Conditions: Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 100
Healthy volunteers: no

Brief summary:
This multicenter, double-blind, 2-arm, randomized study will evaluate the efficacy and safety of bevacizumab plus paclitaxel and caboplatin compared with placebo plus paclitaxel and caboplatin in Chinese participants with newly diagnosed, previously untreated Stage III or Stage IV epithelial ovarian, fallopian tube, or primary peritoneal cancer. Participants whose disease has not progressed after six cycles of paclitaxel and carboplatin with either bevacizumab or placebo will continue treatment with either bevacizumab or placebo until disease progression, unacceptable toxicity, or a maximum of 22 cycles, whichever occurs first.

Detailed description:

Arms:
arm 1: Participants will receive paclitaxel, carboplatin intravenous (IV) infusion on Day 1 of each 21-day cycle for a total of 6 cycles. Bevacizumab IV infusion will start at Cycle 2 for 5 cycles, followed by maintenance therapy up to a maximum of 22 cycles or until disease progression, unacceptable toxicity, or withdrawal, whichever occurs first. arm 2: Participants will receive paclitaxel, carboplatin IV infusion on Day 1 of each 21-day cycle for a total of 6 cycles. Placebo IV infusion will start at Cycle 2 for 5 cycles, followed by maintenance therapy up to a maximum of 22 cycles or until disease progression, unacceptable toxicity, or withdrawal, whichever occurs first.

Interventions: intervention 1: Paclitaxel intervention 2: Bevacizumab intervention 3: Carboplatin intervention 4: Placebo
Intervention descriptions: intervention 1: 175 mg/m\^2 IV infusion on Day 1 of each 21-day cycle. intervention 2: 15 mg/kg IV infusion on Day 1 of each 21-day cycle. intervention 3: Area Under the Curve (AUC) of 6 mg/ml/min on Day 1 of each 21-day cycle. intervention 4: Placebo matched to bevacizumab IV infusion on Day 1 of each 21-day cycle.

Protocol document:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Bevacizumab—F. Hoffmann-La Roche Ltd
Protocol YO40268, Version 3
PROTOCOL
TITLE:
A PHASE III TRIAL OF CARBOPLATIN AND 
PACLITAXEL PLUS PLACEBO VERSUS 
CARBOPLATIN AND PACLITAXEL PLUS 
CONCURRENT AND EXTENDED BEVACIZUMAB IN 
CHINESE WOMEN WITH NEWLY DIAGNOSED, 
PREVIOUSLY UNTREATED, STAGE III OR STAGE IV
EPITHELIAL OVARIAN, FALLOPIAN TUBE, OR 
PRIMARY PERITONEAL CANCER
PROTOCOL NUMBER: YO40268
VERSION NUMBER:
3
EUDRACT NUMBER:
To be determined
IND NUMBER:
113807
NCT NUMBER:
NCT03635489
TEST PRODUCT:
Bevacizumab (RO4876646)
MEDICAL MONITOR:
 M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
DATE AMENDED:
30 August 2017
Version 2:  23 August 2018
Version 3:  See electronic date stamp below.
 
04-Nov-2019 14:51:05
Title
Approver's Name
Date and Time (UTC)
Protocol Number: 
 Report Number: 
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PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol YO40268 has been amended to align the tumor assessment and 
patient reported outcome (PRO) schedules with the follow-up schedules of patients with 
no documented disease progression.  Additional updates to the protocol are provided.  
Changes to the protocol are summarized below:

The pharmacy manual has been deleted as a source for further details regarding the 
administration, preparation, and storage of carboplatin and paclitaxel
(Section 4.3.2.3).

The use of Chinese herbal medicine with anti-cancer indication are permitted prior to 
screening.  However, the use of these herbal therapies is still prohibited during the 
study (Section 4.4.2.1).

To improve the collection of efficacy and safety data, the tumor assessment 
schedule has been updated to align with the follow-up schedule of patients with no 
documented disease progression (Section 4.5.5 and Appendix 1).

The requirement that all ECGs be obtained prior to other procedures and after
3 hours of any meal has been removed (Section 4.5.7).

The management of adverse events related to bevacizumab has been updated to 
align with the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.0.  A new Table 8, Causal Attribution Guidance, has been added 
(Section 5.1.4.2; Tables 3 and 8).

The Medical Monitors and their contact information have been updated 
(Section 5.4.1).

Language has been updated to indicate that therapeutic or elective abortions are not 
considered adverse events unless performed because of an underlying maternal or 
embryofetal toxicity.  In such cases, the underlying toxicity should be reported as a 
serious adverse event.  Language has also been added to clarify that all abortions 
are to be reported on the paper Clinical Trial Pregnancy Reporting Form (Section 
5.4.3.2).

