................................................................................... 54
STATISTICAL METHODS ......................................................................................................................... 56
8.1
SAMPLE SIZE DETERMINATION ...................................................................................................................56
8.2
ANALYSIS POPULATIONS .............................................................................................................................56
8.3
ANALYSIS VARIABLES .................................................................................................................................57
8.3.1
Primary efficacy variable ..................................................................................................................... 57
8.3.2
Secondary efficacy variable: overall survival ...................................................................................... 58
8.3.3
Other secondary efficacy variables ...................................................................................................... 58
8.4
STATISTICAL ANALYSIS ..............................................................................................................................58
Page 7 of 66
8.4.1
Descriptive statistics............................................................................................................................. 58
8.4.2
Baseline analysis .................................................................................................................................. 59
8.4.3
Primary efficacy analysis ..................................................................................................................... 59
8.4.4
Sensitivity analysis of the primary variable.......................................................................................... 60
8.4.5
Secondary efficacy analysis.................................................................................................................. 60
8.4.6
Multiplicity issues................................................................................................................................. 60
8.4.7
Safety analysis ...................................................................................................................................... 60
8.4.8
Subgroup analysis ................................................................................................................................ 60
8.5
ON-STUDY AND PRE-STUDY CLOSURE ACTIVITIES .......................................................................................61
8.5.1
Protocol Violations and Blind Review.................................................................................................. 61
8.5.2
Data Monitoring................................................................................................................................... 61
8.5.3
Interim analysis .................................................................................................................................... 61
8.5.4
Stopping rules....................................................................................................................................... 61
8.5.5
DSMB analysis ..................................................................................................................................... 61
8.6
STATISTICAL ANALYSIS PLAN .....................................................................................................................62
9
REFERENCES .............................................................................................................................................. 63
10
APPENDICES................................................................................................................................................ 66
APPENDIX I
Declaration of Helsinki
APPENDIX II
Subject Information and Informed Consent Form
APPENDIX III
Charter of Clinical Event Adjudication Committee (CEAC)
APPENDIX IV
Charter of Data Safety and Monitoring Board (DSMB)
Page 8 of 66
<
1
PROTOCOL SYNOPSIS
Study Title
A randomized, double blind, placebo controlled, multicentre trial of
Abagovomab maintenance therapy in patients with epithelial ovarian
cancer after complete response to first line chemotherapy.
Study Code
Sponsor Code: ABA-01
BB-IND
BB-IND 10724
EuDRACT No.
EuDRACT No. 2006-002801-30
Study Drug
Abagovomab: murine anti-idiotypic antibody against CA125 antigen.
Clinical Phase
Phase II/III.
Duration of the study
48 months: estimated duration of double blind observation (DBO)
period with start/end expected on 3Q 2006 / 3Q 2010.
AGO Study Code: AGO-OVAR 10
After the end of DBO period, overall survival data will continue to be
collected in an open fashion, for additional 5 years (i.e. up to 7 years
from the randomization of the last patient).
Objectives
Primary objective:
To evaluate the benefit in terms of recurrence free survival (RFS) of
Abagovomab vs placebo as maintenance therapy after clinical
complete response to debulking surgery and standard platinum/taxane
1st line chemotherapy.
Secondary objectives:
1. to compare the effect of Abagovomab vs placebo in terms of
overall survival (OS);
2. to evaluate the safety and tolerability of repeated doses of
Abagovomab;
3. to evaluate the time course of immune response induced by
repeated doses of Abagovomab, namely induction of Ab3 and
HAMA;
4. to evaluate in a subset of approximately 10% of patients additional
immunologic parameters (i.e. Ab1’ and CA125-specific T cell
response).
Study centers
Approximately 120 centers distributed in Europe and USA.
Page 9 of 66
Study design
Randomized, double blind, placebo controlled, multinational,
multicentre study, with randomization 2:1 to abagovomab: placebo.
Study Treatments/
Abagovomab verum 2mg/ml suspension for subcutaneous (SC)
injection.
Schedule and Route of
Administration
Abagovomab placebo suspension for SC injection.
During the first 6 weeks of treatment (induction phase) patients will
receive the study drug as 1 ml suspension by SC route every 2 weeks
(i.e. at randomization and then at week 2, 4 and 6).
Thereafter (maintenance phase), the study drug will be administered
SC every 4 weeks until evidence of disease recurrence or up to 94
weeks (approximately 21 months) after the randomization of the last
patient.
Any additional anti-cancer therapy will not be allowed until evidence
of disease recurrence.
Number of patients
870 randomized patients, of which 580 in the Abagovomab arm and
290 in the placebo arm.
Inclusion criteria
At a maximum of 8 weeks after the last cycle of 1st line standard
platinum/taxane chemotherapy, patients must fulfil all the following
inclusion criteria to be eligible for entry into the study:
Age ≥ 18 years;
Properly executed written informed consent;
History of histological and CA125 (> 35 U/ml) confirmed
diagnosis of stage III-IV epithelial ovarian, fallopian tube, or
primary peritoneal cancer;
History of debulking surgery and standard platinum/taxane based
non-investigational chemotherapy;
Complete clinical response defined as:
Normal physical examination;
No symptoms suggestive of persistent cancer;
No definite evidence of disease by computed tomography (CT)
of the abdomen and pelvis within the previous 4 weeks;
Negative chest x-ray (or chest CT scan) within the previous 4
weeks;
Serum CA125 level < 35 U/ml.
Adequate hematologic, renal and hepatic function:
ANC >1.5 x 109/l;
Platelets > 75 x 109/l;
Page 10 of 66
Exclusion criteria
Haemoglobin > 6.2 mmol/l (>9.9 mg/dl);
Serum creatinine < 1.5 x ULN;
Bilirubin < 1.5 x ULN; AST, ALT, AP < 2.5 x ULN.
ECOG Performance Status (PS) < 2.
Patients are ineligible to participate in the study, if any of the following
criteria are present:
any other invasive malignancies, with the exception of nonmelanoma skin cancer or cervical carcinoma in situ, within the
last 5 years or whose previous cancer treatment contraindicates
this protocol therapy;
known active autoimmune disease requiring chronic treatment
with immunosuppressive agents (e.g., rheumatoid arthritis,
ulcerative colitis, etc.);
known immune deficiency (e.g. HIV, hypogammaglobulinemia,
etc.);
known infection with hepatitis B, or hepatitis C;
history of recent myocardial infarction (< 6 months) or
decompensated heart failure (NYHA class > III);
previous or concomitant use of any anti-cancer therapy other
than the platinum-taxane 1st line chemotherapy;
concomitant use of any other investigational agent;
any prior investigational anti-cancer vaccine or monoclonal
antibody;
known allergy to murine proteins;
any significant medical or psychiatric condition, drug or alcohol
abuse that might prevent the patient from complying with all
study procedures;
clinically significant active infection;
concomitant use of any immunosuppressive agent (e.g., steroids,
cyclosporin, etc.);
major surgery within the previous 2 weeks;
radiotherapy within the previous 4 weeks;
any significant toxicity from prior chemotherapy;
unreliability or inability to follow protocol requirements.
Page 11 of 66
Study procedures
Screening/Randomization
Patients will be screened and randomized within a maximum of 8
weeks from the last cycle of standard platinum/taxane chemotherapy.
Screening procedures (encompassing informed consent signature,
verification of inclusion/exclusion criteria and baseline laboratory
procedures, see attached flow chart of study schedule) should be
completed within 2 weeks prior to randomizing eligible patients to
Abagovomab or placebo (2:1 ratio). CT of abdomen and pelvis and
chest X-ray must be performed within 4 weeks of randomization.
The randomization will be stratified by the following baseline
prognostic factors in order to preserve the randomization ratio within
each stratum:
Tumor size after debulking surgery (i.e. residual tumor < 1 cm; >
1 cm);
FIGO stage (i.e. III; IV);
Serum CA125 level after the first 3 cycles of chemotherapy (< 35
U/ml, > 35 U/ml).
Treatment/Double blind Observation (DBO) period
After randomization, patients will be visited for safety evaluation and
will receive study treatment every 2 weeks for the first 4 doses
(induction phase) and, starting from week 10 (end of induction/start of
maintenance phase) every 4 weeks until the end of treatment, which
will occur after 21 months from the randomization of the last patient.
CT scan of abdomen and pelvis, and any other imaging techniques if
needed, will be performed every 12 weeks, together with physical and
gynecological examination for assessment of disease recurrence. Chest
x-ray will be repeated every 24 weeks. Vital signs measurement and
blood sampling for safety laboratory parameters will be performed at
week 4, week 10, and then every 12 weeks.
CA 125 assay will be performed at week 0 (i.e. the same day of the
first Abagovomab administration), at week 10 and then every 12 weeks
and results will be kept blinded until the end of double blind period.
Blood sampling for immunologic evaluation will be performed at week
0, at week 10, and repeated at week 22, 58, and 94, and in any case at
the final study visit (see below).
Patients who remain on treatment until the end of DBO period will
attend a final study visit for safety and efficacy 12 weeks after the last
administered dose.
In case of early treatment discontinuation patients will also attend a
final study visit 12 weeks from the last administered dose (or within 4
weeks and without CT scan in case of treatment discontinuation for
disease recurrence). All patients who early discontinued the study
Page 12 of 66
treatment will continue to be monitored for safety and survival status
by phone or mail (either directly or via the patient’s general
practitioner - GP) every 12 weeks until the end of DBO period.
Along the study all patients will have assessments scheduled at the
same interval and frequency.
End of treatment and End of DBO period
Treatment administration will end 21 months after the randomization
of the last patient and the DBO period of study will end 12 weeks later,
i.e. 24 months after the randomization of the last patient. At that time
all patients on treatment will undergo a final study visit, encompassing
the same efficacy and safety assessments scheduled during the
observation period. Patients who have prematurely discontinued study
treatment will undergo the final visit as described above.
Survival follow-up
After the end of double blind period, survival data will continue to be
collected in an open fashion by phone or mail (either directly or via the
patient’s GP) every 3 months for 5 years (i.e. up to 7 years from the
date of randomization of the last patient).
Overall, based on a 2-year recruitment time, the individual observation
period (double blind) for evaluation of recurrence free survival (RFS)
will range from 2 up to 4 years, with a minimum treatment period of 21
months and a minimum observation period of 2 years.
For survival, the expected individual follow-up period (double blind +
open) will range from 7 to 9 years.
Efficacy
and
assessments
safety Efficacy:
Physical and gynecological examination and CT scan of
abdomen and pelvis will be obtained at screening (CT scan to be
repeated if not performed in the previous 4 weeks prior to
randomization), at week 10 (end of induction phase/start of
maintenance phase) and then every 12 weeks, with the last
assessment performed at the final study visit (without CT-scan if
disease recurrence has been previously documented)
Chest X-ray will be performed at screening (if not performed in
the previous 4 weeks prior to randomization) and every 24 weeks
and at the final study visit (not to be performed in case disease
recurrence has been previously documented).
CT scan can be performed at any time during the study if disease
recurrence is suggested by physical examination or other clinical
findings. Additional imaging techniques (e.g. NMR) may be
performed if specifically requested by the Investigator to
document disease recurrence.
Page 13 of 66
Immunologic tests (Ab3, HAMA) will be performed in all
patients at week 0, and repeated at week 10 (end of induction
phase/start of maintenance phase), and at week 22, 58 and 94 and
in any case at the final study visit. At the same time points
additional immunologic parameters will be measured in a subset
of approximately 10% of patients.
Serum CA125 must obtained in each patient during the screening
procedure and will be used by the investigator to confirm the
completeness of the clinical response. Serum CA125 will be also
assayed at week 0, at week 10 and then every 12 weeks until the
end of DBO period. All the CA125 assays obtained after the
screening phase will be performed in a centralized lab facility
independent from Sponsor and Investigators. The results of these
CA125 assays will be kept blinded along the DBO period.
Survival status will be collected along study conduct. After the
DBO period or after early treatment discontinuation, survival
data will continue to be collected in each patient every 12 weeks
by phone or mail (either directly or via the patient’s GP) for
additional 5 years (i.e. for 7 years after the date of randomization
of the last patient).
Safety:
Before receiving any study treatment dose, patients will undergo
a general medical visit for monitoring of adverse events and
recording of any change in concomitant medication and ECOG
performance status at week 0, and then every 2 weeks (induction
phase) and every 4 weeks starting from week 10 (maintenance
phase).
Clinical laboratory tests and vital signs measurements will also
be performed prior to dosing, at week 4, week 10 and then every
12 weeks, with the last assessment performed at the final study
visit (12 weeks after last administered dose).
For patients with premature treatment discontinuation a final
study visit will be performed within 4 weeks (in case of
discontinuation for disease recurrence) OR 12 weeks (any other
reason) from last administered dose. Thereafter, safety will
continue to be monitored every 12 weeks until completion of the
DBO period by phone (or by visit at the center if deemed
appropriate by the investigator) for collection of any adverse
drug reactions.
An independent Data and Safety Monitoring Board will review
the safety data on a regular basis along study conduct.
Page 14 of 66
Study end points
Efficacy
Primary end point:
Recurrence Free Survival (i.e. time from the date of randomization to
documentation of disease recurrence or death from any cause).
Disease recurrence is defined as the appearance of any lesion or
development of tumor-related symptoms evaluated by medical
examination and documented by CT scan.
If the CT scan is not informative enough to document or to rule out
the recurrence of disease, additional imaging techniques (e.g. NMR,
etc) should be requested by the Investigator to document disease
recurrence. Ultrasound documentation is not accepted per se as
adequate documentation of disease recurrence. If any additional
imaging technique leads to the diagnosis of recurrence, then the
disease recurrence has to be considered as ‘documented’ even in the
presence of a negative CT scan. In addition, the histologic or
cytological documentation of disease recurrence can substitute
imaging confirmation in case of pleural or peritoneal effusion.
An independent Clinical Event Adjudication Committee (CEAC) will
review all the imaging documentation and any pertinent clinical data
in double blind condition, in order to assess the recurrence of the
disease as well as the date of recurrence.
The assessment of disease recurrence made by the CEAC will be used
for the primary efficacy analysis, whereas the assessment made by the
investigator will be used for clinical management of the patient.
Secondary end points:
Overall Survival (i.e. time from the date of randomization to all-cause
death).
Safety
Incidence and severity of toxicity, recorded by the US-NCI Common
Toxicity Criteria (CTC v.3).
Immunologic evaluation
Time course of Ab3 and HAMA levels.
Time course of Ab1’ and CA125-specific T cell response (in a
subset of approximately 10% patients).
Page 15 of 66
Sample size
A total number of 870 randomized patients (580 in the Abagovomab
arm and 290 in the placebo arm) will provide more than 90% power in
rejecting the null hypothesis of equality between Abagovomab and
placebo on RFS according to the following assumptions:
Median RFS for placebo arm = 18 months;
Hazard ratio in RFS between Abagovomab and placebo = 1.33
(leading to an approximate benefit of 6 months of Abagovomab
over placebo);
Recruitment period = 24 months;
Minimum follow-up for each patient = 24 months (i.e. average
time on-study of 36 months);
Significance level (α) = 5% (two-sided)
Overall drop-out rate = 10%
The expected number of recurrences to observe in the trial is 535 (338
in the Abagovomab arm and 197 in placebo arm).
The sample size of 870 randomized patients will also provide more
than 80% power for detecting the superiority of Abagovomab over
placebo in the secondary end-point of overall survival (OS) according
to the following assumptions:
Median OS for placebo arm = 40 months;
Hazard ratio in OS between Abagovomab and placebo = 1.30
(leading to an approximate benefit of 12 months of Abagovomab
over placebo);
Minimum follow-up for each patient = 84 months (i.e. average
time of survival follow-up of 96 months);
Significance level (α) = 5% (two-sided). No adjustment for
multiplicity will be adopted due to the nature of the secondary analysis.
Analysis population
Safety Population: all patients receiving at least one study drug
administration.
ITT population: all patients randomized.
Per Protocol population: all the patients of the ITT population
excluding patients who experience major protocol violations prior to
the documentation of ‘disease recurrence’, if any.
Statistical analyses
The primary analysis will answer to the primary trial objective by
applying a Cox proportional hazard model having treatment as major
covariate and adjusted by the three predefined prognostic
stratification factors.
The same model will be applied also for the evaluation of the
secondary endpoint, OS, at the end of the survival follow-up.
Page 16 of 66
STUDY SCHEDULE
SCREENING/
RANDOMIZATION
TREATMENT/DOUBLE BLIND OBSERVATION PERIOD
OPEN SURVIVAL
Follow Up
up to 2 yrs after last randomized pt
8 wks from last
chemotherapy cycle
Treatment Administration/Efficacy and Safety Assessment
W-2 to W0*
Abagovomab/placebo
Inclusion/exclusion criteria
Informed consent
Demographics
Medical history
PS (ECOG)
Physical and
Gynecological examination
Vital signs
12-lead ECG
Haematology/Serum
Chemistry/Urinalysis
Serum CA125 marker
CT scan (abdomen & pelvis)
Chest X-ray
HAMA, Ab3 tests
Adverse Events
Concomitant medication
Survival status
X
X
X
X3
X
X
Induction Phase
W0* W2 W4 W6
X
X
X
X
X
X
X
X
X
X
X
X
X5
X7
X
Maintenance Phase
every 4
every 12
wks
wks
2
X
X
W10
X
X
X
Final
Study Visit1
12 wks after
last dose1
X
X
X
X
X
X
X
X
X
X
X
X4
X4
X
X
X
Monitored throughout the observation period9
10
10
10
10
10
X
X
X
X
X
11
Monitored throughout the observation period
X4
X
X7
X8
X4
X6
X7
X
X9
10
X
11
X
10
X
up to 7 yrs after last
randomized pt
Survival status
every 12 wks
Page 17 of 66
NOTE to the STUDY SCHEDULE
* Week 0 corresponds to randomization and first administration of study treatment.
1
Final study visit for safety and efficacy corresponds to end of the double blind observation period (24 months after the last randomized patient and 12
weeks after the last administered dose) for regular end of treatment. In case of early treatment discontinuation, the final study visit will be performed 12
weeks after the last administered dose or within 4 weeks (and without CT scan and chest X-ray) in case of treatment discontinuation for disease recurrence.
2
Abagovomab or placebo will be administered every 4 weeks up to 94 weeks (approx. 21 month) after last randomized patient OR until disease recurrence
is documented.
3
Including main tumor characteristics (e.g. histopathological grading, FIGO stage III/IV and III sub-categories [IIIA, IIIB, IIIC)], size f the residual tumor
after surgery [0 cm, < 1cm, > 1cm]).
4
Samples will be collected but results of CA125 assay will be kept blinded until the end of DBO period.
5
CT scan to be done at screening if performed > 4 weeks prior to randomization.
6
CT scan to be repeated at final study visit only if disease recurrence has not been previously documented.
7
Chest X-Ray to be done at screening if performed > 4 weeks prior to randomization; to be repeated every 24 wks, and at final study visit (only if disease
recurrence has not been previously documented).
8
ONLY at week 22, 58 and 94.
9
AE to be recorded at study center prior to each dose. In case of early treatment discontinuation (for disease recurrence or any other reason) adverse events
will continue to be monitored by phone (or visit at center if deemed appropriate by the investigator) for collection of ADRs up to the end of the double
blind observation period.
10
ONLY changes in concomitant medication from screening will be recorded.
11
In case of early treatment discontinuation (for reasons other than death) survival status will continue to be monitored in double blind condition by phone
every 12 weeks up to the end of the double blind observation period, and then in open fashion during the survival follow up
Page 18 of 66
2
INTRODUCTION
Ovarian cancer is the sixth most common cancer in women, accounting for 204,572 new cases
every year worldwide and it is the leading cause of gynecological cancer deaths in EU and in
USA. In 2002, the incidences of ovarian cancer in Europe and USA were estimated at 63,467
and 22,491 new cases, respectively (Ferlay J et al, 2004). At the time of diagnosis, over 70% of
patients present with advanced disease, which requires an aggressive therapeutic approach
(surgery plus cytotoxic chemotherapy). The overall 5-year survival rate for patients with
advanced stage disease is about 20-30% (Berek JS et al., 2003).
The optimal management of patients with advanced ovarian cancer achieving a clinical complete
response (CR) after surgery and first-line chemotherapy (platinum/taxane based) remains to be
determined. Despite the good response rate reported after first line chemotherapy (up to 80%),
the disease will recur in the majority of patients. Experimental administration of paclitaxel (12 vs
3 cycles) administered intravenously (IV) q28 days as maintenance therapy in women with
clinical CR after 6 cycles of platinum/paclitaxel regimen led to a prolongation of progressionfree survival (PFS) (21 vs 28 months, after 3 cycles and 12 cycles, respectively) (Markman M et
al., 2003). However, recent data shows no impact of this regimen on overall survival (Markman
M et al., 2006). Similar findings were obtained from the Multicentre Italian Trials in Ovarian
Cancer (MITO) group, where 4 cycles of topotecan, administered as maintenance therapy to
patients responding to standard carboplatin and paclitaxel first-line therapy failed to demonstrate
benefit in terms of progression free survival (PFS) (De Placido S et al., 2004). Alternative
therapies (e.g. maintenance or consolidation therapy) that would delay or prevent recurrences
after obtaining a CR, ideally with minimal toxicity and without adversely impacting the patients’
quality of life, are strongly needed (Ozols R, 2003; Sabbatini P et al., 2006).
Among innovative strategies using immunologic approaches against tumor-associated antigens,
Oregovomab (Mab-B43.13, Ovarex), a monoclonal antibody directed against the tumorassociated antigen (TAA) CA125 and currently in Phase III clinical development, demonstrated
a significant prolongation of median time to relapse in comparison to placebo (24.0 vs 10.8
months); however benefit was obtained only in a population with ‘favourable prognostic factors,’
defined as optimal debulking surgery, a complete response to first-line chemotherapy, and a
positive immune response to treatment (Berek JS et al., 2004).
Clinical data to date with Abagovomab, a murine monoclonal anti-idiotypic antibody, able to
induce an active response against the CA125 TAA, is promising and warrants a randomized trial
to confirm efficacy.
Page 19 of 66
2.1
THE INVESTIGATIONAL PRODUCT: ABAGOVOMAB
The active drug substance (Abagovomab) is a murine monoclonal antibody (MW 165-175 kDa)
generated against the murine antibody OC125, which is able to recognize specifically the TAA
CA125 and to induce an active immune response against it. Immunization of patients with
Abagovomab demonstrated to induce an anti-anti-idiotypic immune response (Ab3) which leads
to an anti-CA125 immune reaction (Wagner U et al., 2001). Since the high-molecular weight
glycoprotein CA125 is detectable in more than 80% of patients with epithelial ovarian cancer,
the therapeutic administration of a specific vaccine capable of inducing a sufficient immune
response against CA125 represents a promising approach. The generated immune response can
be considered in the context of the immune network hypothesis of Niels Jerne (Jerne NK, 1974).
According to this theory, the anti-TAA antibody (Ab1) variable antigen-binding regions contain
immunogenic idiotypic determinants that are able to induce the production of so-called antiidiotypic antibodies (Ab2). A subset of these antibodies is able to mimic functionally the original
antigen. The immunization obtained by anti-idiotypic antibodies is expected to induce in the
patient a specific humoral immune response (Ab3 and Ab1’) together with the cellular reaction
directed against cells expressing the original TAA.
The drug product is a white suspension for subcutaneous injection containing the anti-idiotypic
antibody Abagovomab adsorbed onto aluminum hydroxide and suspended in a buffered and
isotonic saline solution to adjust the pH to about 7.5. The drug product is free of any
preservatives. It is provided in type I glass vials closed with a rubber stopper and an aluminum
flip-off cap.
The final product is manufactured according to GMP and relevant regulatory requirements for
parenteral preparations. Abagovomab drug product is available in 2 mg/ml vials, with each dose
to be administered as 1 ml suspension by subcutaneous route every two weeks during the
induction phase (first four doses) and then every 4 weeks during the maintenance phase. Stability
studies indicate that Abagovomab is stable at 2 °C to 8 °C for at least 6 months.
2.2
CLINICAL EXPERIENCE WITH ABAGOVOMAB
The clinical development of Abagovomab went through three clinical studies, starting with a
Phase Ib/II Proof of Concept (POC) study to demonstrate the safety of Abagovomab and its
ability to stimulate a specific immunologic response, and followed by two Phase I clinical
studies (one of these studies performed under IND in the USA) which evaluated the effect of
different doses, routes of administration and duration of treatment on the safety and immune
response, prior to selecting the optimal dose/schedule for the Phase II-III pivotal trial.
The main results of the POC study have been previously published (Wagner U et al., 2001;
Reinartz S et al., 2004). Results from the two Phase I studies are in press (Sabbatini P et al.,
2006; Pfisterer J et al., 2006). A brief summary of the three studies is included.