To improve the collection of efficacy and safety data, the PRO assessment schedule 
has been updated to align with the follow-up schedule of patients with no 
documented disease progression (Appendix 1).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9
PROTOCOL SYNOPSIS .................................................................................... 10
1.
BACKGROUND .......................................................................................... 20
1.1
Background on Background on Ovarian, Primary 
Peritoneal, and Fallopian Tube Cancers................................ 20
1.2
Background on Bevacizumab................................................ 22
1.3
Study Rationale and Benefit-Risk Assessment...................... 23
2.
OBJECTIVES AND ENDPOINTS ............................................................... 23
3.
STUDY DESIGN......................................................................................... 25
3.1
Description of the Study......................................................... 25
3.1.1
Overview of Study Design ..................................................... 25
3.1.2
Bevacizumab and Chemotherapy.......................................... 26
3.1.3
Placebo and Chemotherapy .................................................. 26
3.2
End of Study.......................................................................... 28
3.3
Rationale for Study Design.................................................... 28
3.3.1
Rationale for Dose and Schedule.......................................... 28
3.3.2
Delay of Initial Treatment with Bevacizumab......................... 29
3.3.3
Rationale for Patient Population ............................................ 29
3.3.4
Rationale for Control Group................................................... 30
3.3.5
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 30
4.
MATERIALS AND METHODS .................................................................... 31
4.1
Patients.................................................................................. 31
4.1.1
Inclusion Criteria.................................................................... 31
4.1.2
Exclusion Criteria................................................................... 34
4.2
Method of Treatment Assignment and Blinding..................... 36
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 37
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 37
4.3.1.1
Bevacizumab and Placebo .................................................... 37
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4.3.1.2
Chemotherapy (Carboplatin and Paclitaxel) .......................... 39
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 39
4.3.2.1
Timing and Sequence of Treatment 
Administration........................................................................ 39
4.3.2.2
Bevacizumab and Placebo .................................................... 41
4.3.2.3
Carboplatin and Paclitaxel..................................................... 42
4.3.3
Additional Required Medication............................................. 44
4.3.3.1
Prophylactic Measures for Carboplatin.................................. 44
4.3.3.2
Premedication for Paclitaxel .................................................. 44
4.3.4
Investigational Medicinal Product Accountability ................... 44
4.3.5
Continued Access to Bevacizumab ....................................... 45
4.4
Concomitant Therapy ............................................................ 45
4.4.1
Permitted Therapy................................................................. 45
4.4.2
Cautionary Therapy ............................................................... 46
4.4.2.1
Herbal Therapies................................................................... 46
4.4.3
Prohibited Therapy ................................................................ 46
4.5
Study Assessments ............................................................... 46
4.5.1
Informed Consent Forms and Screening Log........................ 47
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 47
4.5.3
Physical Examinations........................................................... 47
4.5.4
Vital Signs.............................................................................. 48
4.5.5
Tumor and Response Evaluations......................................... 48
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 49
4.5.7
Electrocardiograms................................................................ 50
4.5.8
Patient-Reported Outcomes .................................................. 50
4.5.8.1
EORTC QLQ-C30 and EORTC QLQ-OV28 .......................... 51
4.5.8.2
FACT-G Single Item GP5 ...................................................... 52
4.5.8.3
EuroQol 5 Dimension, 5 Level............................................... 52
4.5.9
Eastern Cooperative Oncology Group 
Performance Status............................................................... 52
4.6
Treatment, Patient, Study, and 
Site Discontinuation............................................................... 52
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4.6.1
Study Treatment Discontinuation........................................... 52
4.6.2
Patient Discontinuation from Study........................................ 53
4.6.3
Study Discontinuation............................................................ 54
4.6.4
Site Discontinuation............................................................... 54
5.
ASSESSMENT OF SAFETY....................................................................... 54
5.1
Safety Plan ............................................................................ 54
5.1.1
Risks Associated with Bevacizumab ..................................... 55
5.1.2
Risks Associated with Paclitaxel............................................ 55
5.1.3
Risks Associated with Carboplatin......................................... 55
5.1.4
Management of Patients Who Experience 
Specific Adverse Events........................................................ 55
5.1.4.1
Dose Modifications, Interruptions, and Delays....................... 55
5.1.4.2
Management of Adverse Events Related to 
Bevacizumab/Placebo ........................................................... 56
5.1.4.3
Management of Adverse Events Related to 
Carboplatin/Paclitaxel............................................................ 61
5.2
Safety Parameters and Definitions ........................................ 65
5.2.1
Adverse Events ..................................................................... 65
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 66
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 67
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 68
5.3.1
Adverse Event Reporting Period ........................................... 68
5.3.2
Eliciting Adverse Event Information....................................... 68
5.3.3
Assessment of Severity of Adverse Events ........................... 68
5.3.4
Assessment of Causality of Adverse Events ......................... 69
5.3.5
Procedures for Recording Adverse Events............................ 70
5.3.5.1
Infusion-Related Reactions.................................................... 70
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 71
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 71
5.3.5.4
Persistent or Recurrent Adverse Events................................ 71
5.3.5.5
Abnormal Laboratory Values ................................................. 72
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5.3.5.6
Abnormal Vital Sign Values ................................................... 72
5.3.5.7
Abnormal Liver Function Tests.............................................. 73
5.3.5.8
Deaths ................................................................................... 73
5.3.5.9
Preexisting Medical Conditions.............................................. 74
5.3.5.10
Lack of Efficacy or Worsening of Ovarian, 
Fallopian Tube, or Primary Peritoneal Cancer....................... 74
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 74
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 75
5.3.5.13
Patient-Reported Outcome Data ........................................... 75
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 76
5.4.1
Emergency Medical Contacts................................................ 76
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 77
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 77
5.4.2.2
Events That Occur after Study Drug Initiation........................ 77
5.4.3
Reporting Requirements for Pregnancies.............................. 78
5.4.3.1
Pregnancies in Female Patients............................................ 78
5.4.3.2
Abortions ............................................................................... 78
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 78
5.5
Follow-Up of Patients after Adverse Events .......................... 79
5.5.1
Investigator Follow-Up........................................................... 79
5.5.2
Sponsor Follow-Up ................................................................ 79
5.6
Adverse Events That Occur after the 
Adverse Event Reporting Period ........................................... 79
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 79
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 80
6.1
Determination of Sample Size ............................................... 80
6.2
Summaries of Conduct of Study............................................ 81
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 81
6.4
Efficacy Analyses .................................................................. 81
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6.4.1
Primary Efficacy Endpoint...................................................... 81
6.4.2
Secondary Efficacy Endpoints............................................... 82
6.4.2.1
Overall Survival ..................................................................... 82
6.4.2.2
Objective Response Rate (ORR)........................................... 82
6.4.2.3
Duration of Response............................................................ 83
6.4.2.4
Patient-Reported Disease Symptoms, Function 
and Health-Related Quality of LifeEORTC Data ................ 83
6.4.3
Exploratory Efficacy Endpoints.............................................. 84
6.4.3.1
Patient-Reported Disease and/or Treatment-
Related SymptomsEORTC Data........................................ 84
6.4.3.2
FACT-G, Single Item GP5 Data............................................. 85
6.4.3.3
Health Economic Data........................................................... 85
6.4.4
Handling of Missing Data....................................................... 85
6.5
Safety Analyses..................................................................... 85
6.6
Interim Analysis ..................................................................... 86
7.
DATA COLLECTION AND MANAGEMENT ............................................... 86
7.1
Data Quality Assurance......................................................... 86
7.2
Electronic Case Report Forms............................................... 87
7.3
Source Data Documentation.................................................. 87
7.4
Use of Computerized Systems .............................................. 88
7.5
Retention of Records............................................................. 88
8.
ETHICAL CONSIDERATIONS.................................................................... 88
8.1
Compliance with Laws and Regulations ................................ 88
8.2
Informed Consent.................................................................. 89
8.3
Institutional Review Board or Ethics Committee.................... 90
8.4
Confidentiality........................................................................ 90
8.5
Financial Disclosure .............................................................. 90
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 91
9.1
Study Documentation ............................................................ 91
9.2
Protocol Deviations................................................................ 91
9.3
Site Inspections ..................................................................... 91
9.4
Administrative Structure......................................................... 91
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9.5
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 91
9.6
Protocol Amendments ........................................................... 92
10. REFERENCES ........................................................................................... 93
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 24
Table 2
Treatment Regimens and Order of Administration...................... 40
Table 3
Bevacizumab Dose Management for Adverse Events................ 57
Table 4
Dose Levels of Chemotherapy.................................................... 61
Table 5
Modification Instructions for DLT Hematologic Toxicity............... 62
Table 6
Paclitaxel Dose Level for Different Hepatic Values..................... 63
Table 7
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 69
Table 8
Causal Attribution Guidance ....................................................... 70
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 27
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 99
Appendix 2
Response Evaluation Criteria in Solid Tumors (RECIST), V 
1.1: Modified Excerpt from Original Publication ........................ 104
Appendix 3
CA-125 Response and Progression Evaluation Criteria ........... 116
Appendix 4
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire ........................................ 117
Appendix 5
Quality of Life Questionnaire Ovarian Cancer Module 28......... 119
Appendix 6
Patient Questionnaire FACT-G Single Item GP5 ...................... 121
Appendix 7
Patient Questionnaire EuroQol 5 Dimension, 5-Level 
Questionnaire............................................................................ 122
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III TRIAL OF CARBOPLATIN AND 
PACLITAXEL PLUS PLACEBO VERSUS 
CARBOPLATIN AND PACLITAXEL PLUS 
CONCURRENT AND EXTENDED BEVACIZUMAB, 
IN CHINESE WOMEN WITH NEWLY DIAGNOSED, 
PREVIOUSLY UNTREATED, STAGE III OR 
STAGE IV, EPITHELIAL OVARIAN, FALLOPIAN 
TUBE OR PRIMARY PERITONEAL CANCER
PROTOCOL NUMBER:
YO40268
VERSION NUMBER:
3
EUDRACT NUMBER:
113807
IND NUMBER:
To be determined
NCT NUMBER:
NCT03635489
TEST PRODUCT:
Bevacizumab (RO4876646)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to the Sponsor or designee.  Contact details will be provided to the 
Investigator prior to study start.
Protocol Number: 
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PROTOCOL SYNOPSIS
TITLE:
A PHASE III TRIAL OF CARBOPLATIN AND PACLITAXEL PLUS 
PLACEBO VERSUS CARBOPLATIN AND PACLITAXEL PLUS 
CONCURRENT AND EXTENDED BEVACIZUMAB, IN CHINESE
WOMEN WITH NEWLY DIAGNOSED, PREVIOUSLY UNTREATED, 
STAGE III OR STAGE IV, EPITHELIAL OVARIAN, FALLOPIAN 
TUBE OR PRIMARY PERITONEAL CANCER
PROTOCOL NUMBER:
YO40268
VERSION NUMBER:
3
EUDRACT NUMBER:
To be determined
IND NUMBER:
113807
NCT NUMBER:
NCT03635489
TEST PRODUCT:
Bevacizumab (RO4876646)
PHASE:
Phase III
INDICATION:
Stage III or Stage IV Epithelial Ovarian, Fallopian Tube, or Primary 
Peritoneal Cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of bevacizumab compared with placebo in 
combination with paclitaxel and carboplatin in Chinese patients with newly diagnosed, 
previously untreated FIGO Stage III with any gross (macroscopic or palpable) residual disease 
or FIGO Stage IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.
Specific objectives and corresponding endpoints for the study are outlined in the table below.
In this protocol, "study treatment" refers to the combination of treatments assigned to patients 
as part of this study (i.e., bevacizumab/placebo plus paclitaxel and carboplatin).
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
bevacizumab versus placebo in 
combination with paclitaxelcarboplatin
PFS after randomization, defined as the time from
randomization to the first occurrence of disease 
progression or death from any cause during the study 
(whichever occurs first), as determined by the 
investigator according to RECIST v1.1
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Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
bevacizumab versus placebo in 
combination with paclitaxelcarboplatin
OS after randomization, defined as the time from 
randomization to death from any cause
ORR, defined as a CR or PR, as determined by the 
investigator according to RECIST v1.1 for patients 
with measurable residual disease after primary 
surgery
DOR, defined for patients who had an OR and 
defined as the time from the first occurrence of a 
documented OR to disease progression, as 
determined by the investigator according to 
RECIST v1.1 or death from any cause, whichever
occurs first for patients with measurable residual 
disease after primary surgery
To evaluate patient-reported 
abdominal symptoms of OC 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin, as measured 
by two items from the Abdominal/GI
Symptom Scale of the EORTC 
QLQ-OV28
Clinically meaningful improvement in 
patient-reported abdominal pain or bloating, defined 
as a 10-point decrease from the baseline score on 
either of the two items (Items 31 and 32) of the 
EORTC QLQ-OV28 Abdominal/GI Symptom Scale
To evaluate patient-reported 
outcomes (PROs) of function and 
health-related quality of life (HRQoL) 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Clinically meaningful improvement in 
patient-reported function and HRQoL, defined as a 
10-point increase from the baseline score on each 
of the function (physical, role, emotional, social) and 
global health status/HRQoL scales of the EORTC 
QLQ-C30
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate PROs of 
disease/treatment-related symptoms 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Mean and mean changes from the baseline score in 
disease and/or treatment-related symptoms by 
assessment timepoint and between treatment arms 
as assessed by all symptom items and/or scales of 
the EORTC QLQ-C30 and QLQ-OV28
To evaluate any treatment burden 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Proportion of patients reporting each response 
option at each assessment timepoint by treatment 
arm for item GP5 from the FACT-G (“I am bothered 
by side effects of treatment.”)
To evaluate and compare between 
treatment arms patients' health utility, 
as measured by the EQ-5D-5L to 
generate utility scores for use in 
economic models for reimbursement
Health utility scores of the EQ-5D-5L questionnaire
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Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
bevacizumab versus placebo in 
combination with 
paclitaxelcarboplatin
Occurrence and severity of adverse events, with 
severity determined according to NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical laboratory 
test results
CR complete response; DOR duration of response; EORTC European Organization for 
Research and Treatment of Cancer; GIgastrointestinal; HRQoL health-related quality of life; 
NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events; 
OC ovarian cancer; OR objective response; OS overall survival; PFS progression-free 
survival; PR partial response; PRO patient-reported outcome; QLQ-C30 Quality of Life 
Questionnaire Core 30; QLQ-OV28 Quality of Life Questionnaire Ovarian Cancer Module 28; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1.
Study Design
Description of Study
This is a Phase III, double-blind, two-arm, randomized study designed to evaluate the efficacy 
and safety of bevacizumab administered with paclitaxel plus carboplatin compared with placebo 
administered with paclitaxel plus carboplatin in Chinese patients with newly diagnosed, 
previously untreated FIGO Stage III with any gross (macroscopic or palpable) residual disease 
or FIGO Stage IV epithelial ovarian, fallopian tube, or primary peritoneal cancer.  Approximately 
100 patients are expected to be randomized. 
A patient-signed Informed Consent Form will be obtained before any study-specific procedures 
are undertaken. 
After informed consent is obtained, patients who meet the eligibility criteria will be randomized in 
a 1:1 ratio to the bevacizumab and carboplatin plus paclitaxel arm or the placebo and 
carboplatin plus paclitaxel arm.  Re-screening for any reason is not allowed.
Randomization will be stratified according to the following factors:  FIGO stage and debulking 
status (Stage III optimally debulked versus Stage III suboptimally debulked versus Stage IV) 
and Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1 or 2).
Patients will receive a maximum of six cycles of carboplatin/paclitaxel with either bevacizumab 
or placebo. Patients whose disease has not progressed after six cycles of chemotherapy with 
either bevacizumab or placebo will continue treatment with either bevacizumab or placebo until 
disease progression, unacceptable toxicity, or a maximum of 22 cycles, whichever occurs first. 
The details of each treatment arm are described below.
Number of Patients
Approximately 100 patients are expected to be enrolled in this study.
Target Population
The target population is patients with newly diagnosed, previously untreated, FIGO Stage III 
with any gross (macroscopic or palpable) residual disease or FIGO Stage IV epithelial ovarian, 
fallopian tube, or primary peritoneal cancer.
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment
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
A histologic diagnosis of EOC, peritoneal primary carcinoma, or fallopian tube cancer, FIGO 
Stage III with any gross (macroscopic or palpable) residual disease or FIGO Stage IV 
defined surgically at the completion of initial abdominal surgery and with appropriate tissue 
available for histologic evaluation
Patients with Stage III cancer for which the largest maximal diameter of any residual 
tumor implant at the completion of this initial surgery is no greater than 1 cm will be 
defined as having “optimally debulked” tumors.  All others will be defined as 
“suboptimally debulked” tumors.  Measurable disease on postoperative imaging 
studies is not required for eligibility.

Patients with the following histologic epithelial cell types are eligible:  serous 
adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, 
undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, 
transitional cell carcinoma, malignant Brenner tumor, or adenocarcinoma not otherwise 
specified

ECOG Performance Status 0, 1, or 2

Life expectancy of at least 12 weeks

Adequate hematological function indicated by all of the following:
−
ANC 1.5 109/L (ANC is not to be induced or supported by granulocyte colony-
stimulating factors [G-CSFs])
−
Platelet count 100 109/L (without transfusion)
−
Hemoglobin 9.0 g/dL:  Patients may receive RBC transfusions to attain this value. 

Adequate liver function indicated by all of the following: 
−
Serum bilirubin 1.5 the institutional upper limit of normal (ULN)
Patients with known Gilbert disease who have serum bilirubin level 3 ULN 
may be enrolled in the study.
−
AST, ALT, and alkaline phosphatase (ALP) 2.5 ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5 ULN
Patients with documented liver or bone metastases:  ALP 5 ULN

Adequate renal function indicated by all of the following: 
−
Serum creatinine (Scr) 1.5 ULN or calculated creatinine clearance (Ccr) 50 mL/min
−
Urinalysis for proteinuria 2unless a 24-hour urine protein 1 g is demonstrated

Blood coagulation parameters:  prothrombin time (PT) such that the international
normalized ratio (INR) is 1.5 (or an in-range INR, usually between 2 and 3, if a patient was 
on a stable dose of therapeutic warfarin for management of venous thrombosis, including 
pulmonary thromboembolus) and activated partial thromboplastin time (aPTT) is
1.5 ULN.  The use of full-dose oral or parenteral anticoagulants is permitted as long as 
the INR or aPTT is within therapeutic limits (according to the medical standard of the 
enrolling institution), and the patient has been on a stable dose of anticoagulants for at least 
2 weeks prior to randomization.

Neurologic function:  neuropathy (sensory and motor) of the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 1 or better

Enrollment between 1 and 12 weeks after initial surgery is performed for the combined 
purpose of diagnosis, staging, and cytoreduction
Patients with measurable and non-measurable disease are eligible.  Patients may or 
may not have cancer-related symptoms.