Page 20 of 66
2.2.1
Phase Ib/II study - Proof of concept for specific immune response induced by
Abagovomab and tolerability of repeated doses
Study title: Anti-idiotype vaccine for patients with advanced ovarian carcinomas with the murine
monoclonal anti-idiotype antibody Mab ACA125 (Anti-ID OC 125): determination of
immunological therapy effects (Phase Ib/II) – Study Code DFG Wa 740/2-1
This was a Phase Ib/II, multicenter study to evaluate the safety and immunogenicity of repeated
doses of Abagovomab in 119 patients with recurrent ovarian cancer, carcinoma of the fallopian
tube, peritoneal carcinoma or with other CA125-positive malignant tumors. Patients were
eligible for treatment if they had positive history of debulking surgery and previous platinumbased chemotherapy.
Abagovomab was to be administered as a 1 ml suspension containing 2 mg of Abagovomab via
intra-muscular (IM) route every 2 weeks for a total of 4 doses (induction Phase), followed by
monthly doses until disease progression. Safety and efficacy (immune and clinical responses) of
repeated Abagovomab vaccinations were the main study endpoints. The median overall survival
was also assessed.
The population recruited in this ‘first in human’ study was heterogeneous, particularly in terms
of types and number of cycles of previous therapies, and therefore in terms of prognosis.
Mean patient exposure to Abagovomab was 9.7 doses for a median of 4.9 months (range 0.554.8 months). Repeated 2 mg IM vaccinations were well-tolerated and no drug-related serious
adverse events were reported. The most frequent drug-related adverse event (i.e. with drug
relationship classified as any of the following: certain/definitely related, probable, possible and
unknown/conditional unclassified) was local reaction at the injection site, reported in 13 patients
(25 events). No serious allergic reactions could be detected within a follow up period of up to 56
months. A specific anti-anti-idiotypic antibody (Ab3) was induced in 68.1% of patients; antiCA125 antibodies (Ab1’) were induced in 50.4% of patients and an antibody-dependent cellmediated cytotoxicity (ADCC) was observed in the serum of 26.9% of patients. In terms of the
scheduled doses, the results of the study suggested that a median of 4 induction bi-weekly doses
was sufficient to induce detectable Ab3 titers. The monthly repeated administrations of
Abagovomab were then able to maintain an elevated Ab3 titer, as depicted below.
Page 21 of 66
Serum Ab3 concentration in responding patients who received repeated monthly doses of
Abagovomab (Phase I/II POC study results)
13
Natural logarithm of Ab3 titre (ng/ml)
12
11
10
9
Mean
Median
8
7
6
5
4
3
2
1
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
92
96 100 104 108 112
Weeks
The median survival of all patients was 19.4 months (range 0.5-56.1 months). Notably, patients
with an Ab3 response (Ab3+) showed a significantly longer survival (median 23.4 months)
compared with patients without an immune response (Ab3-) (median 4.9 months) (p<0.001). It is
also worth mentioning that Ab3 responders received more Abagovomab doses compared with
the Ab3 non-responders (mean 12.3+9.5 vs. 4.3+2.1), with the ‘responding’ patients being in the
study for a longer time.
2.2.2
Phase I studies: influence of dose, route of administration and duration of
treatment on the specific immune response induced by Abagovomab and its
tolerability
Two studies have been performed:
- Study title: Phase I trial of the monoclonal anti-idiotype antibody ACA125 in patients with
epithelial ovarian, fallopian tube, or peritoneal cancer – Study Code ACA125-01
The aim of this open label, randomized study was to compare the safety and efficacy (in terms of
immune response) of two different doses (0.2 mg and 2 mg as 1 ml solution) of Abagovomab,
administered either by the intramuscular (IM) or the subcutaneous (SC) route, in order to
evaluate any potential effect of the dose and/or the route of administration on the induction of an
immune response.
The trial was performed under IND in three centers in the USA including 44 patients (42
received study treatment) with stage II-IV epithelial ovarian cancer. Eligible patients received at
least one platinum-based chemotherapy regimen before study entry and could have had
asymptomatic residual disease or elevated CA125 or could have been in complete clinical
remission. A total of six Abagovomab vaccinations were scheduled and given every two weeks,
Page 22 of 66
for a total of 4 injections during the induction phase (week 0, 2, 4, 6), and then monthly for two
additional injections (maintenance phase). Study endpoints were the safety of and immune
response to Abagovomab in the four treatment groups (0.2mg IM, 0.2 SC, 2 mg IM, 2mg SC).
All 42 randomized patients received at least one administration of Abagovomab (9 patients in the
0.2 mg IM group and 11 patients in each of the remaining groups). The total number of
vaccinations administered per patient ranged from 2 to 6, with 66.7% of patients receiving the 6
scheduled vaccinations. The major reason for early treatment termination was disease
progression.
Thirty-three patients reached the fourth dose and underwent immunologic tests: in all patients,
regardless of the treatment group, Ab3 titer was positive at the first evaluation point (week 10),
with a further increase in titer in the subsequent follow-up samples collected up to 6 weeks after
the last administered dose (see tabulated summary data).
Ab3 titer (mg/mL) by dose and route of administration (Phase I study)
0.2 mg IM
Pts
2.0 mg IM
Median
Pts
0.2 mg SC
Median
Pts
Median
2.0 mg SC
Pts
Median
Visit 6 (Week 10)
6
69.8
10
40.5
10
53.3
7
63.0
Follow-up 1 (Week 16)
4
330.0
7
246.3
10
209.1
5
474.0
Follow-up 2 (Week 20)
4
489.1
4
193.1
8
179.5
3
364.5
Statistical tests showed that there was no effect of the route of administration or of the
administered dose on Ab3 or HAMA titer.
The best overall response obtained in Ab3+ patients (n=33) was stable disease (12 patients,
36.4%).
Overall, 42 patients were evaluable for safety. The most frequent drug-related adverse events
were reported in the following numbers of patients: injection site reaction (n=15), myalgia
(n=15), injection site pain (n=14), and pyrexia (n=7); all but one of these adverse events were
reported as Grade 1-2 CTC severity (there was one injection site erythema that was graded 3-4).
No drug- related serious adverse events were reported.
The results of this study confirmed the good tolerability of the 2 mg dose, which had previously
been associated with improved overall survival in the POC study. The immune response induced
by the SC route as well as its tolerability was not statistically or clinically different from that
with the IM route; this would favor the SC route for repeated, long-term administration for
patient convenience.
Page 23 of 66
- Study Title: A Phase I trial of ACA125 in patients with recurrent epithelial ovarian fallopian
tube or peritoneal cancer - Study code AGO OVAR 2.8
The aim of this open-label study was to collect additional data on the 2 mg SC dose of
Abagovomab and to compare the Ab3 response following a short (6 doses) versus longer (9
doses) treatment duration. Abagovomab was given as a 2 mg dose SC in both treatment duration
arms.
To fulfil the inclusion criteria, patients must have received a second-line chemotherapy (after
failure of a platinum-based first-line chemotherapy) within the last 6 weeks and have
asymptomatic measurable disease, elevated CA125 or to be in complete clinical remission.
Thirty-six patients with stage I-IV epithelial ovarian cancer were enrolled.
In this study, 88.9% of patients in the “short-term” arm completed the planned 6 vaccinations,
while 44.4% of patients in the “long-term” arm received all the planned 9 vaccinations; for both
arms, the main reason for premature study termination was disease progression.
Thirty-three of 36 patients were evaluable for the immune response (in the remaining three
patients Ab3 titer was not measured because they prematurely went off study due to progressive
disease [n=2] and death [n=1]).
Ab3 resulted positive in all evaluable patients (100%), with a further increase in the Ab3 titer in
the treatment arm exposed to 9 doses of Abagovomab (see tabulated summary data).
Ab3 titer (µ
µg/mL) following 2 mg SC at the end of induction
and during maintenance period (Phase I study)
End of induction
Maintenance period
Week 10
Week 14
Week 26
No. Pts*
Median
No.Pts*
Median
No. Pts*
Median
Short treatment (6 doses)
17
47.0
16
96.0
-
-
Long treatment (9 doses)
14
48.1
12
109.5
8
292.9
* Number of patients reaching the assessment time point
No severe drug-related toxicity was recorded in either treatment group. The most frequent
adverse events (mainly grade 1-2) were: anemia, leucopenia, neutropenia, injection site
reactions, fatigue and nausea.
Overall, the results of this second Phase I/II study confirmed the good tolerability of repeated
administrations of Abagovomab and provided additional supporting evidence on the induction of
an active immune response using the 2 mg dose and SC route of administration selected for the
Phase III trial.
Page 24 of 66
2.2.3
Summary of clinical experience with Abagovomab
In phase I/II studies, Abagovomab proved to be effective in generating a specific immune
response (as expressed as Ab3) against CA125 positive cells. Antibody responses were
associated with increased survival. Treatment with Abagovomab was well tolerated
independently from the duration of treatment and route of administration (SC vs IM).
The results of these studies support the dose/schedule selection (2 mg SC every 2 weeks for 4
injections followed by monthly maintenance injections) that will be used in this randomized,
double blind, multicentre trial in which Abagovomab will be compared to placebo as
maintenance therapy in stage III-IV ovarian cancer patients after completion of successful frontline therapy (surgery and standard platinum-taxane chemotherapy).
Page 25 of 66
3
ETHICAL AND LEGAL ASPECTS
3.1
GENERAL ASPECTS
This study will be carried out in compliance with the study protocol, the recommendations on
biomedical research on human subjects of the current version of Declaration of Helsinki
(Appendix I), ICH-Good Clinical Practice Guidelines and local ethical and legal requirements.
Furthermore, the study will be conducted in compliance with the Sponsor and/or the appointed
Contract Research Organization (CRO) SOPs.
All clinical work conducted under this protocol is subject to Good Clinical Practice rules. This
includes an inspection by the Sponsor, Sponsor’s representatives and/or relevant Regulatory
Health Authority representatives at any time. All investigators must agree to the inspection of
study-related records by the relevant Regulatory Health Authority representatives and/or the
Sponsor representatives, which must be performed in accordance with national laws concerning
personal data protection.
3.2
INDEPENDENT ETHICS COMMITTEE AND LEGAL REQUIREMENTS
Before starting any study procedure in a center, the corresponding independent Ethics
Committee (EC)/Institutional Review Board (IRB) has to approve the study conduct. For this
purpose documents requested by the IRB/EC for reviewing the clinical study have to be
submitted to the corresponding IRB/EC.
In addition, all national legal requirements for the conduct of a clinical trial have to be followed
prior to start of the study.
The competent authority and the IRB/EC of the participating country will be informed about the
end of the study or the premature study termination within the requested time period.
3.3
SUBJECT INFORMATION AND INFORMED CONSENT
The subject will be informed of the following: purpose of the research; explanation of the trial
treatment(s) and probability for random assignment to each treatment; explanation of the
expected duration of subject’s participation; approximate number of subjects involved in the
study; description of procedures to be followed (i.e., visits, physical exam, laboratory tests, chest
x-ray, CT scan, etc.); subject’s responsibilities; identification of any procedures that are
experimental; description of any reasonably foreseeable risks or discomforts to the subject;
possibility of unforeseen risks; description of benefits to the subject or to others reasonably
expected from research (including possibility of no benefits); explanation of the extent to which
Page 26 of 66
confidentiality will be maintained allowing access to original medical records by appropriate
regulatory agency, IRB/EC, Sponsor or representative and statement that if the records of the
trial are published, the subject’s identity will remain confidential; disclosure of appropriate
procedures or alternative treatments and their risks and benefits; for research involving more
than minimal risk, an explanation to whether any compensation and an explanation as to whether
any medical treatment are available if injury occurs; an explanation of whom to contact with
questions regarding the research, subject’s rights, and study related injury; a statement
addressing voluntary participation (i.e., subject may refuse to participate without penalty or loss
of benefits, subject may discontinue without penalty or loss of benefits); a statement naming
circumstances under which a subject may be discontinued without consent; additional costs to
the subject (if any) that may result from participation in the study; the consequences of a
subject’s decision to withdraw and procedures for orderly termination (i.e., notify site, return
diary and unused drug, have appropriate safety assessments completed); statement explaining
that the subject or legal representative will be informed in a timely manner if information
becomes available that may affect the subject’s willingness to participate in the trial; statement
that a signed and dated copy of the consent form will be given to the subject; informed consent
will not include any language that causes the subject, or the subject’s legal representative to
waive or to appear to waive any legal rights, or that releases or appears to release the
investigator, the institution, the sponsor, or their agents from liability for negligence; and that the
consent does not contain any language that coerces the subject to participate or to continue to
participate in the study. HIPAA requirements must be met and the HIPAA statement must be
signed by the subject or subject’s legal representative.
The investigator will inform the subjects about the subject’s insurance taken out by the Sponsor
and any duties that may arise therefrom.
A subject information sheet and informed consent form explaining all the above-mentioned
items in detail must be approved by the IRB/EC; it will be submitted to the subject in the
corresponding native languages and in accordance with local laws and regulations and must be
signed and dated by the subject before any trial-related procedure may be performed. A template
of the information sheet and informed consent is provided in Appendix II.
The investigator must store the original of the signed consent form in the Investigator‘s File.
Any revision to the subject information sheet and/or written informed consent form must receive
the independent ethics committee approval prior to implementation.
3.4
SUBJECT INSURANCE
For subjects participating in the study, Menarini Ricerche S.p.A. has stipulated an insurance
policy in accordance with regulatory requirements.
A copy of the insurance certificate will be provided to each investigator and will be filed in the
Investigator’s File at the centers and in the Trial Master File.
Page 27 of 66
3.5
RECORD RETENTION
All documentation pertaining to the study will be kept by Menarini Ricerche S.p.A. for the
lifetime of the product. The final report, pertaining to this study, will be kept for additional five
years.
CRO will provide each Investigator with an Investigator’s Site File, which should be used to file
the Investigator’s Brochure, protocol, drug accountability records, correspondence with the
IRB/EC, concerned authorities, Sponsor and CRO, and other study-related documents.
As required by International Conference of Harmonization GCP guidelines, the Investigator
must keep patient’s file and essential documents (including the Investigator’s copy of the CRF,
patients information and consent forms, drug accountability records and Patient Identification
List) until at least two years after the last approval of a marketing application in an International
Conference of Harmonization region; until there are no pending or contemplated marketing
applications in an International Conference of Harmonization region, or at least two years have
elapsed since the formal discontinuation of clinical development of the investigational product.
In addition, the Investigator must make provision for the patient’s records to be kept for the same
period of time.
No data should be destroyed without the consent of the Sponsor. Menarini Ricerche S.p.A. will
inform the Investigator in writing of the need for record retention and will notify the Investigator
in writing when the trial related records are no longer needed.
Patients' records and other original data will be archived according to the archiving regulations
or facilities of the investigational sites. The original CRFs will be archived by Menarini Ricerche
S.p.A. with the final report and all other documentation pertaining to the trial according to the
Sponsor’s SOPs.
3.6
CONFIDENTIALITY
By signing this study protocol, the investigator affirms that any information furnished by
Menarini Ricerche S.p.A. and/or Sponsor’s representative pertaining to this study will be
maintained in confidence, and that such information will be divulged to IRB/EC or regulatory
authorities only under an appropriate understanding of confidentiality with such a committee or
institution.
In order to maintain the subjects’ confidentiality, identification of all patients data collected from
the investigator will be by subject initials and study number. The investigator agrees that within
local regulatory restrictions and ethical considerations, Menarini Ricerche S.p.A. or its
representative or any regulatory agency may consult and/or copy study documents in order to
verify data in the CRF.
Page 28 of 66
The Investigator or a designee will maintain a personal list of subject numbers and subject names
(Subject Identification List) to enable records to be found at a later stage.
The subjects’ medical records pertinent to the study will be reviewed by the study monitors of
the Sponsor or CRO or representatives of Sponsor’s and/or regulatory authorities, to assure
adequate source documentation, accuracy and completeness of CRFs. The review will be
conducted in accordance with the Sponsor and/or CRO SOPs and with strict adherence to
professional standards of confidentiality, GCP and the relevant data protection legislation.
3.7
PROTOCOL ADHERENCE AND STUDY PROTOCOL AMENDMENTS
An amendment is a written description of change(s) to or formal clarification of a study protocol
which may impact on the conduct of the clinical study, potential benefit of the clinical study, or
may affect subject safety, including changes of study objectives, study design, subject
population, sample size, study procedures, or significant administrative aspects.
Such amendments will be agreed upon and approved in writing by the Principal Investigator, the
Sponsor’s representatives and the appointed CRO. If those amendments are substantial and are
likely to have an impact on the safety of the patients, the Sponsor they will be submitted for
approval to IRB/EC and regulatory authority(ies) in the participating country(ies) with reason
and contents of these amendments for revision and approval.
If the IRB/EC approves the amendment and the competent authority has raised no reason for
non-acceptance of the amendment, the clinical trial will be conducted following the amended
protocol.
Changes which have no significant impact on medical or scientific validity of the study will be
agreed upon and approved in writing by the Principal Investigator, Menarini Ricerche S.p.A. and
the appointed CRO, and the IRB/EC will be notified of this protocol amendment.
Any revision of the protocol will be integrated in an updated study protocol. The Principal
Investigator must ensure full compliance with the updated study protocol.
3.8
STUDY COMMENCEMENT
Prior to enrolment of any subject into the study, the Investigator must provide Menarini Ricerche
S.p.A. and the appointed CRO with the following documents:
•
Signed copy (original) of the IRB/EC approved protocol;
•
IRB Membership List/DHHS Number;
•
IRB Approval Document;
•
IRB/EC Statement of GCP Compliance;
•
Form FDA 1572 (Investigator’s Statement);
•
Financial Disclosure Form;
Page 29 of 66
•
Proof of Medical Licensure;
•
Curricula vitae (CV) of all personnel who take part in the study;
•
Name and location of the laboratory used for laboratory assays including laboratory
certification number and date of certification;
•
List of Normal Values for laboratory tests;
•
Investigator Acknowledgement of IB and addenda;
•
Copy of the approved Informed Consent form by the EC;
•
HIPAA Authorization content, if applicable.
3.9
USE OF INFORMATION AND PUBLICATION
All information concerning the study drug supplied by Menarini Ricerche S.p.A. in connection
with this clinical study, and not previously published, is considered confidential and proprietary
information. The information includes the Investigator’s Brochure, the Investigational Medicinal
Product Dossier, the Clinical Protocol, Case Report Forms and assay methods. This confidential
information shall remain the sole property of Menarini Ricerche S.p.A., shall not be disclosed to
others without prior written consent from Menarini Ricerche S.p.A. and shall not be used except
in the performance of this clinical study.
The information developed during the conduct of this clinical study is also considered
confidential and will be used by Menarini Ricerche S.p.A. in connection with the development of
the study drug.
The Investigator is obliged to provide Menarini Ricerche S.p.A. or its other designee with
complete test results, all study data and access to all study records derived from this clinical
study.
A clinical study report covering clinical and statistical aspects will be prepared by Menarini
Ricerche S.p.A. or its designee.
Menarini Ricerche S.p.A. recognizes the importance of communicating medical study data and
therefore encourages their publication in reputable scientific journals and at seminars or
conferences.
Once the clinical study report is prepared, an original manuscript on the study results will be
written by the coordinating investigators. Besides the coordinating investigators, members of the
Steering Committee will be co-authors. Principal investigators of each recruiting center with
corresponding Institutions will be also listed in a separate appendix.
Any results of medical investigations with the study drug and/or publication/lecture /manuscripts
base thereon, shall be exchanged and discussed with Menarini Ricerche S.p.A. representatives 60
days prior to submission for publication or presentation. Due regards shall be given to Menarini
Ricerche’s legitimate interests, e.g., manuscript authorship, obtaining optimal patent protection,
coordinating with other ongoing studies in the same field, and protecting confidential data and
information.
Page 30 of 66
4
QUALITY ASSURANCE
Audits may be conducted by the Quality Assurance Unit of CRO or Menarini Ricerche S.p.A.
and an inspection by the regulatory authorities may also be conducted. This is to ensure that the
performance and the data generation are in compliance with International Conference of
Harmonisation guidelines for GCP and CRO Quality Procedures.
At investigational sites, the auditor and inspector should have direct access to facilities,
laboratories, and all data (including source data) and documentation for inspection.
Confidentiality of patient data will be maintained. All audits and inspections will be documented
and kept on record.
Page 31 of 66
5
INVESTIGATORS
AND
STUDY
ADMINISTRATIVE
STRUCTURES
Coordinating Investigator
Prof. Jacobus Pfisterer
Frauenklinik
Universitätsklinikum Mannheim
D - 68167 Mannheim (GERMANY)
Phone: +49 621 383 2386
Fax: +49 621 383 3814
E-mail: [email protected]
Sponsor
Menarini Ricerche S.p.A.
Clinical Research
Via Sette Santi 1
50131 Firenze (ITALY)
Phone: +39 055 56809990
Fax: +39 055 5680597
Clinical Research, Corporate Director
and Sponsor’s Representative
Angela Capriati, MD, PhD
Clinical Research, Director
Full Development
Lorenzo Melani, MD, PhD
Clinical Research Physician
Monica Bertolotti, MD
Biostatistician
Giacomo Mordenti, Stat.D
Data Manager
Simona Scartoni, Stat.D
Drug Safety Manager
Joaquim Vallés
Laboratorios Menarini, S.A.
Clinical Research
Alfons XII, 587
08918 Badalona (Barcelona), Spain
Page 32 of 66
Quality Assurance
Head of Quality Assurance
Contract Research Organization
Project Manager EU
Project Manager NA
Drug Safety Unit
Research Toxicology Center S.p.A.
Quality Assurance Unit
Via Tito Speri 12
I-00040 Pomezia (ITALY)
Maria Mercede Brunetti, Biol D
Pharmaceutical Research Associates España,
S.A.U.
Avenida de Europa, 19 Edificio 1, 2ª Planta
28224 Pozuelo de Alarcón
Madrid (SPAIN)
Phone: +34 91 708 1110
Fax: +34 91 708 1111
Mario Aznar
Wendy Kerby
Melanie Weber
Drug Safety Center Europe
PRA International
Dybamostrasse 13-15
D-68165 Mannheim
Phone + 49 621 8782-252
Fax + 49 621 8782-181
Email: [email protected]
Page 33 of 66
6
STUDY OBJECTIVES
Primary objective:
To evaluate the benefit in terms of recurrence free survival (RFS) of Abagovomab vs placebo as
maintenance therapy after clinical complete response to debulking surgery and standard
platinum/taxane 1st line chemotherapy.
Secondary objectives:
1. to compare the effect of Abagovomab vs placebo in terms of overall survival (OS);
2. to evaluate the safety and tolerability of repeated doses of Abagovomab;
3. to evaluate the time course of immune response induced by repeated doses of Abagovomab,
namely induction of Ab3 and HAMA;
4. to evaluate in a subset of approximately 10% patients additional immunologic parameters
(e.g. Ab1’ and CA125-specific T cell response).
Page 34 of 66
7
INVESTIGATIONAL PLAN
7.1
OVERALL STUDY DESIGN AND PLAN DESCRIPTION
ABA-01 is a randomized, double blind, placebo controlled, multicentre study.
Abagovomab or placebo (2:1 ratio) will be administered as maintenance therapy in patients with
epithelial ovarian cancer (FIGO stage III-IV) in clinical complete response after the completion
of front-line treatment (surgery plus standard platinum/taxane chemotherapy).
Randomization of patients to study treatment should be completed within 8 weeks from the last
administered cycle of chemotherapy. The 8 week-time lag is deemed as the most appropriate to
fully benefit from a biological agent as maintenance therapy in patients in complete disease
remission.
The study will be conducted and evaluated in accordance with all relevant international and
national guidelines and regulations on GCP/ICH and with ethical standards for human
experimentation established by the Declaration of Helsinki (see Appendix I). Every patient must
provide written informed consent to participate in the study.
The study will be performed in about 120 study centers in Europe and in USA, with a projected
average number of seven patients/center.
The study will be performed in double blind condition with a survival follow-up performed in
open-label conditions, as follows:
the double blind observation (DBO) period of study spans from the randomization of the first
patient up to 24 months after the randomization of the last patient, with a minimum and
maximum individual observation period for the evaluation of RFS of 24 and 48 months,
respectively. During the DBO period, study treatment will be administered from
randomization up to 21 month after the randomization of the last patient or until a disease
recurrence is documented.
The open survival follow-up will start from the end of DBO period and will be continued for
additional 5 years, i.e. up to 7 years from the randomization of the last patient.
The overall study plan and main assumption are depicted in the study flow-chart.
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Study Flow Chart
End of
DBO
period
Last drug intake
End of Survival Follow-up
Last pt in
1st pt in
0
24
months
108
48
3 months
Double blind treatment and observation period
Open Survival follow-up
STUDY ASSUMPTIONS
Recruitment period (expected):
24 months
Treatment period:
from randomization until disease progression or
up to 21 months after randomization of the last
patient
Final study visit
12 weeks after the last administered dose for
patients who regularly completed the treatment or
in case of early treatment discontinuation for
reasons other than disease recurrence;
4 weeks after last administered dose in case of
early treatment discontinuation for disease
recurrence.