Patients in this trial may receive ovarian estrogen with or without progestin replacement 
therapy as indicated at the lowest effective dose(s) for control of menopausal symptoms at 
any time, but not progestins for management of anorexia during study treatment or prior to 
disease progression
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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% per year 
during the treatment period and for at least 6 months after the last dose of bevacizumab, 
paclitaxel, or carboplatin, whichever is later.  Women must refrain from donating eggs 
during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries, fallopian tubes, and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the completion of PRO questionnaires
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Current diagnosis of borderline epithelial ovarian tumor or recurrent invasive epithelial 
ovarian, primary peritoneal, or fallopian tube cancer treated with surgery only (such as 
patients with Stage IA or IB low-grade epithelial ovarian or fallopian tube cancers)
Patients with a prior diagnosis of a borderline tumor that was surgically resected and 
who subsequently developed unrelated, new invasive epithelial ovarian, peritoneal 
primary, or fallopian tube cancer are eligible, provided that they have not received prior 
chemotherapy for any ovarian tumor.

Prior radiotherapy to any portion of the abdominal cavity or pelvis 
Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, 
provided that it was completed more than 3 years prior to randomization and the 
patient remains free of recurrent or metastatic disease.

Prior chemotherapy for any abdominal or pelvic tumor, including neoadjuvant chemotherapy 
for ovarian, primary peritoneal, or fallopian tube cancer.  
Patients may have received prior adjuvant chemotherapy for localized breast cancer, 
provided that it was completed more than 3 years prior to randomization and that the 
patient remains free of recurrent or metastatic disease. 

Any prior targeted therapy (including, but not limited to, vaccines, antibodies, or tyrosine 
kinase inhibitors) or hormonal therapy for management of their epithelial ovarian or 
peritoneal primary cancer 

Synchronous primary endometrial cancer, or a history of primary endometrial cancer unless 
all of the following conditions are met:  
−
Stage not greater than Stage IB
−
No more than superficial myometrial invasion, without vascular or lymphatic invasion
−
No poorly differentiated subtypes, including papillary serous, clear cell, or other FIGO 
Grade 3 lesions

With the exception of nonmelanoma-related skin cancers and other specific malignancies 
as noted above, patients with other invasive malignancies who had (or have) any evidence 
of the other cancer present within the last 5 years or whose previous cancer treatment 
contraindicates study treatment

Prior or current treatment with any anti-angiogenic, including bevacizumab. 

Treatment with any other investigational agent or previous participation in another clinical 
trial within 30 days prior to randomization in this study.
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
Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive 
hepatitis B surface antigen (HBsAg) test result at screening, with the following exception:
Patients with a past or resolved HBV infection, defined as having a negative HBsAg 
test result and a positive total hepatitis B core antibody (HBcAb) test result at 
screening, are eligible for the study if HBV DNA is negative or undetectable.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test 
result and a positive HCV RNA test result at screening

A positive test result for HIV

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Current or recent (within 10 days prior to randomization) use of aspirin (325 mg/day) or
other non-steroidal anti-inflammatory agents known to inhibit platelet function  

Serious non-healing wounds, ulcers, or bone fractures  
This includes history of abdominal fistula, GI perforation, or intra-abdominal abscess 
within 28 days prior to randomization.  Patients with granulating incisions healing by 
secondary intention with no evidence of fascial dehiscence or infection are eligible but 
require weekly wound examinations.

Active bleeding or pathologic conditions that carry high risk of bleeding, such as known 
bleeding disorder, coagulopathy, or tumor involving major vessels 

History or evidence upon physical examination of CNS disease, including primary brain 
tumor, seizures not controlled with standard medical therapy, any brain metastases, or 
history of cerebrovascular accident (CVA; stroke), transient ischemic attack (TIA), or 
subarachnoid hemorrhage within 6 months of the first date of treatment on this study 

History of hypertensive crisis or hypertensive encephalopathy

Patients with clinically significant cardiovascular disease; this includes the following:
−
Uncontrolled hypertension, defined as systolic 150 mmHg or diastolic 90 mmHg
−
Myocardial infarction or unstable angina 6 months prior to randomization
−
New York Heart Association (NYHA) Class II or greater congestive heart failure (CHF)
−
Serious cardiac arrhythmia requiring medication (This does not include asymptomatic, 
atrial fibrillation with controlled ventricular rate.)
−
NCI CTCAE Grade 2 peripheral vascular disease (at least brief [ 24 hours] episodes 
of ischemia managed non-surgically and without permanent deficit)
−
History of CVA within 6 months prior to randomization

Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human 
or humanized antibodies

Have known sensitivity to any component of paclitaxel

Patients scheduled to undergo an invasive procedure as defined below: 
Major surgical procedure within 28 days prior to the first date of bevacizumab/placebo 
therapy (Cycle 2) or anticipated during the course of the study.  This includes, but is 
not limited to, abdominal surgery prior to disease progression, such as colostomy or 
enterostomy reversal, interval or secondary cytoreductive surgery, or second-look 
surgery. 
Core biopsy or other minor surgical procedures performed within 7 days prior to the 
anticipated first dose of bevacizumab/placebo therapy, with the following exception:  
The interval of time between placement of a central vascular access device (CVAD) 
(e.g., Port-A-Cath®) and the first dose of bevacizumab for a patient must be no shorter 
than 2 days with a well-healed incision 
Protocol Number: 
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
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 6 months after the last dose of bevacizumab, paclitaxel, or carboplatin, whichever is 
later
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to randomization.

Patients with clinical symptoms or signs of GI obstruction and who require parenteral 
hydration and/or nutrition

Evidence of any other disease, neurologic or metabolic dysfunction, physical examination 
finding, or laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of any of the study drugs, puts the patient at higher risk for 
treatment-related complications, or may affect the interpretation of study results

Requirement for treatment with any medicinal product that contraindicates the use of any of 
the study drugs, may interfere with the planned treatment, affects patient compliance, or 
puts the patient at high risk for treatment-related complications

History or evidence of thrombotic disorders within the last 6 months prior to randomization
End of Study
The end of the study period is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for PFS analysis or safety follow-up is 
completed by the last patient, whichever occurs later.  Additionally, the Sponsor may decide to 
terminate the study at any time.
Investigational Medicinal Products
The investigational medicinal product (IMP) for this study is bevacizumab.
Test Product (Investigational Drug)
Patients in the bevacizumab and chemotherapy arm will receive bevacizumab and 
paclitaxel/carboplatin combination therapy as follows:

Chemotherapy:
−
Paclitaxel 175 mg/m2 IV over 3 hours on Day 1
−
Carboplatin area under the concentrationtime curve (AUC) 6 IV administered 
over 30 minutes on Day 1 of each cycle

Bevacizumab:  Bevacizumab 15 mg/kg IV on Day 1 of Cycle 2 Q3W starting at Cycle 2 until 
disease progression, unacceptable toxicity, a maximum of 21 cycles, or withdrawal,
whichever occurs first
Each chemotherapy cycle is to be repeated Q3W until disease progression, unacceptable
toxicity, a maximum of six cycles, or withdrawal, whichever comes first.
Paclitaxel will be the first drug of the regimen to be administered to patients in each cycle in 
both arms, followed by carboplatin and then bevacizumab.
Comparator
Patients in the placebo and chemotherapy arm will receive placebo and paclitaxel/carboplatin 
combination therapy as follows: 

Chemotherapy:
−
Paclitaxel 175 mg/m2 IV over 3 hours on Day 1
−
Carboplatin AUC 6 mg/mL/min IV over 30 minutes on Day 1