48 months (24 months for recruitment +
21 month of treatment + 3 months for final
estudy visit)
Overall double blind study period :
Page 36 of 66
RFS Observation period (double blind):
Survival follow up:
max:
48 months
min:
24 months
mean:
36 months
max:
108 months
min:
84 months
mean:
96 months
At a maximum of 8 weeks from the completion of the last chemotherapy cycle, patients with
clinically documented complete response and no definite radiographic evidence of disease on
CT scan of abdomen and pelvis and negative chest X-say, obtained within the previous 4 weeks,
will be screened for eligibility and those who will meet all the inclusion criteria and none of the
exclusion criteria will be randomized. Serum CA125 must be obtained in each patient during the
screening procedure and will be used by the investigator to confirm the completeness of the
clinical response. Screening procedures must be completed within 2 weeks prior to
randomization and will be considered as baseline assessments (the only exception being Ca 125
level and immunological parameters collected at time= 0 that are considered as baseline
assessment).
During the first 6 weeks of treatment (induction phase) patients will receive a subcutaneous (SC)
administration of study drug every 2 weeks (i.e. at randomization and then at week 2, 4 and 6).
Thereafter (maintenance phase, starting from week 10), the study drug will be administered SC
every 4 weeks until evidence of disease recurrence or up 94 weeks (approximately 21 months)
after the randomization of the last patient.
CT scan will be performed at week 10 and thereafter every 12 weeks until completion of DBO
period or until documentation of recurrence. Chest X-ray will be performed every 24 weeks until
completion of DBO period or until documentation of recurrence. CA125 assay will be
performed at week 0 and subsequently at the same time points of CT scan, but results will be
kept blinded until the end of DBO period.
Safety will be evaluated by monitoring adverse events every 4 weeks (prior to each study drug
administration); in addition physical examination, laboratory safety tests and vital sign
measurements will be performed at week 4, week 10, and every 12 weeks until the end of DBO
period. In case of early treatment discontinuation for disease recurrence, complete safety
assessment will be performed at the final study visit within 4 weeks after the last administered
dose; after then, safety will continue to be monitored by phone (via patient or patient’s GP) every
12 weeks until the end of DBO period for collection of adverse drug reactions.
Survival status will be collected along the double blind observation period (by phone in case of
early treatment discontinuation for disease recurrence or any other cause). Survival will continue
to be monitored every 12 weeks by phone (to patient or patient’s GP) during the survival follow
up period (i.e. up to 7 years from the randomization of the last patient).
Page 37 of 66
The induction of a specific immune response will be periodically assessed during the trial by
measuring the Ab3 and HAMA titers in all patients who received at least 1 treatment dose, with
the last assessment performed at the final study visit. Furthermore, in a subset of about 10% of
patients, additional immunologic assays (i.e. CA125 specific antibodies Ab1’and analysis of
CA125-specific T cell immune response) will also be performed (see § 7.7.2). This subset of
patients will be selected mainly on the basis of logistic considerations (e.g. close proximity of
study center with the central lab performing the assays).
The minimum patient’s observation (double blind) period will be 24 months (mean expected
observation follow-up equal to 36 months, considering a 2-year recruitment phase and a 2-year
follow up from the randomization of the last patient). The minimum survival follow up (double
blind + open) period will be 7 years.
7.2
DISCUSSION OF STUDY DESIGN AND PLAN DESCRIPTION
The objective of this study is to confirm the benefit of Abagovomab on the Recurrence Free
Survival (RFS) and the Overall Survival (OS) as compared to placebo in patients with stage III
or IV ovarian cancer after debulking surgery and platinum/taxane first line chemotherapy.
A time of up to 8 weeks between the end of chemotherapy and the start of Abagovomab
vaccination is considered optimal to fully recover from any toxicity from previous chemotherapy
and fully benefit from receiving a biological agent as maintenance of the complete remission
status.
The placebo controlled design will allow the double-blind evaluation of efficacy and safety of
Abagovomab, while the 2:1 randomization design in favor of Abagovomab has been selected to
give patients a greater chance to receive the active treatment and to collect safety information on
a greater number of patients.
The choice of the RFS as the primary endpoint is in line with the recent FDA guidelines (Clinical
Trial Endpoints for the Approval of Cancer Drugs and Biologics, draft version, April 2005) for
the clinical development of a non-cytotoxic maintenance anticancer therapy in the adjuvant
setting after definitive treatments. Data on RFS will be collected blinded over a minimum of 2
years and up to 4 years after randomization. However, a much longer open follow-up period
prolonged up to 5 years after completion of double blind observation period will allow for
evaluation of OS as a secondary endpoint.
The sample size and the study timelines give enough power to detect meaningful differences
between Abagovomab and placebo both on RFS and on OS.
Efficacy will be closely assessed by frequent clinical and instrumental (imaging) evaluation of
the potential onset of recurrence over 2-4 years from the first drug administration, and by
thorough monitoring of the survival status for 7-9 years. An independent Clinical Event
Adjudication Committee (CEAC) will review all the imaging documentation and pertinent
Page 38 of 66
clinical data in double blind condition, in order to assess the recurrence of the disease as well as
the date of recurrence in the most objective fashion.
The effect of Abagovomab treatment on the humoral and cellular immune response will be also
evaluated, to explore the patient’s immune response and any impact on the clinical outcome.
Safety will be assessed by close monitoring of adverse events during treatment up to the end of
the DBO period, with the final assessment 12 weeks after the last administered dose. In case of
treatment discontinuation for disease recurrence the final study visit is anticipated within 4
weeks after the last dose in order to avoid potential bias of the effects of subsequent
therapies/disease recurrence status. Long-term safety follow-up data will be also collected in
patients with premature treatment discontinuation by collecting adverse drug reactions every 12
weeks until completion of the DBO period.
7.3
RANDOMIZATION
Eligible patients will be randomized, according to a central randomization procedure, by IVRS to
receive Abagovomab or placebo in a 2: 1 ratio. The randomization list will be stratified
according to the following baseline prognostic factors, without forcing the number of patients in
each stratum:, in order to preserve the randomization ratio within each stratum.
tumor size after debulking surgery (i.e. residual tumor < 1 cm; > 1 cm);
serum CA125 level after the first 3 cycles of chemotherapy (< 35 U/ml, > 35 U/ml).
The randomization list will be generated by an independent statistician using a validated
computer program. The block size will not be disclosed to the investigators.
IVRS will also be used for breaking the code in case the investigator deems necessary the
unblinding of study treatment for safety reasons (see § 7.7.5). In any case, all the efforts will be
done to provide a secure 24-hours available contact between the Investigator and the Sponsor or
its designee to promptly document and explain any premature unblinding of the investigational
product (see §7.7.7).
7.4
STUDY POPULATION
7.4.1
Number of subjects/centers
A total of 870 patients will be randomized according to a 2:1 randomization ratio to
Abagovomab or placebo. Assumptions for the sample size calculation are described in Section
8.1.1.
The study will be conducted in about 120 study centers distributed in Europe and USA.
Page 39 of 66
7.4.2
Inclusion Criteria
At a maximum of 8 weeks after the last cycle of first line standard platinum/taxane
chemotherapy, patients must fulfil all the following inclusion criteria:
7.4.3
Age ≥ 18 years;
Properly executed written informed consent;
History of histological and CA125 confirmed diagnosis (CA125 > 35 U/ml) of stage III-IV
epithelial ovarian, fallopian tube, or primary peritoneal cancer;
History of debulking surgery and standard platinum/taxane based non-investigational
chemotherapy;
Complete clinical response defined as:
Normal physical examination;
No symptoms suggestive of persistent cancer;
No definite evidence of disease by computed tomography (CT) of the abdomen and
pelvis within the previous 4 weeks;
Negative chest x-ray (or CT chest) within the previous 4 weeks;
Serum CA125 level < 35 U/ml.
Adequate haematologic, renal and hepatic function:
ANC >1.5 x 109/l;
Platelets > 75 x 109/l;
Haemoglobin > 6.2 mmol/l (>9.9 mg/dl);
Serum creatinine < 1.5 x ULN;
Bilirubin < 1.5 x ULN; AST, ALT, AP < 2.5 x ULN.
ECOG PS < 2.
Exclusion criteria
Patients are ineligible to participate to the study if any of the following criteria are met:
Any other invasive malignancies, with the exception of non-melanoma skin cancer or
cervical carcinoma in situ, within the last 5 years or whose previous cancer treatment
contraindicates this protocol therapy;
Known active autoimmune disease requiring chronic treatment with immunosuppressive
agents (e.g., rheumatoid arthritis, ulcerative colitis, etc.);
Known immune deficiency (e.g. HIV, hypogammaglobulinemia, etc.);
Known infection with hepatitis B, or hepatitis C;
History of recent myocardial infarction (< 6 months) or decompensated heart failure
(NYHA class > III);
Previous or concomitant use of any anti-cancer therapy other than the platinum-taxane first
line chemotherapy;
Concomitant use of any other investigational agent;
Page 40 of 66
7.4.4
Any prior investigational anti-cancer vaccine or monoclonal antibody;
Known allergy to murine proteins;
Any significant medical or psychiatric condition, drug or alcohol abuse that might prevent
the patient from complying with all study procedures;
Clinically significant active infection;
Concomitant use of any immunosuppressive agent (e.g., steroids, cyclosporin, etc.);
Major surgery within the previous 2 weeks;
Radiotherapy within the previous 4 weeks;
Any significant toxicity from prior chemotherapy;
Unreliability or inability to follow protocol requirements.
Removal of subjects from therapy or assessment
Subjects can withdraw consent for participation in the study at any time without prejudice. The
investigator can withdraw a subject if, in his/her clinical judgement, it is in the best interest of
the subject or if the subject cannot comply with the protocol.
The subject will undergo a final study visit after withdrawal, the cause of which will be recorded
in detail on the CRF. If the withdrawal of a subject resulted from an adverse event, this will be
documented in accordance with procedures described under section “SAE Reporting”.
Whenever possible, the tests and evaluations listed for the final study visit will be carried out. In
addition, the time schedule for safety and overall survival follow-up should be maintained.
NOTE: Subjects who will withdraw consent to participate to the study will be specifically asked
to consent or not to be contacted/provide data on adverse drug reactions, if any, and survival
status by phone or mail (either directly or via the patient’s GP).
7.5
TREATMENT
The investigational medicinal product Abagovomab verum or placebo will be supplied by
Berlin-Chemie AG, Glienicker Weg 125, D-12489 Berlin, Germany. The medication will be
supplied directly by Berlin-Chemie AG to the centers or to authorized central warehouses within
the participating countries.
Manufacturing and distribution will be performed according to GMP requirements.
7.5.1
Identity of Investigational Drugs
Abagovomab drug product is available in vials containing 2 mg Abagovomab as 1 ml
suspension.
The drug product is a white suspension for subcutaneous injection containing the anti-idiotypic
antibody Abagovomab adsorbed onto aluminum hydroxide and suspended in a buffered and
isotonic saline solution to adjust the pH to about 7.5. The drug product is free of any
Page 41 of 66
preservatives. It is provided in type I glass vials closed with a rubber stopper and an aluminum
flip-off cap.
Stability studies indicate that Abagovomab drug product is stable at 2 to 8 °C for at least
6 months.
7.5.2
Packaging
Study treatments will be packaged in individual treatment boxes. Each treatment box will bear an
individual box number and will contain the following materials according to the IVRS packaging
list:
- eight vials with Abagovomab 2mg/ml suspension or Abagovomab placebo suspension (same
packaging and volume) for SC injection and tear-off labels to be affixed on the CRF at the time
of treatment administration to the patient;
- leaflet with instructions.
7.5.3
Labeling
Study medication will be labeled with the multilingual booklet labels including the appropriate
local language according to the GMP/GCP-directives and local legal requirements, including, at
least, the following information:
study code;
product name;
individual box-number;
dosage form, route of administration, quantity of dosage units;
instructions for use;
batch number, expiry date, storage conditions;
‘for clinical trial use only’;
name, address, telephone number of the Sponsor
7.5.4
Storage of Study Medication, Accountability and Dispensing
The investigational medicinal product will be supplied in carton boxes and stored at the hospital
pharmacy in the secondary package at a temperature of 2 to 8 °C. The pharmacist will make an
inventory and acknowledge receipt of all shipments of the study medication, checking also
whether the expiry date allows the administration to the patients.
At the investigator’s site the study medication will be stored in a separate, securely locked,
limited-access storage area at a temperature of 2 to 8 °C, until it is dispensed to the subject.
Investigators will be responsible for dispensing the study medication to the subjects; this will be
documented on the appropriate CRF page.
Page 42 of 66
7.5.5
Schedule of Administration
Abagovomab or placebo will be administered as 1 ml suspension by SC route (into buttocks,
thighs, abdomen or arms) every 2 weeks during the induction phase (at randomization = week 0,
and then at week 2, 4 and 6) and then every 4 weeks up to 21 months from the randomization of
the last patient (approximately 94 weeks) or until disease recurrence. Sites may be rotated.
7.5.6
Dose Adjustment and Modification
Dose reduction is not permitted. Patients are to be removed from the study in case of a Dose
Limiting Toxicity (DLT). According to NCI- CTCAE (version 3.0) DLT is defined by:
> Grade II allergic reaction (Grade II is defined as rush, flushing urticaria, dyspnea, or drug
fever > 38 °C; Grade III is defined as symptomatic bronchospasm, with or without
urticaria, requiring parenteral medications, allergy-related edema or angioedema, or
hypotension; Grade IV is defined as anaphylaxis);
> Grade II autoimmune reaction (Grade II is defined as evidence of autoimmune reaction
involving a non-essential organ or function (e.g. hypothyroidism; Grade III is defined as
reversible autoimmune reaction involving function of a major organ or other adverse event;
Grade IV is defined as autoimmune reaction with life-threatening consequences);
> Grade III hematologic or non-hematologic toxicity including fever (Grade III fever is >
40 °C for < 24 hours);
> Grade III injection site reaction (Grade III is defined as ulceration, or necrosis that is
severe or prolonged, or requiring surgery).
Any patient with Grade II or greater toxicity has to be followed with appropriate safety
assessments until resolution of the event(s).
7.5.7
Discontinuation of Treatment
Treatment can be discontinued at any time if in the best interest of the patient or any of the
following are observed:
patient refusal;
non-compliance of the patient with the protocol;
physician judgment;
DLT as defined above, or life-threatening SAE;
documented disease recurrence.
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The Investigator is ultimately responsible for the safety and the well being of the patients and the
patient may be withdrawn from the treatment at any time during the study if it is believed that
the constraints of the study procedures are detrimental to the patient’s health.
This event must be notified to the study monitor, the reason(s) of withdrawal should be
documented in the CRF and follow-up should be reported.
Patients who early discontinue the study treatment for disease recurrence will undergo a final
study visit for safety and immunological evaluation within 4 weeks after the last treatment
administration; in case treatment is early discontinued for reasons other than disease recurrence
the final study visit will be performed 12 weeks after last treatment administration for efficacy,
safety and immunological evaluation. For all patients with early treatment discontinuation,
safety should be followed until the end of DBO period and survival status should be followed
until the end of the open period unless consent is explicitly withdrawn from the patient.
For patients who withdraw consent please refer also to the note under § 7.6.4.
7.5.8
Concomitant Treatments
Patients are not allowed to receive concurrently any other clinical investigational drug, any other
antineoplastic drug (including chemotherapy, hormonotherapy, immunotherapy) nor radiation
therapy.
The prophylactic use of corticosteroids is not allowed.
Acetaminophen (or equivalent) and diphenhydramine (or equivalent) may be used at the
discretion of the Investigator.
The concomitant treatments must be recorded in the CRF.
7.6
STUDY PROCEDURES
7.6.1
Efficacy and Safety Measurement Flowchart
The following observations and tests are to be performed and recorded on the CRF, as
summarized in the attached study schedule table.
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STUDY SCHEDULE
SCREENING/
RANDOMIZATION
TREATMENT/DOUBLE BLIND OBSERVATION PERIOD
OPEN SURVIVAL
up to 2 yrs after last randomized pt
Follow up
8 wks from last
chemotherapy cycle
Treatment/Efficacy and Safety assessment
W-2 to W0*
Abagovomab/placebo
Inclusion/exclusion criteria
Informed consent
Demographics
Medical history
PS (ECOG)
Physical and
Gynecological examination
Vital signs
12-lead ECG
Haematology/Serum
Chemistry/Urinalysis
Serum CA125 marker
CT scan (abdomen & pelvis)
Chest X-ray
HAMA, Ab3 tests
Adverse Events
Concomitant medication
Survival status
X
X
X
X3
X
X
Induction Phase
W0* W2 W4 W6
X
X
X
X
X
X
X
X
X
X
X
X
X5
X7
4
X
X
X
X10
Final
Study Visit1
Maintenance Phase
every 4
every 12
wks
wks
2
X
X
W10
X
X
X
12 wks after
last dose1
X
X
X
X
X
X
X
X
X
X
X
4
4
X
X
X
X
X7
X
X8
9
X10 X10 X10
X10
X10
11
up to 7 yrs after last
randomized pt
Survival status
every 12 wks
4
X
X6
X7
X
X9
X10
X11
* Week 0 corresponds to randomization and first administration of study treatment.
1.
Final study visit for safety and efficacy corresponds to end of the double blind observation period (24 months after
the last randomized patient and 12 weeks after the last administered dose) for regular end of treatment. In case of
early treatment discontinuation; the final study visit will be performed 12 weeks after the last administered dose or
within 4 weeks (and without CT scan and chest X-ray) for treatment discontinuation due to disease recurrence.
2.
Abagovomab or placebo up to 94 weeks after last randomized patient OR until disease recurrence is documented.
3.
Including main tumor characteristics (e.g. histopathological grading, FIGO stage III/IV and III sub-categories
[IIIA, IIIB, IIIC)], size f the residual tumor after surgery [0 cm, < 1cm, > 1cm]).
4.
Samples will be collected but results of CA125 assay will be kept blinded until the end of DBO period.
5.
CT scan to be done at screening if performed > 4 weeks prior to randomization.
6.
CT scan to be repeated at final study visit only if disease recurrence has not been previously documented.
7.
Chest X-Ray to be done at screening if performed > 4 weeks prior to randomization; to be repeated every 24 wks,
and at final study visit (only if disease recurrence has not been previously documented).
8.
ONLY at week 22, 58 and 94
9.
AE to be recorded at study center prior to dosing. In case of early treatment discontinuation (for disease recurrence
or any other reason) adverse events will continue to be monitored by phone (or visit at center if deemed
appropriate by the investigator) for collection of ADRs up to the end of the double blind observation period.
10. ONLY changes in concomitant medication from screening will be recorded.
11. In case of early treatment discontinuation (for other reason other than death) survival status will continue to be
monitored in double blind condition by phone every 12 weeks up to the end of the double blind observation
period, and then in open fashion during the survival follow up.
Page 45 of 66
7.6.2
Screening/Randomization
Screening and randomization by IVRS must be performed and completed within 8 weeks from
the completion of the last cycle of standard platinum/taxane chemotherapy with documented
clinical complete response. Patients who will meet all the inclusion and none of the exclusion
criteria will be randomized through centralized IVRS as reported under § 7.3.
At screening the following evaluations should be obtained within 2 weeks prior to randomization
in order to be considered baseline assessments:
Inclusion/exclusion criteria assessment;
Written informed consent;
Medical history (including main tumor characteristics, and previous and concomitant
medications);
General medical visit, including physical and gynecological examination;
ECOG performance status;
Vital signs (heart rate, arterial blood pressure);
12-lead ECG;
Clinical laboratory tests (including hematology, serum chemistry, urinalysis);
Serum CA125 level measurement.
At screening the following evaluations should be obtained within 4 weeks prior to randomization
(week 0) in order to be considered baseline assessments:
Imaging exams: CT scan of the abdomen and pelvis and chest X-ray.
NOTE: At the time of randomization, FIGO stage (III; IV) , CA 125 level after 3rd chemotherapy
cycle (< 35 U/ml; > 35 U/ml) and residual tumor (< 1 cm; > 1 cm) after debulking surgery
should be known in order to allow stratification by prognostic factors.
7.6.3
Treatment and Double Blind Observation Period
After randomization, and during the first 6 weeks of treatment (induction phase) patients will
receive at study center a SC administration of study drug every 2 weeks, i.e. at week 0 and then
at week 2, 4 and 6. Thereafter (maintenance phase), the study drug will be administered at study
center every 4 weeks until evidence of disease recurrence or up to 94 weeks (approximately 21
months) after the randomization of the last patient. Medical visit for recording of adverse events
and change of concomitant medication, if any, and assessment of performance status will be
performed prior to each dosing.
Laboratory parameters for safety evaluation will be performed at week 4, at week 10 (end of
induction/start of maintenance phase) and every 12 weeks until end of DBO. Blood sampling for
CA125 assay and immune response will be performed at week 0, week 10 and every 12 weeks
until end of DBO period. The assessment of disease recurrence will be performed at week 10 and
every 12 weeks until end of DBO period.
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In particular, the following evaluations will be obtained:
INDUCTION PHASE (week 0, and week 2, 4 and 6, prior to dosing)
Recording of adverse events;
Recording of change in concomitant medication.
CA125 assay, HAMA and Ab3 antibodies (ONLY at week 0).
Vital signs (heart rate, arterial blood pressure- ONLY at week 4);
Clinical laboratory tests (including hematology, serum chemistry and urinalysis- ONLY at
week 4).
MAINTENANCE PHASE (week 10 until end of DBO period)
Every 4 weeks
Recording of adverse events;
Recording of change in concomitant medication.
Every 12 weeks
General medical visit including physical and gynecological examination;
Vital signs (heart rate, arterial blood pressure);
Imaging exams: CT scan of abdomen and pelvis;
Clinical laboratory tests (including hematology, serum chemistry and urinalysis);
Serum CA125 level.
Every 24 weeks
chest X-ray.
ONLY at week 10, 22, 58, 94 (and in all cases at final visit)
Blood sampling for the immunologic tests
All patients in the study will have assessments scheduled at the same interval and frequency,
with the final efficacy and safety assessment (including all assessments listed above) to be
performed at the end of the DBO period at the last study visit, i.e. 24 months after the
randomization of the last patient and 12 weeks after the last scheduled dose in case of regular
treatment termination.
Patients with early treatment discontinuation will also attend the final study visit 12 weeks after
the last administered dose, the only exception being patients with early treatment discontinuation
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for disease recurrence who will attend the final visit within 4 weeks after the last administered
dose. In all cases, patients who early discontinue treatment will continue to be monitored for
safety (adverse reactions) and survival status by phone or mail (either directly or via the patient’s
GP) every 12 weeks until the end of the DBO period.
(NOTE: CT scan and chest X-ray will be performed at final study visit ONLY in case of early
treatment discontinuation for reasons other than disease recurrence).
7.6.4
End of treatment and double blind observation period
Treatment will end 21 months from the randomization of the last patient, and the DBO period
will end 12 weeks after the last administered dose, i.e. 24 months from the randomization of the
last patient. At that time all patients on study will undergo a final study visit, encompassing the
same efficacy and safety assessments scheduled during the observation period (see § 7.6.3).
7.6.5
Overall survival follow-up
After completion of DBO period, survival data will continue to be collected under open
conditions by phone or mail (either directly to the patient or via the patient’s GP) every 3 months
for additional 5 years (i.e. individual survival follow-up ranging from 7 to 9 years based on the
time of randomization). Survival status should be followed in ALL patients, including those who
prematurely terminate the study treatment, unless consent has been specifically withdrawn by the
patient.
7.7
EFFICACY AND SAFETY ASSESSMENT
7.7.1
Primary efficacy endpoint
The primary efficacy endpoint is the RFS (i.e. the time from the date of randomization to
documented disease recurrence or death).
Disease recurrence is defined as the appearance of any lesion or development of tumor-related
symptoms evaluated by medical examination. Disease recurrence must be documented by CT
scan.
If the CT scan is not informative enough to document or to rule out the recurrence of disease,
additional imaging techniques (e.g. NMR) should be requested by the Investigator to document
disease recurrence. If any additional imaging technique leads to the diagnosis of recurrence, then
the disease recurrence has to be considered as ‘documented’ even in the presence of a negative
CT scan. In addition, the histologic or cytological documentation of disease recurrence can
substitute imaging confirmation in case of pleural or peritoneal effusion. Ultrasound
documentation is not accepted per se as adequate documentation of disease recurrence.
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Disease recurrence will be assessed every 12 weeks by physical examination (pelvic examination
inclusive) and CT scan of abdomen and pelvis. Chest X-ray will be performed every 24 weeks.
CT scan must be performed at any time during the study if disease recurrence is suggested by
physical examination or other clinical findings.
All images collected for the assessment of disease recurrence and all pertinent clinical data will
be reviewed by an independent Clinical Event Adjudication Committee (CEAC) The CEAC will
adjudicate the recurrence data and the relevant date of recurrence by reviewing all study images
(i.e. CT scans and other images used by the Investigator for evaluating patient status) and clinical
data deemed necessary for the adjudication. The rules and revision process of the CEAC are
detailed in the CEAC charter (see Appendix III).
The data adjudicated by the CEAC will be used for the primary analysis, whereas the assessment
made by the Investigator will be used for clinical management of the patient.
7.7.2
Secondary efficacy endpoints
Overall survival will be determined as the time from randomization to all-cause death.