Placebo:  Placebo IV on Day 1 Q3W starting at Cycle 2 until disease progression, 
unacceptable toxicity, a maximum of 21 cycles, or withdrawal, whichever occurs first
Each chemotherapy cycle will be repeated Q3W until disease progression, unacceptable toxicity, 
a maximum of six cycles, or withdrawal, whichever comes first. 
Paclitaxel will be the first drug of the regimen to be administered in each cycle in both arms, 
followed by carboplatin and then placebo.
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Bevacizumab—F. Hoffmann-La Roche Ltd
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Non-Investigational Medicinal Products
Carboplatin and paclitaxel are the non-investigational medicinal products (NIMPs) for this study.  
Sites will obtain and utilize commercially available carboplatin and paclitaxel.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is PFS, which will be assessed by the investigator using 
RECIST v1.1.  The study is not fully powered for the primary endpoint; instead consistency with 
the global pivotal study (GOG218) will be considered for the primary endpoint.
PFS after randomization is defined as the time from randomization to the first documented 
occurrence of disease progression or death from any cause during the study (whichever occurs 
first), as determined by the investigator according to RECIST v1.1.  Data for patients who have 
not experienced disease progression or death will be censored at the last tumor assessment.  
Data for patients with no post-baseline tumor assessment will be censored at the date of 
randomization plus 1 day.
The primary endpoint of PFS will be analyzed between treatment and control arms based on the 
stratified log-rank test.  The HR of PFS in the experimental arm compared with the control arm 
will be estimated using a stratified Cox regression model, and the 95% CI will be provided.  The 
stratification factors will be those used during randomization, as recorded in eCRF.  Results 
from an unstratified analysis will also be presented.  Kaplan-Meier methodology will be used to 
estimate median PFS for each treatment arm, and Kaplan-Meier curves will be constructed to 
provide visual descriptions of the difference between the treatment and control arms.
The Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median PFS 
and OS for each treatment arm.
Determination of Sample Size  
The purpose of this study is to confirm the efficacy and safety of bevacizumab in a population of 
Chinese women with advanced ovarian, fallopian tube, and primary peritoneal cancers who 
have not received prior chemotherapy for this disease, and to investigate the consistency in 
treatment effect between Chinese patients and the patients in global study for the purpose of 
registration in China.  The primary efficacy results will be bridged with those of the pivotal 
Study GOG218.
A total of approximately 100 patients will be randomized in a 1:1 ratio to either the bevacizumab 
or placebo arms of the study.  The final analysis of the primary endpoint of PFS will be 
performed when approximately 56 PFS events have occurred in the ITT population (56% of 100 
patients), which will provide an 80% probability of demonstrating consistency with the global 
study.
Interim Analyses
There will be no planned interim analysis.
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Bevacizumab—F. Hoffmann-La Roche Ltd
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
ALP
alkaline phosphatase
aPTT
activated partial thromboplastin time
AUC
area under the concentrationtime curve
BML
below measurable limit
BUN
blood urea nitrogen
Ccr
creatinine clearance
CHF
congestive heart failure
CR
complete response
CRF
Case Report Form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CVA
cerebrovascular accident
DLT ANC
dose-limiting toxicity neutropenia
DLT PLT
dose-limiting toxicity thrombocytopenia
eCRF
electronic Case Report Form
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
EMA
European Medicines Agency
EORTC QLQ-C30
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30
EQ-5D-5L
EuroQol 5 Dimension, 5-Level Questionnaire
FACT-G
Functional Assessment of Cancer Therapy–General
FDA
Food and Drug Administration
FDG-PET
(18)F-Fluorodeoxyglucose positron emission 
tomography
FIGO
International Federation of Gynecology and Obstetrics
G-CSF
granulocyte colony-stimulating factor
GCIG
International Gynecologic Cancer Intergroup
GFR
glomerular filtration rate
GI
gastrointestinal
GOG
Gynecologic Oncology Group
HR
hazard ratio
HRQoL
health-related quality of life
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Bevacizumab—F. Hoffmann-La Roche Ltd
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Abbreviation
Definition
ICH
International Conference for Harmonization
IMP
Investigational Medicinal Product
IND
Investigational New Drug (application)
INR
international normalized ratio
IRB
Investigational Review Board
IWRS
interactive Web-based response system
Kd
dissociation constant
LPLV
last patient, last visit
mCRC
metastatic colorectal cancer
MRI
magnetic resonance imaging
NaCl
sodium chloride
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
nonsmall cell lung cancer
NYHA
New York Heart Association
OC
ovarian cancer
ORR
objective response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
PT
prothrombin time
Q3W
every 3 weeks
RECIST v 1.1
Response Evaluation Criteria in Solid Tumors, 
Version 1.1
SAiL
Safety of Avastin in Lung Cancer
Scr
serum creatinine
SD
stable disease
TIA
transient ischemic attack
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VEGF-A
vascular endothelial growth factorA
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Bevacizumab—F. Hoffmann-La Roche Ltd
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1.
BACKGROUND
1.1
BACKGROUND ON BACKGROUND ON OVARIAN, PRIMARY 
PERITONEAL, AND FALLOPIAN TUBE CANCERS
Ovarian, fallopian tube, and primary peritoneal cancers remain leading causes of 
cancer-related mortality among women worldwide.  Globally, epithelial ovarian 
cancer (EOC) is the most common type of ovarian cancer. It affects 238,719 women 
annually and results in 140,200 cancer-related deaths, with an annual incidence of 
52,100 (22,500 deaths) in China (Ferlay et al. 2013, Chen et al. 2016).  EOC, fallopian 
tube cancer, and primary peritoneal cancer (commonly named as ovarian cancer 
thereafter) comprise tumors of extra-uterine Müllerian origin and share common clinical 
and biological behavior.  They are typically grouped together in treatment paradigms and 
clinical investigations, as will be done in this current study.
The diagnosis of ovarian cancer (OC) at an early stage is uncommon because of its 
typically asymptomatic nature (Ebell et al. 2016).  Even patients with more 
advanced-stage disease typically experience only vague non-specific symptoms that 
result in further delays in diagnosis.  Thus, most patients with OC already have 
disseminated disease and advanced-stage disease upon initial diagnosis that make the 
likelihood of cure remote.  The 5-year survival rate among patients with Stage I OC is 
85% whereas the 5-year survival rates for patients with advanced Stage III or Stage IV 
OC are 39% and 17%, respectively (SEER database).  Despite advances in 
perioperative and operative techniques, and a better understanding of the biology of OC, 
cure rates for OC have remained flat for more than a decade (Sopik et al. 2015).
The standard of care (SOC) for OC at initial diagnosis includes primary tumor reduction 
surgery, followed by platinum (carboplatin) and taxane (paclitaxel) systemic 
chemotherapy (McGuire 1996; Piccart 2000; Ozols et al. 2003, Ledermann et al. 2013).  
Recently, the Society of Gynecologic Oncology (SGO) identified the initiation of 
chemotherapy within 42 days following primary cytoreductive surgery as a quality 
indicator for improving OC care (https://www.sgo.org/quality-outcomes-and-
research/quality-indicators/).  Unfortunately, despite the high sensitivity of OC to initial 
platinum and taxane combination chemotherapy, the majority of women who are
diagnosed with advanced-stage disease will relapse and ultimately succumb to their 
cancer.  Many strategies that attempt to improve the clinical efficacy of first-line ovarian 
cancer (1LOC) cytotoxic chemotherapy regimens have been studied since carboplatin 
and paclitaxel were identified as the two key chemotherapies for OC. Adding a third 
cytotoxic agent to the carboplatin and paclitaxel doublet only increased hematologic
toxicity, without commensurate increases in progression-free survival (PFS) and overall 
survival (OS), thus reinforcing the importance of carboplatin and paclitaxel as the 
frontline regimen (Bookman et al. 2009).
Despite the challenges observed with the manipulation or addition of cytotoxic 
chemotherapy agents to a carboplatin and paclitaxel doublet, the clinical experience with 
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biological agents, notably bevacizumab, has been more promising.  Two randomized 
Phase III studies (Study Gynecology Oncology Group [GOG] 218; Study International 
Collaborative Ovarian Neoplasm [ICON]) of bevacizumab in patients with advanced OC 
who are treatment naive, demonstrated improvement in PFS (Burger et al. 2011, Perren 
et al. 2011).  Study GOG218, which combined the standard dose of bevacizumab        
(15 mg/kg every 3 weeks [q3W]) with carboplatin and paclitaxel followed by bevacizumab 
monotherapy for 16 cycles, showed a significant improvement in the Response 
Evaluation Criteria in Solid Tumors (RECIST)-determined PFS (i.e., excludes the CA125 
elevations and nonprotocol-specified therapies), with a 35% reduction in the risk of 
progression or death and an increase of 6 months in the median PFS from 12 months
to 18 months (Burger et al. 2011).
A pronounced benefit was also identified in Study BO17707 (ICON7) in a subgroup of 
patients who were at a particularly high risk for cancer recurrence.  Patients who were 
treated with bevacizumab in this high-risk subgroup (i.e., International Federation of 
Gynecology and Obstetrics [FIGO] Stage IV disease or FIGO Stage III disease and 
1.0 cm of residual disease after debulking surgery) experienced a reduction of 27% in 
their risk for progression that corresponded to an improvement of 5.5 months in their  
PFS (Perren et al. 2011).  Furthermore, the treatment benefit in patients who were 
administered bevacizumab was evaluated in a subgroup analysis of Study GOG262, a 
Phase III study in which 80% of patients (including some in the neoadjuvant setting) 
were administered bevacizumab with chemotherapy (Chan et al. 2016).  Although the 
primary objective of Study GOG262 was to test the clinical benefit of treatment with 
carboplatin combined with weekly paclitaxel or paclitaxel every 21days, an analysis of 
patients administered carboplatin and paclitaxel every 21 days showed a longer PFS 
when bevacizumab was added to the treatment compared with patients for whom it was 
not added (14.7 months vs. 10.3 months).  This finding further supports the treatment 
benefit of the inclusion of bevacizumab in 1L OC treatment (Chan et al. 2016).  
Studies GOG218 and ICON7 led to the regulatory approval in the European Union
(December 2011), the United States (June 2018), and other countries of bevacizumab 
combined with carboplatin and paclitaxel for the treatment of women with previously 
untreated OC at an advanced stage and is the recommendation by major guidelines as a 
new SOC.
Although surgery remains the cornerstone of 1L OC treatment, two seminal studies that 
evaluated the neoadjuvant approach compared with traditional primary surgery, followed 
by adjuvant chemotherapy, demonstrated similar duration in PFS and OS between the 
two approaches (Vergote et al. 2010; Kehoe 2016).
The current armamentarium of surgery, cytotoxic chemotherapy, and bevacizumab 
comprise key effective current treatment options for patients with OC. However, 
bevacizumab is not approved for the treatment of OC in China.
Bevacizumab—F. Hoffmann-La Roche Ltd
21/Protocol YO40268, Version 3
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Bevacizumab—F. Hoffmann-La Roche Ltd
22/Protocol YO40268, Version 3
1.2
BACKGROUND ON BEVACIZUMAB
Bevacizumab is a recombinant humanized monoclonal antibody to VEGF composed of 
human IgG1 framework regions and antigen-binding complementary determining regions 
from a murine monoclonal antibody (VEGF A.4.6.1) that binds to and neutralizes human 
VEGF activity. Bevacizumab has a molecular mass of approximately 149 kDa and is 
glycosylated.
Bevacizumab recognizes all isoforms of VEGF with a dissociation constant (Kd) of 
approximately 8 10 -10 M. It does not recognize other peptide growth factors tested 
(fibroblast growth factor, epidermal growth factor, hepatocyte growth factor, platelet-
derived growth factor, and nerve growth factor). It may exert a direct anti-angiogenic 
effect by binding to and clearing VEGF from the tumor environment. Additional 
anti-tumor activity may be obtained through the effects of bevacizumab on tumor 
vasculature, interstitial pressure, and blood vessel permeability, providing for enhanced 
chemotherapy delivery to tumor cells (Jain 2001).
Bevacizumab has shown benefit when added to chemotherapy in preclinical models of 
several tumors (Kim et al. 1993; Warren et al. 1995; Borgstrom et al. 1999).  In animal 
models of subcutaneous human lung cancer (Calu-6 cell line), the combination of 
anti-VEGF and cisplatin resulted in markedly enhanced biologic activity compared with 
the activity of either agent alone (Kabbinavar et al. 1995).
Bevacizumab has already been tested in many Phase I, II, and III studies in patients with 
a variety of solid tumors, as a single agent or in combination with chemotherapy.  
Bevacizumab has been approved in many countries for the treatment of metastatic 
colorectal cancer (mCRC), locally recurrent or metastatic breast cancer (mBC),
advanced, metastatic, or recurrent nonsmall cell lung cancer (NSCLC), advanced 
and/or metastatic renal cell cancer (mRCC), malignant glioma (WHO Grade IV),
glioblastoma, epithelial ovarian, fallopian tube and primary peritoneal cancer, and 
cervical cancer. 
To date, bevacizumab has been approved for two indications in China, mCRC and 
advanced, metastatic, or recurrent NSCLC. 
Globally, it is estimated that a total of 32,237 patients have received bevacizumab 
through participation in clinical trials across cancer indications, of which 475 have been 
patients with OC (until 25 February 2016).  It is estimated that 2,394,526 patients have 
been exposed to bevacizumab through participation in company-sponsored studies or 
through commercially available product (until 25 February 2016).  
The safety profile of bevacizumab, when used in addition to carboplatin/paclitaxel
chemotherapy in OC, was as expected based on the known toxicities of the individual
components.
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Bevacizumab—F. Hoffmann-La Roche Ltd
23/Protocol YO40268, Version 3
Refer to the Bevacizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
For nearly two decades, surgery and platinum-based combination chemotherapy have
been the standard first-line treatment for patients with advanced OC. Attempts to 
improve this standard two-drug chemotherapy by adding a third cytotoxic drug failed to 
affect either PFS or OS and resulted in an increase in toxic effects (du Bois et al. 2006; 
Pfisterer et al. 2006; Bookman et al. 2009; Hoskins et al. 2010).
Recently, two pivotal Phase III (GOG218 and ICON7) studies have demonstrated the 
benefit of bevacizumab use in addition to carboplatin plus paclitaxel chemotherapy in a 
predominantly Caucasian patient population with OC (Burger et al. 2011; 
Perren et al. 2011).  The safety profile of bevacizumab, when used in addition to 
carboplatin/paclitaxel chemotherapy in OC, was as expected based on the known 
toxicities (see Section 1.2). As a result, bevacizumab in combination with carboplatin 
and paclitaxel, has been approved in the European Union for the front-line treatment of 
advanced (FIGO Stages IIIB, IIIC, and IV, 1988 edition) epithelial ovarian, fallopian tube, 
or primary peritoneal cancer and in the United States for advanced (Stage III or IV) 
ovarian cancer following initial surgical resection. The recommended dose regimen is 
15 mg/kg administered Q3W for 15 months or until disease progression.  Neither of the
global Phase III trials included Chinese women with OC. Therefore, the efficacy and 
safety of bevacizumab in addition to paclitaxel and carboplatin in Chinese patients with 
OC have yet to be evaluated.
The purpose of this study is to confirm the efficacy and safety of bevacizumab in a 
randomized, double-blind, placebo-controlled, comparative setting in a population of 
Chinese women with advanced ovarian, fallopian tube, and primary peritoneal cancers
who have not received prior chemotherapy for their disease. The benefit-risk profile for 
bevacizumab in combination with paclitaxel and carboplatin is expected to be in line with 
the positive benefit-risk observed in GOG218.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of bevacizumab compared with placebo 
in combination with paclitaxel and carboplatin in Chinese patients with newly diagnosed, 
previously untreated FIGO Stage III with any gross (macroscopic or palpable) residual 
disease or FIGO Stage IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.
Specific objectives and corresponding endpoints for the study are outlined in Table 1.
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., bevacizumab/placebo plus paclitaxel and carboplatin).
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Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
bevacizumab versus placebo in 
combination with paclitaxelcarboplatin
PFS after randomization, defined as the time from
randomization to the first occurrence of disease 
progression or death from any cause during the study 
(whichever occurs first), as determined by the 
investigator according to RECIST v1.1 (see
Appendix 2)
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
bevacizumab versus placebo in 
combination with paclitaxelcarboplatin
OS after randomization, defined as the time from 
randomization to death from any cause
ORR, defined as a CR or PR, as determined by the 
investigator according to RECIST v1.1 for patients 
with measurable residual disease after primary 
surgery
DOR, defined for patients who had an OR and 
defined as the time from the first occurrence of a 
documented OR to disease progression, as 
determined by the investigator according to 
RECIST v1.1 or death from any cause, whichever 
occurs first for patients with measurable residual 
disease after primary surgery
To evaluate patient-reported 
abdominal symptoms of OC
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin, as measured 
by two items from the Abdominal/GI 
Symptom Scale of the EORTC QLQ-
OV28
Clinically meaningful improvement in 
patient-reported abdominal pain or bloating, defined 
as a 10-point decrease from the baseline score on 
either of the two items (Items 31 and 32) of the 
EORTC QLQ-OV28 Abdominal/GI Symptom Scale 
(see Appendix 5)
To evaluate patient-reported 
outcomes (PROs) of function and 
health-related quality of life (HRQoL)
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Clinically meaningful improvement in 
patient-reported function and HRQoL, defined as a 
10-point increase from the baseline score on each 
of the function (physical, role, emotional, social) and 
global health status/HRQoL scales of the EORTC 
QLQ-C30 (see Appendix 4) 
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate PROs of 
disease/treatment-related symptoms 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Mean and mean changes from the baseline score in 
disease and/or treatment-related symptoms by 
assessment timepoint and between treatment arms 
as assessed by all symptom items and/or scales of 
the EORTC QLQ-C30 and QLQ-OV28
To evaluate any treatment burden
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Proportion of patients reporting each response 
option at each assessment timepoint by treatment 
arm for item GP5 from the FACT-G (“I am bothered 
by side effects of treatment.”) (see Appendix 6)
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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objectives 
(cont.)
Corresponding Endpoints (cont.)
To evaluate and compare between
treatment arms patients' health utility,
as measured by the EQ-5D-5L to
generate utility scores for use in
economic models for reimbursement
Health utility scores of the EQ-5D-5L questionnaire
(see Appendix 7)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
bevacizumab versus placebo in 
combination with
paclitaxelcarboplatin
Occurrence and severity of adverse events, with 
severity determined according to NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical laboratory 
test results
CRcomplete response; DORduration of response; EORTCEuropean Organization for 
Research and Treatment of Cancer; GIgastrointestinal; HRQoLhealth-related quality of life; 
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
OCovarian cancer; ORobjective response; OSoverall survival; PFSprogression-free 
survival; PRpartial response; PROpatient-reported outcome; QLQ-C30Quality of Life 
Questionnaire Core 30; QLQ-OV28Quality of Life Questionnaire Ovarian Cancer Module 28; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a Phase III, double-blind, two-arm, randomized study designed to evaluate the 
efficacy and safety of bevacizumab administered with paclitaxel plus carboplatin
compared with placebo administered with paclitaxel plus carboplatinin Chinese patients 
with newly diagnosed, previously untreated FIGO Stage III with any gross (macroscopic 
or palpable) residual disease or FIGO Stage IV epithelial ovarian, fallopian tube, or 
primary peritoneal cancer.  Approximately 100 patients are expected to be randomized.
A patient-signed Informed Consent Form will be obtained before any study-specific 
procedures are undertaken. 
After informed consent is obtained, patients who meet the eligibility criteria will be 
randomized in a 1:1 ratio to the bevacizumab and carboplatin plus paclitaxel arm or the 
placebo and carboplatin plus paclitaxel arm. Re-screening for any reason is not allowed.
Randomization will be stratified according to the following factors: FIGO stage and 
debulking status (Stage III optimally debulked versus Stage III suboptimally debulked
versus Stage IV) and Eastern Cooperative Oncology Group (ECOG) Performance 
Status (0 vs. 1 or 2).
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Patients will receive a maximum of six cycles of carboplatin/paclitaxel with either 
bevacizumab or placebo. Patients whose disease has not progressed after six cycles of 
chemotherapy with either bevacizumab or placebo will continue treatment with either 
bevacizumab or placebo until disease progression, unacceptable toxicity, or a maximum 
of 22 cycles, whichever occurs first. The details of each treatment arm are described
below.
3.1.2
Bevacizumab and Chemotherapy
Patients in the bevacizumab and chemotherapy arm will receive bevacizumab and 
paclitaxel/carboplatin combination therapy as follows:

Chemotherapy:
−
Paclitaxel 175 mg/m2 IV over 3 hours on Day 1
−
Carboplatin area under the concentrationtime curve (AUC) 6 IV administered
over 30 minutes on Day 1 of each cycle

Bevacizumab:  Bevacizumab 15 mg/kg IV on Day 1 of Cycle 2 Q3W starting at Cycle 
2 until disease progression, unacceptable toxicity, a maximum of 21 cycles, or 
withdrawal, whichever occurs first
Each chemotherapy cycle is to be repeated Q3W until disease progression, 
unacceptable toxicity, a maximum of six cycles, or withdrawal, whichever comes first.
Paclitaxel will be the first drug of the regimen to be administered to patients in each 
cycle in both arms, followed by carboplatin and then bevacizumab.
3.1.3
Placebo and Chemotherapy
Patients in the placebo and chemotherapy arm will receive placebo and 
paclitaxel/carboplatin combination therapy as follows: 

Chemotherapy:
−
Paclitaxel 175 mg/m2 IV over 3 hours on Day 1
−
Carboplatin AUC 6 mg/mL/min IV over 30 minutes on Day 1

Placebo:  Placebo IV on Day 1 Q3W starting at Cycle 2 until disease progression, 
unacceptable toxicity, a maximum of 21 cycles, or withdrawal, whichever occurs first
Each chemotherapy cycle will be repeated Q3W until disease progression, unacceptable 
toxicity, a maximum of six cycles, or withdrawal, whichever comes first. 
Paclitaxel will be the first drug of the regimen to be administered in each cycle in both 
arms, followed by carboplatin and then placebo.
A schedule of activities is provided in Appendix 1.
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In the Chinese Phase I study (BP20689), the PK profile of bevacizumab in Chinese 
patients was similar to that of the PK profile in Caucasian patients, resulting in 
comparable exposures when administered at the same dose (see Section 1.3.1 
Pharmacology of Bevacizumab in the Investigator’s Brochure). In other cancer trials,
such as Safety of Avastin in Lung Cancer (SAiL), which included Chinese patients, 
results in the Chinese subgroup suggested that the efficacy and tolerability of 
bevacizumab 15 mg/kg Q3W was similar to that observed in the entire study population 
(Tsai et al. 2011).
Therefore, the dose regimen of 15-mg/kg bevacizumab Q3W in combination with 
paclitaxel plus carboplatin in this study has been selected on the basis of robust clinical 
evidence with the objective to confirm the efficacy and safety of bevacizumab in Chinese 
patients with advanced OC.
3.3.2
Delay of Initial Treatment with Bevacizumab
Owing to a concern for potential wound healing complications related to bevacizumab in 
this trial, bevacizumab/placebo therapy will begin at the start of Cycle 2 of carboplatin 
and paclitaxel combination chemotherapy.
3.3.3
Rationale for Patient Population
This study will enroll Chinese patients with newly diagnosed, previously untreated, 
FIGO Stage III with any gross (macroscopic or palpable) residual disease or FIGO 
Stage IV epithelial ovarian, fallopian tube, or primary peritoneal cancer (i.e., cancers of 
extra-uterine Müllerian origin).  The eligibility criteria for this study include patients who 
are at the highest risk for a poor clinical outcome and, therefore, represent those in great 
need for new, more effective treatments.
Because of its predisposition to present in an advanced stage with large tumor volume, 
EOC, fallopian tube carcinoma, and primary peritoneal carcinoma remain the leading 
cause of death among all gynecologic malignancies with poor 5-year OS rates of 39% 
(Stage III) and 17% (Stage IV) (Goff et al. 2012; Ferlay et al. 2013; American Cancer 
Society 2016; Siegel et al. 2016).  Furthermore, certain tumor characteristics, such as 
postoperative macroscopic residual disease and Stage IV disease, portend especially 
poor prognosis and a high risk for recurrence. Despite effective cytotoxic agents therapy, 
recurrence rates remain high for patients with advanced stage OC, thereby highlighting 
the need to avail novel and durable therapies for these patients and thus justifying their 
inclusion in this study.
Both GOG218 and ICON7 studies included previously untreated epithelial ovarian, 
primary peritoneal, or fallopian tube cancer, Stage III optimal (macroscopic or palpable 
residual), Stage III suboptimal, and Stage IV patients. ICON7 also included high-risk 
FIGO Stage I andIIA patients. Although both studies showed benefit in PFS, there were
more data supporting bevacizumab's effect in patients with Stage III and IV disease, and 
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the EMA approval is for this population. Therefore, the Stage IIIandIV patient 
population was chosen by the Sponsor as the target group in this trial.
3.3.4
Rationale for Control Group
For nearly two decades, the standard treatment for women with advanced OC has been
surgery and platinum-based chemotherapy.  Attempts to improve the efficacy of this 
standard two-drug chemotherapy by adding a third cytotoxic drug failed to affect either 
PFS or OS and resulted in an increase in toxic effects (du Bois 2006; Pfisterer et al. 
2006; Bookman et al. 2009; Hoskins et al. 2010). Although intraperitoneal 
chemotherapy has extended OS from 12 months to 17 months, it is an option only for 
women with advanced OC who have a small amount of residual disease after surgery
(Armstrong et al. 2006). One trial in Japan demonstrated an alternative regimen with 
weekly paclitaxel administration, which provided a sustained significant improvement in 
PFS for patients receiving dose-dense therapy compared with conventional treatment 
(Katsumata et al. 2009, 2013).
The fifth GCIG Ovarian Cancer Consensus Conference (Karam et al. 2017) 
recommended that the control arm in international clinical trials of first-line chemotherapy 
of OC should be six cycles of combination IV chemotherapy with carboplatin (AUC 5 to 
AUC 6 mg/mL/min) and paclitaxel (175 mg/m2 given as a 3-hour infusion) administered 
Q3W.  Carboplatin and paclitaxel, given in this manner, are considered the international 
standard of care (Aabo et al. 1998; du Bois 2001; McGuire and Markman 2003; Stuart et 
al. 2011).  This regimen was also regarded as the Category 1 recommendation in China 
editions of the NCCN guidelines for epithelial ovarian cancer (Version 2, 2015), which is 
the most commonly used regimen in China.
3.3.5
Rationale for Patient-Reported Outcome Assessments
Abdominal symptoms (e.g., bloating, increased abdominal size, and abdominal pain) are 
ranked as the top symptoms in terms of frequency, severity, and duration by patients 
with OC and represent a significant burden in women with newly diagnosed advanced 
disease (Olson et al. 2001; Goff et al. 2004; Matsuo et al. 2011; Friedlander and 
King 2013; Donovan et al. 2014).  Prioritizing measurement of patient-reported 
abdominal symptoms is important because these common advanced symptoms are 
most likely to be affected by early treatment and are critical in the assessment of 
clinical benefit (Donovan et al. 2014; Herzog et al. 2014). In this study, improvements 
in the symptoms of bloating and abdominal pain will be assessed with the use of the 
valid and reliable European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire Ovarian Cancer Module 28 (EORTC QLQ-OV28) to provide 
a direct measure of clinical benefit in this patient population (Cull et al. 2001; 
Greimel et al. 2003).
The EORTC QLQ-OV28 includes a seven-item abdominal/gastrointestinal (GI symptom 
scale (Items 3137; see Appendix 5).  Improvement in abdominal symptoms as 
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identified by Item 31 ("Did you have abdominal pain?") and Item 32 ("Do you have a 
bloated feeling in your abdomen/stomach?") will be assessed as a key secondary 
endpoint to document the effect of bevacizumab on two of the most predominant and 
burdensome symptoms of advanced OC (Cella et al. 2003). Instead of analyzing the 
entire abdominal/GI scale, this secondary endpoint definition is based on an analysis of 
the two single items that identify and assess two distinct symptoms that are the most 
clinically relevant and important to newly diagnosed patients with advanced OC (Olson 
et al. 2001; Cella et al. 2003; Goff et al. 2004; Matsuo et al. 2011; Goff 2012; Friedlander 
and King 2013; Donovan et al. 2014). 
To provide supplementary information to describe clinical benefit in the patient 
population and support and inform on the benefit-risk assessment of bevacizumab 
therapy, a global assessment of the impact of treatment on patients’ functioning and
health-related quality of life (HRQoL) will be conducted and analyzed as secondary 
efficacy endpoints with the functional (role, physical, emotional, and social) and global 
health status/HRQoL scale scores of the validated, reliable EORTC Quality of Life 
Questionnaire Core 30 (QLQ-C30) (Aaronson et al. 1993).  In addition, an exploratory 
efficacy endpoint has been specified to evaluate any treatment burden patients may 
experience with the addition of bevacizumab, which will be assessed by analyzing the 
proportion of patients who select each response option at each assessment timepoint by 
treatment arm for the single item GP5 (“I am bothered by side effects of treatment”) from 
the physical well-being subscale of the validated and reliable Functional Assessment of 
Cancer Therapy–General (FACT-G) Quality of Life InstrumentVersion 4 (Cella et al. 
1993; Webster et al. 1999). Patients will also complete the validated EuroQol 5 
Dimension, 5-Level Questionnaire (EQ-5D-5L) (Herdman et al. 2011; Janssen et al. 
2013; see Appendix 7) to generate utility scores to inform pharmacoeconomic 
evaluations.  As such, the utility results will not be included in the Clinical Study Report 
(CSR).
Given the duration of treatment and the potential for long-term treatment impact, all 
patient-reported outcome (PRO) measures will be assessed at specified timepoints while 
patients are receiving treatment and during the follow-up period after treatment 
discontinuation as defined in the schedule of activities (see Appendix 1).
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 100 patients with newly diagnosed, previously untreated, FIGO Stage III 
with any gross (macroscopic or palpable) residual disease or FIGO Stage IV epithelial 
ovarian, fallopian tube, or primary peritoneal cancer will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form
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
Age18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