Survival status will be continuously assessed in all patients during DBO period and
afterwards every 12 weeks up to 7 years from the randomization of the last patient by
phone or mail (either directly to the patient or via the patient’s GP).
Time course of immunologic parameters (HAMA, Ab3) will be assessed in all patients, by
comparing levels at week 0, at the end of the induction (start of maintenance phase/ week
10) and at week 22, 58, and 94 weeks while on treatment and in case of treatment
termination at 4 to 12 weeks after the last administered dose. Time course of additional
immunologic parameters (CA125-specific antibodies (Ab1’) and CA125-specific T cell
immune response) will be evaluated in a subset of about 10% of patients from centers who
meet the criteria required for the collection/shipment of the blood samples (mainly close
proximity to the central laboratory of immunological assay).
All the immunologic tests will be performed according to published procedures (Wagner
U. et al., 2001; Reinhartz S et al., 2004). All these assays will be performed at the
Department of Clinical Pathology (Dr. Mosiello), RTC S.p.A., Pomezia, Italy, with the
exception of the analysis of CA125-specific T cell immune response, which will be
conducted at the Institute of Gynecology and Obstetrics of the University “Sacro Cuore”,
Rome (Dr. Fattorossi). The results of all immunologic assays will be kept blinded along the
double blind observation period.
CA125 will be tested in each patient at week 0, week 10 and then repeated every 12 weeks
until the end of the DBO period or up to disease recurrence. CA125 assay will be
performed in a centralized lab facility independent from Sponsor and Investigators. Results
of CA125 tests will be kept blinded along the DBO period. Since Abagovomab vaccination
may interfere with the interpretation of CA125 assay results, CA125 will not be used to
determine clinical relapse.
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7.7.3
Safety Assessment
While on treatment, recording of adverse events and ECOG performance status evaluation will
be done every 2 weeks during the induction phase and every 4 weeks during the maintenance
phase prior to dosing. A complete safety assessment will be performed at week 4, week 10 and
every 12 weeks thereafter until the end of DBO period, and it will include physical examination,
vital signs measurements, ECOG performance status, monitoring of adverse events (see § 7.7.4),
changes in concomitant medication and the following laboratory safety tests to be performed at
the local laboratory:
Hematology: Hb, WBC with differential count, platelets.
Serum chemistry: total bilirubin, alkaline phosphatase, ALT, AST, total protein, albumin,
Na+, K+, Cl-, γGT, LDH, glucose, BUN and creatinine. Creatinine clearance has to be
determined (Cockroft-Gault method) in case of creatinine >1.5 x institutional ULN.
Urinalysis: urine dipstick.
Safety evaluation will be repeated at the final study visit, to be performed 12 weeks after the last
administered dose or within 4 weeks in case of early treatment discontinuation for disease
recurrence.
7.7.4
Monitoring of Adverse Events
Adverse events will be collected at each visit prior to dosing, with the last assessment at the final
study visit, and will be recorded in the appropriate section of the CRF.
In case of early treatment discontinuation, the occurrence of adverse drug reactions, if any, will
be monitored by phone (or general medical visit as deemed appropriate by the Investigator)
every 12 weeks until the end of the DBO period.
Adverse events will be classified according to the following definitions/criteria:
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered a
pharmaceutical product and which does not necessarily have to have a causal relationship with
this treatment.
Adverse Drug Reaction (ADR)
Any noxious and unintended responses to a medicinal product related to any dose should be
considered an Adverse Drug Reaction. That means that a causal relationship between the product
and the adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.
Serious Adverse Event (SAE)
Any untoward medical occurrence that at any dose:
-
results in death;
-
is life-threatening;
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NOTE: the term life-threatening in the definition of “serious” refers to an event in which the
patient was at risk of death at the time of the event; it does not refer to an event which
hypothetically might have caused death if it were more severe.
-
requires hospitalization or prolongation of existing hospitalization;
-
results in persistent or significant disability/incapacity;
-
is a congenital anomaly/birth defect
-
is another medically important condition that may jeopardize the patient or may require
intervention to prevent one of the other outcomes listed in the definition above.
Expectedness
AEs are expected when their nature, severity or outcome are consistent in the safety section of
the Investigator’s Brochure.
Causality criteria
- “Certainly related”: an AE is considered certainly related to a drug when a clinical event,
including a laboratory test abnormality, occurs in a plausible time relation to the
administration of the drug, and which cannot be explained by concurrent disease or other
drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be
clinically plausible. The event must be definitive pharmacologically or phenomenologically,
using a satisfactory rechallenge procedure if necessary.
- “Probably related”: an AE is considered probably related to a drug when a clinical event,
including a laboratory test abnormality, with a reasonable time relation to the administration
of the drug, is unlikely to be attributed to concurrent disease or other drugs or chemicals,
and which follows a clinically reasonable response on withdrawal (dechallenge).
Rechallenge information (AE reappearance after drug reintroduction) is not required to fulfil
this definition.
- “Possibly related”: an AE is considered possibly related to a drug when a clinical event,
including a laboratory test abnormality, with a reasonable time relation to the administration
of the drug, could also be explained by concurrent disease or other drugs or chemicals.
Information on drug withdrawal (dechallenge) may be lacking or unclear.
- “Unlikely related”: an AE is considered unlikely related to a drug when other drugs,
chemicals or underlying disease provide plausible explanations and/or the temporal relation
to the administration of the drug makes a causal relation improbable.
- “Not related”: an AE is considered not related to the use of a drug in case of existence of a
clear alternative explanation and/or unreasonable temporal relationship, and/or non
plausibility.
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Grading criteria
The criteria used for grading adverse events are the Common Toxicity Criteria (CTC v.3.0)
of US-NCI. The highest severity grade reached in a given cycle should be reported in the
CRF.
All AEs must be followed-up until the AE has completely resolved, stabilized or the sequelae
can be assessed by the Investigator. The results of additional diagnostic measures as the result of
an AE, such as laboratory tests, ECG, imaging, must be available at site and provided at
Sponsor’s request.
7.7.5
Breaking of Treatment Code
The investigator always has the right to unblind the treatment code by contacting the IVRS if he
or she thinks this knowledge is necessary to adequately treat the patient.
Unblinding is a rare occurrence and should only be recommended for cases where the subject's
treatment code must be known to offer adequate care for the patient’s immediate condition. Thus
the treatment code should only be unblinded if the knowledge of whether the patient is receiving
Abagovomab or placebo could be of benefit to the patient (for example, it should not be opened
following the death of the patient).
The reason for breaking the code will be always stated by the investigator.
7.7.6
SAE Reporting
All SAEs occurring within 12 weeks after treatment discontinuation, whether or not related to
study drug, must be reported to the Drug Safety Unit (DSU) by sending the CRF-AE recording
pages by fax immediately and not later than within one calendar day, specifying the judgement
on causal relationship between the SAE and the study medication. The Investigator must also fill
in the “Serious Adverse Event” form.
At the earliest possible date, preliminary reports should be followed by detailed reports and
documentation that may be available, for example, hospital case records, autopsy reports, and/or
other pertinent documents. Reports should be sent to the CRO Drug Safety Unit for the study:
DSU contact :
Melanie Weber
Manager, Drug Safety Center Unit
PRA International
Dynamostrasse 13-15
D-68165 Mannheim (Germany)
Phone + 49 621 8782-252
Fax +49-621-8782-181
Email: [email protected]
The Investigator should not wait to receive additional information to fully document the event
before notifying a SAE, though additional information may be requested. Where applicable,
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information from relevant laboratory results, hospital case records and autopsy reports should be
obtained. The Investigator is also required to submit follow-up reports to the DSU until the SAE
has resolved or, in the case of permanent impairment, until the SAE stabilizes.
In line with the revision of the Directive 2001/20/EC issued by the European Commission in
April 2004, in order to avoid systematic unblinding and expedited reporting of events that have
an impact on the efficacy endpoints, the Drug Safety Unit will assess the expectancy of all
received drug-related SAEs on the basis of the consistency with Abagovomab Investigator’s
Brochure. Moreover, all SAEs that can be clearly related to disease progression and/or to
subsequent anticancer therapies as per Investigator’s judgement will be considered as expected,
thus avoiding unblinding.
Any SUSAR or any death during the study must be reported immediately, with the exception of
death certainly due to disease recurrence and/or to subsequent therapies that do not require to be
immediately notified. All SAEs that meet the criteria of serious unexpected ADRs will be
reported to the relevant Regulatory Authority within the required timeframe, depending on the
local regulations. Regulatory agencies will be notified as soon as possible but no later than 7
calendar days after the Sponsor’s first knowledge of fatal or life-threatening unexpected ADR
and no later than 15 calendar days after the Sponsor’s first knowledge of the other serious
unexpected ADRs.
The Sponsor or its designee will also communicate all suspected non-fatal SUSARs in an
expedited fashion to all concerned Investigators, who in turn will be instructed to report these
events to their EC/IRB, when required and/or regulatory authorities.
DSMB will review safety data on the ongoing trial on a regular basis and when necessary will
recommend to the sponsor whether to continue, modify or terminate the trial. This procedure will
be described in ad hoc DSMB Charter (Appendix IV). The DSMB opinion and
recommendations will be timely submitted by the Sponsor or its designee to the involved
Regulatory Authorities and Ethics Committees, as most appropriate.
7.7.7
24 - hour Medical Monitoring and SAE fax receipt
A dedicated phone and/or pager number is provided to all investigators and clinical monitors
participating in a clinical trial for a 24-hour telephone coverage. If the person on duty cannot
receive the call immediately, a voice mailbox is activated and the call is returned as soon as
possible.
The CRO Global Medical and Safety Service (GMSS) has dedicated fax machines that work 24hours per day, but faxes are processed only during local office hours (Monday through Friday,
excluding local public holidays). Faxes received outside of local business hours are processed
during the next working day, with highest priority. The fax machines are also checked regularly
during the weekend/holidays if there are 3 or more sequential non-working days.
7.8
STUDY COMMITTEES
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A Steering Committee, an independent Clinical Event Adjudication Committee (CEAC), and a
Data and Safety Monitoring Board (DSMB) will be established for the study.
7.8.1
Steering Committee
The Steering Committee, consisting of the Coordinating Investigator and the national
coordinators from participating countries, is entrusted to maintain the quality of the study
conduct, the overall study co-ordination, to periodically assess the study progress and to address
policy issues. The Committee chairperson will be responsible for communicating with the
DSMB and the Sponsor.
7.8.2
Independent Clinical event Adjudication Committee (CEAC)
An independent Clinical Event Adjudication Committee (CEAC), consisting of three
independent radiologists and one oncologist (all blinded to patients’ treatment and local
radiologist’s report), will review in double blind condition all CT scans for each patient, as well
as other imaging records such as NMR and pertinent clinical data to adjudicate the presence of
disease recurrence and the relevant date. The assessment of disease recurrence and date of
recurrence made by the CEAC will be used for the primary analysis.
Tumor measurements and response will not be evaluated in this protocol, since they are not
study end-points.
The structure, procedures and work-flow of the CEAC is described in details in a separate
Charter (see Appendix III).
7.8.3
Data and Safety Monitoring Board (DSMB)
The independent Data and Safety Monitoring Board (DSMB), consisting of five independent
medical oncologists and one independent biostatistician, will conduct the monitoring of safety
data during the course of the study and will periodically update the Sponsor and the Steering
Committee. The duties of the DSMB, the adopted operational procedures as well as the
frequency of meetings/teleconferences of the DSMB are described in the DSMB Charter (see
Appendix IV).
7.8.4
Data Quality Management
7.8.4.1
Subject Records
The Investigator will maintain individual subject records separate from the CRF. These records
should include demographic data, medical history and other notes if appropriate.
When the study is terminated all signed Informed Consent Forms should be archived in the
Investigator’s File.
7.8.4.2
Case Report Forms
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All the patient information collected during the study will be recorded in the CRFs identified by
an unique code (e.g. subject screening number). It is the responsibility of the Investigator to
ensure that the CRFs are properly and completely filled in. Every visit must be signed by the
Investigator, attesting that the entered data have been verified. During the conduct of the clinical
part of the study the CRF must be available and up-to-date so that they always reflect the latest
observations on the subjects enrolled into the study.
All original laboratory form as well as any original documentation pertinent to the study
procedures must be available for review in each subject’s record.
Entries shall be made in English language, legibly and in black ink using a ball-point pen.
Corrections to the CRF must be made in a manner to not obscure the original entry, drawing a
line through the original item, with Investigator’s initials and date.