A histologic diagnosis of EOC, peritoneal primary carcinoma, or fallopian tube cancer, 
FIGO Stage III with any gross (macroscopic or palpable) residual disease or FIGO 
Stage IV defined surgically at the completion of initial abdominal surgery and with 
appropriate tissue available for histologic evaluation
Patients with Stage III cancer for which the largest maximal diameter of any 
residual tumor implant at the completion of this initial surgery is no greater than 
1 cm will be defined as having “optimally debulked” tumors. All others will be 
defined as “suboptimally debulked” tumors. Measurable disease on 
postoperative imaging studies is not required for eligibility.

Patients with the following histologic epithelial cell types are eligible: serous 
adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, 
undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, 
transitional cell carcinoma, malignant Brenner tumor, or adenocarcinoma not 
otherwise specified

ECOG Performance Status 0, 1, or 2

Life expectancy of at least 12 weeks

Adequate hematological function indicated by all of the following:
−
ANC1.5109/L (ANC is not to be induced or supported by granulocyte colony-
stimulating factors [G-CSFs])
−
Platelet count 100109/L (without transfusion)
−
Hemoglobin 9.0 g/dL:  Patients may receive RBC transfusions to attain 
this value.

Adequate liver function indicated by all of the following: 
−
Serum bilirubin 1.5 the institutional upper limit of normal (ULN)
Patients with known Gilbert disease who have serum bilirubin level 
3 ULN may be enrolled in the study.
−
AST, ALT, and alkaline phosphatase (ALP) 2.5 ULN, with the following 
exceptions:
Patients with documented liver metastases:  AST and/or ALT 5 ULN
Patients with documented liver or bone metastases:  ALP 5 ULN

Adequate renal function indicated by all of the following: 
−
Serum creatinine (Scr) 1.5 ULN or calculated creatinine clearance (Ccr)
50 mL/min
−
Urinalysis for proteinuria 2unless a 24-hour urine protein 1 g is 
demonstrated
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
Blood coagulation parameters:  prothrombin time (PT) such that the international
normalized ratio (INR) is 1.5 (or an in-range INR, usually between 2 and 3, if a 
patient was on a stable dose of therapeutic warfarin for management of venous 
thrombosis, including pulmonary thromboembolus) and activated partial 
thromboplastin time (aPTT) is 1.5ULN.  The use of full-dose oral or parenteral 
anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits 
(according to the medical standard of the enrolling institution), and the patient has 
been on a stable dose of anticoagulants for at least 2 weeks prior to randomization.

Neurologic function: neuropathy (sensory and motor) of the National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade1 or better

Enrollment between 1 and 12 weeks after initial surgery is performed for the 
combined purpose of diagnosis, staging, and cytoreduction
Patients with measurable and non-measurable disease are eligible. Patients 
may or may not have cancer-related symptoms.

Patients in this trial may receive ovarian estrogen with or withoutprogestin
replacement therapy as indicated at the lowest effective dose(s) for control of 
menopausal symptoms at any time, but not progestins for management of anorexia 
during study treatment or prior to disease progression

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of1% 
per year during the treatment period and for at least 6 months after the last dose of 
bevacizumab, paclitaxel, or carboplatin, whichever is later.  Women must refrain from 
donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or 
uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures, including the completion of PRO questionnaires
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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Current diagnosis of borderline epithelial ovarian tumor or recurrent invasive 
epithelial ovarian, primary peritoneal, or fallopian tube cancer treated with surgery 
only (such as patients with Stage IA or IB low-grade epithelial ovarian or fallopian 
tube cancers)
Patients with a prior diagnosis of a borderline tumor that was surgically 
resected and who subsequently developed unrelated, new invasive epithelial 
ovarian, peritoneal primary, or fallopian tube cancer are eligible, provided that 
they have not received prior chemotherapy for any ovarian tumor.

Prior radiotherapy to any portion of the abdominal cavity or pelvis 
Prior radiation for localized cancer of the breast, head and neck, or skin is 
permitted, provided that it was completed more than 3 years prior to 
randomization and the patient remains free of recurrent or metastatic disease.

Prior chemotherapy for any abdominal or pelvic tumor, including neoadjuvant 
chemotherapy for ovarian, primary peritoneal, or fallopian tube cancer.  
Patients may have received prior adjuvant chemotherapy for localized breast 
cancer, provided that it was completed more than 3 years prior to 
randomization and that the patient remains free of recurrent or metastatic 
disease. 

Any prior targeted therapy (including, but not limited to, vaccines, antibodies, or 
tyrosine kinase inhibitors) or hormonal therapy for management of their epithelial 
ovarian or peritoneal primary cancer 

Synchronous primary endometrial cancer, or a history of primary endometrial cancer
unless all of the following conditions are met: 
−
Stage not greater than Stage IB
−
No more than superficial myometrial invasion, without vascular or lymphatic 
invasion
−
No poorly differentiated subtypes, including papillary serous, clear cell, or other 
FIGO Grade 3 lesions

With the exception of nonmelanoma-related skin cancers and other specific 
malignancies as noted above, patients with other invasive malignancies who had (or 
have) any evidence of the other cancer present within the last 5 years or whose 
previous cancer treatment contraindicates study treatment

Prior or current treatment with any anti-angiogenic, including bevacizumab. 

Treatment with any other investigational agent or previous participation in another 
clinical trial within 30 days prior to randomization.
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
Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a 
positive hepatitis B surface antigen (HBsAg) test result at screening, with the 
following exception:
Patients with a past or resolved HBV infection, defined as having a negative 
HBsAg test result and a positive total hepatitis B core antibody (HBcAb) test 
result at screening, are eligible for the study if HBV DNA is negative or 
undetectable.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody 
test result and a positive HCV RNA test result at screening

A positive test result for HIV

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Current or recent (within 10 days prior to randomization) use of aspirin (325 mg/day) 
or other non-steroidal anti-inflammatory agents known to inhibit platelet function  

Serious non-healing wounds, ulcers, or bone fractures  
This includes history of abdominal fistula, GI perforation, or intra-abdominal 
abscess within 28 days prior to randomization.  Patients with granulating 
incisions healing by secondary intention with no evidence of fascial dehiscence 
or infection are eligible but require weekly wound examinations.  

Active bleeding or pathologic conditions that carry high risk of bleeding, such as 
known bleeding disorder, coagulopathy, or tumor involving major vessels 

History or evidence upon physical examination of CNS disease, including primary 
brain tumor, seizures not controlled with standard medical therapy, any brain 
metastases, or history of cerebrovascular accident (CVA; stroke), transient ischemic 
attack (TIA), or subarachnoid hemorrhage within 6 months of the first date of 
treatment on this study 

History of hypertensive crisis or hypertensive encephalopathy

Patients with clinically significant cardiovascular disease; this includes the following:
−
Uncontrolled hypertension, defined as systolic 150 mmHg or diastolic
90 mmHg
−
Myocardial infarction or unstable angina 6 months prior to randomization
−
New York Heart Association (NYHA) Class II or greater congestive heart failure 
(CHF)
−
Serious cardiac arrhythmia requiring medication (This does not include 
asymptomatic, atrial fibrillation with controlled ventricular rate.)
−
NCI CTCAE Grade 2 peripheral vascular disease (at least brief [ 24 hours] 
episodes of ischemia managed non-surgically and without permanent deficit)
−
History of CVA within 6 months prior to randomization

Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human or humanized antibodies
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
Have known sensitivity to any component of paclitaxel

Patients scheduled to undergo an invasive procedure as defined below: 
Major surgical procedure within 28 days prior to the first date of 
bevacizumab/placebo therapy (Cycle 2) or anticipated during the course of the 
study.  This includes, but is not limited to, abdominal surgery prior to disease 
progression, such as colostomy or enterostomy reversal, interval or secondary 
cytoreductive surgery, or second-look surgery. 
Core biopsy or other minor surgical procedures performed within 7 days prior to 
the anticipated first dose of bevacizumab/placebo therapy, with the following 
exception:
The interval of time between placement of a central vascular access device 
(CVAD) (e.g., Port-A-Cath®) and the first dose of bevacizumab for a patient 
must be no shorter than 2 days with a well-healed incision 

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 6 months after the last dose of bevacizumab, paclitaxel, or carboplatin, 
whichever is later
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to randomization.