7.8.4.3
Data Quality Control / Study Monitoring
Study monitors, designated by the CRO, will be assigned to the investigational centers. During
the periodic monitoring visits the CRF will be checked for completeness and consistency with
the corresponding source data. The Investigator will offer the study monitors direct access to all
subject documentation available in the Investigator’s files.
7.8.4.4
Clinical Data Management
The subject data collected in the CRF will be entered into the study database after being verified.
The database will be designed based on the CRF to allow the capture of all data contained in the
CRF. Data entry will be performed using double data entry. Logical checks will be performed in
order to solve data inconsistencies. A clear overview of all clinical data management activities
(e.g. double data entry, storage, verification, correction, coding and retrieval) will be described in
the Data Handling Manual.
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8
STATISTICAL METHODS
8.1
SAMPLE SIZE DETERMINATION
At least 535 recurrences have to be observed during the trial in order to provide a power higher
than 90% power in rejecting the null hypothesis of equality between Abagovomab and placebo
on RFS according to the following assumptions:
Median RFS for placebo arm = 18 months;
Hazard ratio in RFS between Abagovomab and placebo = 1.33 (leading to an approximate
benefit of 6 months of Abagovomab over placebo);
Significance level (α) = 5% (two-sided)
Overall drop-out rate = 10%
A total number of 870 patients (580 in the Abagovomab arm and 290 in the placebo arm)
recruited in 24 months should be followed for at least 24 months (i.e. average time on-study of
36 months) in order to observe the requested number of events.
The study size will provide a power higher than 80% if the hazard ratio in RFS will remain
higher than 1.28 or in case the median RFS for placebo arm will be lower than 29 months with
the same hazard ratio between the groups.
This sample size will also provide a power higher than 80% power for detecting the superiority
of Abagovomab over placebo in the secondary end-point of overall survival on the basis of:
Median OS for placebo arm = 40 months;
Hazard ratio in OS between Abagovomab and placebo = 1.30 (leading to an approximate
benefit of 12 months of Abagovomab over placebo);
Minimum follow-up for each patient = 84 months (i.e. average time of survival follow-up
of 96 months);
Significance level (α) = 5% (two-sided).
No adjustment for multiplicity will be adopted due to the nature of secondary analysis.
8.2
ANALYSIS POPULATIONS
The following analysis populations will be considered in the statistical analysis:
Safety population:
all patients receiving at least one study drug administration;
ITT population:
all patients randomized;
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Per protocol population: all the patients of the ITT population excluding patients who
experienced major protocol violations before disease
recurrence.
8.3
ANALYSIS VARIABLES
8.3.1
Primary efficacy variable
The primary efficacy variable is Recurrence Free Survival (RFS) defined as time from
randomization to the event of tumor recurrence (as determined by the Clinical Event
Adjudication Committee- see Appendix III) or death from any cause.
RFS will be calculated as follows:
In case of event:
RFS = event date – date of randomization + 1.
In case of censored information:
RFS = censored date – date of randomization + 1.
Recurrence adjudication flow.
The Clinical Event Adjudication Committee (CEAC) will adjudicate the recurrence data and the
relevant dates by reviewing all patient study images (i.e. CT-scans and any other images used by
the Investigator for evaluating patient status) and clinical data deemed necessary for the
adjudication.
The images will be archived digitally and read in a blinded fashion by the CEAC members. The
image database will be compliant with regulatory guidelines.
At the end of the adjudication process the committee will assign, for each patient, the presence or
absence of recurrence and the recurrence date.
For details of data flow and adjudication process see Appendix III: CEAC charter.
Definition of event date.
In case of adjudicated recurrence the event date will be the recurrence date as adjudicated by the
CEAC.
In case of CRF documented death from any cause in a patient with no adjudicated recurrence the
event date will be the date of death.
Censoring definition.
The recurrence free survival time of a patient will be considered as censored in case of no event
between randomization and individual study end, defined as one the following:
premature treatment termination (before/without any subsequently adjudicated recurrence)
for reasons other than death (e.g. patient drop out, investigator diagnosis of recurrence,
etc).
end of double blind observation period.
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Censoring date.
In case of censoring, the censoring date is defined as the date of the last evaluable image
assessed by the CEAC.
8.3.2
Secondary efficacy variable: overall survival
The secondary efficacy variable is the Overall Survival (OS) calculated as:
In case of all-cause death:
OS = date of death – date of randomization + 1.
In case of censored information not for drop-out:
OS =
In case of censored information for drop-out:
OS =
8.3.3
date of end of observation period (i.e. study end / end of survival follow-up) –
date of randomization + 1.
Last date known alive – date of randomization + 1.
Other secondary efficacy variables
Remaining secondary efficacy variables will be the immune response parameters (Ab3; HAMA).
8.4
STATISTICAL ANALYSIS
8.4.1
Descriptive statistics
All variables (including all generated and transformed variables) will be presented using
appropriate descriptive statistics according to the variable nature:
continuous variables:
number of non missing observations, mean, standard deviation,
minimum, median, maximum;
categorical variables:
number of non missing observations, absolute and relative
frequency;
time to event variables:
number of non missing observations, number and percentage
of censored observations, 1st quartile, median (and its 95% CI),
3rd quartile, Kaplan-Meier survival curves and event rates
every three months, annualized mortality rate (i.e. number of
events per 100 patient years of observation).
The behavior over time of continuous variables will be analyzed by presenting descriptive
statistics for each time point and the absolute and relative difference compared to baseline. The
behavior over time of categorical data will be analyzed by presenting the descriptive statistics for
each time point and the shift compared to baseline.
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All study data will be presented by treatment and by stratification factors within each relevant
analysis population.
8.4.2
Baseline analysis
Baseline patients’ characteristics will be analyzed by descriptive statistics.
8.4.3
Primary efficacy analysis
Primary analysis will be run on RFS in the ITT analysis population.
The superiority of Abagovomab over placebo will be claimed in case of rejection of the null
hypothesis of equality (with observed HR favoring Abagovomab):
H0: HRABAGOVOMAB / PLACEBO = 1
H1: HRABAGOVOMAB / PLACEBO ≠ 1
Due to the time-to-event nature of the primary efficacy variable, survival analysis techniques will
be used.
The clinical trial design includes a prospective stratification in randomization for balancing the
trial arms for important variables that are highly likely to affect the trial’s primary efficacy
variable. Covariate analyses will therefore be employed to adjust for variables that affect the
outcome.
For this reason a Cox proportional hazards model will be used for primary analysis and will have
treatment as major covariate, adjusted only for the predefined prognostic stratification factors:
serum CA125 level after the first 3 cycles of chemotherapy (< 35 U/ml; > 35 U/ml).
Analysis output will be the estimated hazard ratio, its 95% CI and the associated p-value for each
covariate.
As recommended in CPMP/EWP/2863/99, the covariates will enter the model as dichotomized
variables. No additional covariates will be inserted in the primary model. No interaction terms
will be included, since influence of the stratification factors on drug efficacy can be ruled out.
The use of these three covariates is in accordance with ICH guideline E9 where it states “ If one
or more factors are used to stratify the design, it is appropriate to account for those factors in the
analysis”.
The Cox proportional hazards model is a standard model used in failure time analysis. Compared
to parametric analyses, its assumptions are fairly unspecified and will therefore yield robust
estimates of the treatment effect. The model will be applied using the Efron approach for
handling ties, since this approach is known to give a reasonable approximation of the exact
likelihood in presence of ties.
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The Cox model relies on the assumption of proportional hazards. This assumption can be
regarded as justified, since there are no clinical reasons for assuming that the efficacy of
Abagovomab should change over time. Nevertheless this assumption will be examined using
log-log plots of the event times.
The primary hypothesis will be tested using the Wald test for the covariate treatment. The hazard
ratio will be estimated as e β , where β̂ is the Maximum Likelihood (=ML) estimate of the
treatment effect. Confidence intervals will be calculated using the asymptotic normality of the
ˆ
distribution of the ML estimate β̂ . The use of asymptotic distributions is justified due to the
large sample size of the trial.
8.4.4
Sensitivity analysis of the primary variable
Primary analysis results will be explored for sensitivity by an unstratified log-rank test for the
influence of treatment, to assess if the results of the primary analysis are robust also in the
absence of other covariates.
8.4.5
Secondary efficacy analysis
Overall survival will be analyzed similarly to the primary analysis (of RFS) on the ITT
population at the end of the survival follow-up. An exploratory analysis on OS will also be
applied at the end of the double blind observation period.
The time course of immune response parameters will be descriptively analyzed.
8.4.6
Multiplicity issues
All the tests not included in the primary analysis are to be considered descriptive in nature since
they are secondary or exploratory analyses and therefore will not be adjusted for multiplicity.
8.4.7
Safety analysis
The number of patients reporting an adverse event and the number of adverse events will be
summarized by treatment group on the Safety population. Separate sets of tables will be
produced for adverse events by drug relationship, CTC toxicity grade and for those leading to
treatment/study discontinuation. SAEs will be presented as described for AEs.
The other safety parameters will be descriptively analyzed. Descriptive statistics will also be
produced for assessment of compliance, extent of exposure and overall drug(s) administration.
8.4.8
Subgroup analysis
The following subgroups derived from the ITT population will be investigated:
FIGO stage (i.e. III, IV);
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serum CA125 level after the first 3 cycles of chemotherapy (< 35 U/ml, > 35 U/ml).
In each subgroup the primary efficacy variable and overall survival will be analyzed according to
the primary analysis. In addition an exploratory analysis on the interaction “treatment x
subgroup” will be applied.
8.5
ON-STUDY AND PRE-STUDY CLOSURE ACTIVITIES
8.5.1
Protocol Violations and Blind Review
Categories of protocol violations will be defined at the end of double blind observation period
before study unblinding and will be integrated in the statistical analysis.
A blind review meeting will take place in order to evaluate and accept the data management
report, discuss remaining issues (outstanding queries, unresolved errors) and discuss the cases of
major and minor protocol violations. After the blind review meeting has taken place and the
database is considered cleaned, the database will be locked and unblinded.
8.5.2
Data Monitoring
At regular times during the study conduct, the trial database will be transferred to the Sponsor in
order to monitor the overall quality of the trial (e.g. highlight systematic protocol deviations, the
consistency and the quality of data and the appropriateness of the design assumptions). The
Sponsor will always receive and analyze the data under blinded conditions and will never have
access, during the whole trial conduct, to unblinded information. Analyses will never deviate
from these guidelines.
8.5.3
Interim analysis
No interim analyses are planned for this trial.
8.5.4
Stopping rules
No formal statistical stopping rule will be applied.
8.5.5
DSMB analysis
At each meeting the DSMB will receive unblinded data on major safety parameters and on trial
conduct issues (e.g. recruitment, baseline characteristics, eligibility rates etc.). At each meeting
the DSMB can recommend early trial termination or study modification because of safety
concerns, as details in the DSMB charter (see Appendix IV).
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The DSMB can request additional unplanned unblinded analysis of primary outcome in case of
major safety issues from the safety analysis. DSMB will therefore be able to monitor the trial in
its completeness by analysing the overall risk/benefit of the trial results as necessitated by safety
concerns if they arise. There is no planned interim efficacy analysis and the Sponsor will not
receive the results of any efficacy analyses examined by the DSMB before the final study
database lock except in the event of a recommendation to stop or seriously modify the protocol.
In that event, due procedure will be discussed in advance with the DSMB and Regulatory
Agencies.
8.6
STATISTICAL ANALYSIS PLAN
The study statistical analysis plan (SAP) will be finalized prospectively, before the unblinding of
the study treatment. The SAP will follow the protocol and indicate any deviations, but may also
describe additional statistical analyses for efficacy and safety as required/described by the study
committees. In addition, a Data Monitoring Analysis Plan (DMAP) for the DSMB will be
finalized before the first DSMB data review meeting.
The SAP will also detail the handling of missing, unused and spurious data.
If major deviations from the original analyses will occur during the trial a protocol amendment
will be inserted. No major deviations from the original analysis plan will take place after data
unblinding. Minor deviations (e.g. not involving changes in the primary analysis) arising during
the trial will be detailed only in the statistical analysis plan. All statistical analyses not prespecified and run after data unblinding will be considered additional/exploratory analyses.
Page 62 of 66
9
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10
APPENDICES
Page 66 of 66
APPENDIX I
DECLARATION OF HELSINKI
ABA-01, Version 1.0, 4 August 2006
APPENDIX II
SUBJECT INFORMATION AND INFORMED CONSENT FORM
- TEMPLATE -
APPENDIX III
CHARTER OF CLINICAL EVENT ADJUDICATION COMMITTEE
(CEAC)
APPENDIX IV
CHARTER OF DATA SAFETY AND MONITORING BOARD (DSMB)

The following protocol information is provided solely to describe how... research underlying the published report associated with the following article:

Transcription

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