Patients with clinical symptoms or signs of GI obstruction and who require parenteral 
hydration and/or nutrition

Evidence of any other disease, neurologic or metabolic dysfunction, physical 
examination finding, or laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of any of the study drugs, puts the patient at 
higher risk for treatment-related complications, or may affect the interpretation of 
study results

Requirement for treatment with any medicinal product that contraindicates the use of 
any of the study drugs, may interfere with the planned treatment, affects patient 
compliance, or puts the patient at high risk for treatment-related complications

History or evidence of thrombotic disorders within the last 6 months prior to 
randomization
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Randomization will be performed centrally using an interactive voice/Web response 
system (IxRS) that uses stratified block randomization.  After screening, patients who 
meet all eligibility criteria will be randomly assigned in a 1:1 ratio to one of two treatment 
groups:  bevacizumab or placebo.  
Randomization to treatment allocation will also be stratified by:

FIGO stage and debulking status (Stage III optimally debulked vs. Stage III 
suboptimally debulked vs. Stage IV) and

ECOG Performance Status (0 vs. 1 or 2)
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Stratification factors will ensure balance of these strong prognostic factors across 
treatment arms and facilitate unbiased estimate of treatment effect in subgroups based 
on disease severity and performance status.
The study is to be conducted in a double-blind manner to minimize potential bias. 
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS.  Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, he or she 
should contact the Medical Monitor directly.  The investigator should document and 
provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event).
As per health authority reporting requirements, the Sponsor will break the treatment 
code for all serious, unexpected suspected adverse reactions (see Section 5.7) that are 
considered by the investigator or Sponsor to be related to study drug.  The patient may 
continue to receive treatment, and the investigator and patient will remain blinded to 
treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are bevacizumab and 
matching placebo.
All eligible patients will receive a total of six cycles of carboplatin/paclitaxel (given Q3W)
with either bevacizumab or placebo. Bevacizumab/placebo must be initiated at Cycle 2, 
after completion of the six cycles of carboplatin/paclitaxel bevacizumab or placebo will 
be given as a single agent for a maximum of 16 cycles unless unacceptable toxicity or 
RECIST-defined disease progression occurs.
If bevacizumab/placebo treatment is discontinued “prematurely” because of 
unacceptable toxicity or patient refusal, chemotherapy may continue for a maximum of 
six cycles. Likewise, if any component of chemotherapy is discontinued prematurely 
because of toxicity, bevacizumab/placebo and the second component of chemotherapy 
treatment can continue.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Bevacizumab and Placebo
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and will bear a label with the identification required by local law, the protocol number, the 
drug identification, and the dosage.
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Bevacizumab/placebo will be provided as single-use, 400-mg and 100-mg vials 
containing a 25-mg/mL concentrate for solution for IV infusion.  Bevacizumab is provided 
in colorless glass vials with a butyl rubber stopper with aluminum seal and plastic flip-off 
disk.
Upon the receipt of bevacizumab, vials are to be refrigerated at 2C to 8C (36F to 46F) 
and should remain refrigerated until just prior to use.  DO NOT FREEZE.  DO NOT 
SHAKE.  Vials should be kept in their outer carton because of light sensitivity.
VIALS ARE FOR SINGLE USE ONLY.  Vials used for 1 patient may not be used for any 
other patient.  Vials should not be used after the retest date shown on the pack.
Chemical and physical in-use stability has been demonstrated for 48 hours at 22°C to 
30°C in 0.9% sodium chloride (NaCl) solution.  From a microbiological point of view, the 
product should be used immediately.  If not used immediately, in-use storage times and 
conditions are the responsibility of the user and would normally be no longer than 
24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated 
aseptic conditions.
Incompatibilities
No incompatibilities between bevacizumab and polyvinyl chloride or polyolefin bags have 
been observed.  Concentration-dependent changes in the ion-exchange 
chromatography profile were observed when bevacizumab was diluted with dextrose 
solutions (5%).  Therefore, bevacizumab should not be administered or mixed with 
dextrose or glucose solutions.
Stability
Bevacizumab should not be used after the retest date shown on the pack.
The labeling of bevacizumab/placebo will be in accordance with all local legal 
requirements and will be conducted according to Good Manufacturing Practice. As a 
minimum, labels will include the following information:

Bevacizumab/placebo 400 mg or 100 mg

FOR CLINICAL STUDY USE ONLY

F. HoffmannLa Roche Ltd

Investigator _______________

Protocol YO40268

Patient No. _______________

RO4876646/placebo

Store at 2°C8°C

Expiry date  _______________
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For further details, see Bevacizumab Investigator’s Brochure.
4.3.1.2
Chemotherapy (Carboplatin and Paclitaxel)
Sites will obtain and utilize commercially available carboplatin and paclitaxel. For 
information on the formulation and handling of carboplatin and paclitaxel, see the 
pharmacy manual and local prescribing information.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any overdose or incorrect administration of the study treatments should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF.
4.3.2.1
Timing and Sequence of Treatment Administration
The timing of treatment administration is shown in Appendix 1 and Table 2.  All of the 
study treatments are administered intravenously. The sequence of administration is as 
follows for all treatment arms:
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Table 2
Treatment Regimens and Order of Administration
Drug a
Dose and Route of 
Administration
Infusion Period
Cycle 1
Paclitaxel
175 mg/m2 IV

3 hours b
Carboplatin
AUC 6 mg/mL/min
IV b

Over approximately 30 minutes c
Cycles 26 (concurrent treatment)
Paclitaxel
175 mg/m2 IV

3 hours b
Carboplatin
AUC 6 mg/mL/min
IV b

Over approximately 30 minutes c
Bevacizumab or 
placebo
15 mg/kg IV

90 (15) minutes for the first dose 

60 (10) minutes for the second dose,
depending on patient tolerability of the first 
dose

30 (10) minutes for subsequent doses,
depending on patient tolerability of the 
second dose
Cycles 722 (maintenance treatment)
Bevacizumab or 
placebo
15 mg/kg IV
If the previous infusion of bevacizumab or 
placebo is well tolerated by the patient, then 
the infusion period may be reduced to 
30 (10) minutes for subsequent doses.
AUCarea under the concentrationtime curve.
Note:  Treatments should be administered in the order listed for each cycle.
a Institutional desensitization protocols may be implemented, if clinically indicated.
b Exceptions to the paclitaxel infusion time of 3 hours will be allowed for sites that have an 
institutional policy for infusion of paclitaxel more quickly (over 90 minutes) or more 
slowly (up to 4 hours for the first infusion).
c Per institutional standard, carboplatin should be administered immediately after the 
completion of the paclitaxel administration.
If scheduled dosing is precluded because of a holiday and/or weekend, then dosing may 
be postponed to the soonest following date, with subsequent dosing continuing on a 
21-day schedule.  If treatment was postponed for fewer than 3 days, the patient can 
resume the original schedule.
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4.3.2.2
Bevacizumab and Placebo
Bevacizumab will be administered at a dose of 15 mg/kg on Day 1 of each 21-day cycle.  
The initial dose of bevacizumab will be calculated on the basis of a patient’s weight at 
screening and will remain the same throughout the study unless the patient’s weight 
changes by 10% from the baseline body weight, in which case the bevacizumab dose 
should be modified.  Body weight will be re-baselined at the time of dose change, and
dose modifications should occur if the patient's weight changes 10% from the new 
baseline.
The calculated total dose of bevacizumab/placebo must be diluted in a total volume of 
100 mL of 0.9% NaCl solution, United States Pharmacopoeia (USP). In the event that a 
total dose exceeding 1000 mg is administered, dilute the calculated dose of 
bevacizumab/placebo with a sufficient amount of 0.9% NaCl solution to keep the final 
concentration at 1.416.5 mg/mL. Keep 100 mL as the minimal volume to administer 
and limit the infusion volume as much as possible. No incompatibilities between 
bevacizumab/placebo and polyvinylchloride or polyolefin bags have been observed. 
Bevacizumab/placebo should not be administered or mixed with dextrose solutions.
Discard any unused portion left in a vial, as the product contains no preservatives. The 
sterile, single-use vials contain no antibacterial preservatives. Therefore, vials should be 
discarded 8 hours after initial entry. Once diluted in 0.9% NaCl, solutions of 
bevacizumab/placebo must be administered within 8 hours.
Bevacizumab/placebo should be administered as a continuous IV infusion with use of a 
rate-regulating device. Do not administer as an IV push or bolus.
The initial dose of bevacizumab/placebo will be delivered over 90 (15) minutes.  If the 
first infusion is tolerated without any infusion-related adverse events (i.e., fever and/or 
chills), the second infusion may be delivered over 60 (10) minutes.  If the 60-minute 
infusion is well tolerated, all subsequent infusions may be delivered over 
30 (10) minutes.  Bevacizumab/placebo infusions may be slowed or interrupted for 
patients who experience infusion-related symptoms.  If infusion-related symptoms occur, 
patients should be treated in accordance with the best medical practice, and patients will 
be monitored until adequate resolution of signs and symptoms.
To ensure complete delivery of bevacizumab/placebo, the IV infusion line must be 
flushed with 0.9% NaCl. The two recommended methods for flushing the 
bevacizumab/placebo IV infusion line are as follows:

When the bevacizumab/placebo infusion has been completed, add an additional 
50 mL of 0.9% NaCl for injection to the bevacizumab/placebo infusion bag. Continue 
the infusion until a volume equal to that of the volume contained in the infusion line 
has been administered.
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
Replace the empty bevacizumab/placebo infusion bag with a 50 mL bag of 
0.9% NaCl for injection and infuse a volume equal to the volume contained in the 
infusion line.
Note: The additional volume used to flush the IV infusion line is not included in the 
recommended infusion times.
When extravasation of bevacizumab/placebo occurs during an infusion, it is 
recommended that the following action be taken:

Discontinue the bevacizumab/placebo infusion.

Treat the extravasation according to institutional guidelines for extravasation of a 
non-caustic agent.

If a significant volume of bevacizumab/placebo remains in the infusion bag, restart 
the infusion at a more proximal site ipsilaterally or on the contralateral limb.

Continue to observe the patient, document observations, and administer further 
treatment as required.
In the event of a suspected anaphylactic reaction during study drug infusion:

Stop the study drug infusion.

Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug. Do not obstruct arterial flow in the limb.

Maintain an adequate airway.

Administer antihistamines, epinephrine, or other medications as required.

Continue to observe the patient and document observations.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.4.2.
4.3.2.3
Carboplatin and Paclitaxel
The dose of carboplatin for this regimen is AUC 6 mg/mL/min in combination with 
paclitaxel 175 mg/m2 on Day 1 for a maximum of six cycles.
Investigators should follow their institution’s administration guidelines and local 
prescribing information for carboplatin and paclitaxel, in line with the suggested 
guidelines in Figure 1 and Section 5.1.4.3.1.  If there is a significant difference between 
the protocol guidelines and institutional standards of care, please call the Medical 
Monitor. For further details regarding administration, preparation, and storage, refer to 
local prescribing information for carboplatin and paclitaxel. 
In particular, all patients must be premedicated with corticosteroids, antihistamines, and 
H2-receptor antagonists before paclitaxel infusions are administered and in accordance 
with the product information and local institution guidelines.
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Carboplatin should be administered by IV infusion, immediately after the completion of 
paclitaxel administration, over a 30-minute time period to achieve an initial target AUC of 
6 mg/mL/min (Calvert formula dosing) with standard anti-emetic medications, per local 
practice guidelines.
The carboplatin dose of AUC 6 mg/mL/min will be calculated with the use of the Calvert 
formula (Calvert et al. 1989):
Calvert formula:
Total dose (mg)(target AUC)(glomerular filtration rate [GFR]25)
Note:  The GFR used in the Calvert formula to calculate AUC-based dosing should 
not exceed 125 mL/min.
For the purposes of this protocol, the GFR is considered to be equivalent to the 
creatinine clearance (CRCL).  The CRCL is calculated by institutional guidelines or by 
the method of Cockcroft and Gault (1976) with the use of the following formula:
CRCL 
(140age)(wt)
(0.85)
72Scr
Where:
CRCL creatinine clearance in mL/min
age patient's age in years 
wt patient’s weight in kg
Scr serum creatinine in mg/dL
Note:  For patients with an abnormally low serum creatinine level, estimate GFR 
with the use of a minimum creatinine level of 0.7 mg/dL or cap the estimated GFR at 
125 mL/min.
If a patient’s GFR is estimated on the basis of serum creatinine measurements by the 
isotope dilution mass spectroscopy method, the FDA recommends that physicians 
consider a cap on the dose of carboplatin for desired exposure to avoid potential toxicity 
due to overdosing.  On the basis of the Calvert formula described in the carboplatin label, 
the maximum doses can be calculated as follows:
Maximum carboplatin dose (mg)target AUC (mg min/mL)(GFR25 mL/min)
The maximum dose is on the basis of a GFR estimate that is capped at 125 mL/min for 
patients with normal renal function.  No higher estimated GFR values should be used.
For a target AUC6, the maximum dose is 6150900 mg
For a target AUC5, the maximum dose is 5150750 mg
For a target AUC4, the maximum dose is 4150600 mg
Refer to the FDA communication on carboplatin dosing for more details:  
https://ctep.cancer.gov/content/docs/carboplatin_information_letter.pdf
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Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.4.3.
Special Warnings and Precautions for Carboplatin and Paclitaxel 
Any contraindications and special warnings and precautions for the use of carboplatin 
and paclitaxel should be observed, and any medication(s) or therapy(ies)
contraindicated in the local prescribing information of carboplatin and paclitaxel are
contraindicated in patients receiving carboplatin and paclitaxel.
4.3.3
Additional Required Medication
4.3.3.1
Prophylactic Measures for Carboplatin
Carboplatin is considered moderately to highly emetogenic.  Therefore, appropriate 
anti-emetic non-steroidal medication (e.g., aprepitant) should be administered prior to 
the initiation of chemotherapy in accordance with the local practice and standard of care.
4.3.3.2
Premedication for Paclitaxel
All patients should be medicated prior to paclitaxel administration to prevent severe 
hypersensitivity reactions.  Prior to administration of paclitaxel, all patients will receive 
either according to institutional standard of care or the following premedication:

Dexamethasone 20 mg orally approximately 12 hours and 6 hours prior to the 
paclitaxel infusion
Patients may be treated with dexamethasone 10 mg to 20 mg IV within 1 hour 
prior to paclitaxel infusion if the patient did not take the oral dexamethasone.

Diphenhydramine 50 mg IV (or equivalent) 30 minutes to 60 minutes prior to 
paclitaxel infusion

Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent) 30 minutes to 60 minutes 
prior to paclitaxel infusion 
4.3.4
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (bevacizumab and placebo) will be 
provided by the Sponsor where required by local health authority regulations.  The study 
site will acknowledge receipt of IMPs using the Interactive-voice/Web-response system 
(IxRS) to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
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4.3.5
Continued Access to Bevacizumab
Currently, the Sponsor does not have any plans to provide bevacizumab or any other 
study treatments or interventions to patients who have completed the study.  The 
Sponsor may evaluate whether to continue providing bevacizumab in accordance with 
the Roche Global Policy on Continued Access to Investigational Medicinal Product, 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of 
study drug to the study completion/ discontinuation visit.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Anticoagulation
The use of full-dose oral or parenteral anticoagulants is permitted as long as 
the INR or aPTT is within therapeutic limits (according to the medical standard 
of the treating institution) and the patient has been on a stable dose of 
anticoagulants for at least 2 weeks at the start of study treatment. Prophylactic 
use of anticoagulation at baseline and during study treatment for the 
maintenance of patency of permanent indwelling central venous access devices 
is permitted. Prophylactic use of anticoagulation during study treatment for 
patients at high risk of venous thromboembolism is permitted. Bevacizumab or 
anticoagulation treatment will be stopped in case of:
−
Any evidence of tumor invading major blood vessels on any computed 
tomography (CT) scan
−
Any evidence of CNS metastases 
Because of a possible risk of bleeding during treatment with bevacizumab, 
patients should not take more than 325 mg of aspirin daily (or more than 75 mg 
of clopidogrel daily) at least until discontinuation of bevacizumab/placebo 
treatment.
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
at the discretion of the investigator.
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In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists).
Transfusions of blood and blood products, antibiotics, colony-stimulating factors, 
analgesia anti-emetic medications, etc., may be used according to local 
practice/institutional guidelines where appropriate.
If placing a CVAD between bevacizumab doses, placement must occur at least 14 days 
from the prior (i.e., pre-CVAD placement) bevacizumab dose, and at least 7 days from 
the following (i.e., post-CVAD placement) bevacizumab dose.
4.4.2
Cautionary Therapy
4.4.2.1
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. Herbal therapies are permitted before screening. Herbal therapies not 
intended for the treatment of cancer may be used during the study at the discretion of 
the investigator.
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authority approved or experimental, is prohibited for various 
time periods prior to initiation of the study treatment, depending on the agent (see
Section 4.1.2), and during study treatment until disease progression is documented 
and the patient has discontinued study treatment, except as outlined below.

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
during study treatment.

Reassessment (second-look surgery) or cytoreductive surgery
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.
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If scheduled study assessments cannot be obtained because of a holiday and/or 
weekend, these assessments should then be obtained at the soonest following date, 
provided that the soonest following date is not within the windows of scheduled study 
assessments.
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
Randomization of patients with confirmed eligibility should be performed within 3 days 
before the first dose of study treatment.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history,
and use of alcohol and drugs of abuse will be recorded at baseline.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 90 days prior to initiation of 
study treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at screening should include the 
measurement of weight and height, and an evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF.
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Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, temperature, and 
systolic and diastolic blood pressure while the patient is in a seated position.
Vital signs should be measured within 60 minutes prior to each study treatment infusion 
and as clinically indicated.  In addition, vital signs should be measured at other specified 
timepoints as outlined in the schedule of activities (see Appendix 1).
4.5.5
Tumor and Response Evaluations
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response will be assessed by the investigator using 
RECIST, Version 1.1 (RECIST v1.1) (see Appendix 2).
An initial CT scan (with oral or IV contrast) or magnetic resonance imaging (MRI) scan of 
at least the chest, abdomen, and pelvis is required to establish a postsurgical baseline 
for the extent of residual disease within 28 days prior to randomization (Scan 1). If a CT 
scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired 
renal clearance), a non-contrast CT scan of the chest may be performed and MRI scans
of the abdomen and pelvis should be performed.  A CT/MRI scan of the neck and/or 
head may also be performed if necessary.
Follow-up radiographic assessments of disease should use the same imaging modality 
and should encompass the same field as in the initial pre-treatment evaluation.  This 
should be repeated following the schedule below regardless of whether or not the patient 
has measurable disease on the initial CT or MRI scan.  All radiographic assessments will 
be performed according to the time interval (e.g., 9 weeks, 12 weeks, etc.) regardless of 
the treatment cycle (for more detail, see Appendix 1).  Imaging assessments should be 
discontinued if RECIST-defined disease progression is confirmed according to criteria.

Scans 2 and 3:  Every 9 weeks (5 days) from the date of randomization during the 
concurrent treatment phase

Scans 4, 5, 6, and 7:  Every 12 weeks (5 days) in the maintenance phase (the first 
scan in the maintenance phase is performed 12 weeks after the last scan during the 
concurrent treatment phase)

After the completion of all protocol therapy, every 3 months (14 days) for 2 years, 
then every 6 months (14 days) for 3 years.  
CT scans or MRIs after 5 years of survival follow-up may be performed as 
clinically indicated.
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
During or after completion of all study treatment, as clinically indicated at any time for 
clinical suspicion of progressive disease (PD)
Assessments should be performed by the same evaluator, if possible, to ensure internal 
consistency across visits. 
4.5.6
Laboratory, Biomarker, and Other Biological Samples
All laboratory sample collection and testing will be scheduled as indicated in Appendix 1.  
Additional assessments may be performed as clinically indicated.  Normal ranges for the 
local laboratory parameters must be supplied to the study Sponsors before the study 
starts.  It is recommended that the same units and normal ranges be used throughout 
the study; the investigator should notify the Sponsor of any updated reference range.
The total volume of blood loss for laboratory assessments will be approximately 20 mL
per cycle of therapy. 
Baseline laboratory assessments are performed within 14 days prior to initiating study 
treatment, except urinalysis, which should be performed within 7 days prior to study 
treatment initiation.  Any abnormalities that are discovered during patient assessment 
should be further investigated where clinically indicated to ensure that patients are fit to 
be included in the study and to receive study medication. 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells)

Chemistry panel (serum): sodium, potassium, glucose, blood urea nitrogen (BUN)
creatinine, albumin, bilirubin, AST, ALT, and ALP will be collected at baseline 
and subsequent visits as indicated in Appendix 1.

Coagulation: INR and aPTT should be assessed at baseline, during the study visit, 
and when clinically indicated or for monitoring patients who have to receive 
anticoagulants such as coumarin derivates or heparins (according to local standard).

HIV serology
All patients will be tested for HIV infection prior to inclusion into the study, and 
HIV-positive patients will be excluded from the clinical study.

HBV serology:  HBsAg, hepatitis B surface antibody, total HBcAb
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test should be performed at screening.  HBV DNA 
must be negative (i.e., undetectable) prior to randomization.
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
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must be performed to determine if the patient has an active HCV infection.

Pregnancy test
All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test at screening. Urine pregnancy tests 
will be performed as clinically indicated at subsequent visits.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or 
uterus).

Urinalysis, including pH, specific gravity, glucose, protein, ketones, blood and 
microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, 
bacteria) is required at baseline and all subsequent visits, followed by 24-hour urine 
collection in the event of proteinuria 2.

Serum CA125
4.5.7
Electrocardiograms
A 12-lead ECG is required at screening and as clinically indicated.  ECGs should 
be obtained on the same machine whenever possible.
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  
4.5.8
Patient-Reported Outcomes
To more fully characterize the clinical profile of bevacizumab, PRO data will be 
obtained through the use of the following instruments:  EORTC QLQ-C30 and its ovarian 
cancer module EORTC QLQ-OV28; FACT-G single item GP5; and EQ-5D-5L.
The PRO questionnaires, official Chinese versions in booklet format with a cover page, 
will be provided to sites to be distributed by the investigator staff and completed on 
paper by the patient in their entirety at the investigational site. To ensure instrument 
validity and that data standards meet health authority requirements, questionnaires must 
be completed by the patient at the start of the clinic visit before discussion of the 
patient's health state, laboratory results, or health record; before administration of study 
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treatment; and/or prior to the performance of any other study assessments that could 
bias patient's responses. If the patient is unable to complete the measure on her own, 
interviewer assessment is allowed but may only be conducted by a member of the clinic 
staff who reads the questionnaire items to the patient verbatim; no interpretation, 
rephrasing, or rewording of the questions is allowed during interview-assisted completion.
Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site, and the hard copy originals of the questionnaires must be 
maintained as part of the patient’s medical record at the site for source data verification. 
These originals should have the study patient number and date and time of completion 
at the top of each page as well as the respondent’s initials and date of completion at the 
bottom of each page in compliance with good clinical practice. Sites will enter patient 
responses to the PRO questionnaires into the electronic data capture (EDC) system. 
All patients will complete the questionnaires, beginning with the EORTC QLQ-C30, 
followed by the QLQ-OV28, FACT-G single item GP5, and then the EQ-5D-5L at 
timepoints corresponding with in-clinic visits, both while receiving study treatment and 
during the survival follow-up period. Refer to Appendix 1 for the frequency and timing of 
PRO assessments. 
4.5.8.1
EORTC QLQ-C30 and EORTC QLQ-OV28
The EORTC QLQ-C30 and its ovarian cancer module EORTC QLQ-OV28 are validated, 
reliable self-reported measures (Aaronson et al. 1993; Cull et al. 2001; 
Greimel et al. 2003) (see Appendix 4, and Appendix 5, respectively). The EORTC
QLQ-C30 consists of 30 questions that assess five aspects of patient functions (physical, 
emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and 
vomiting, and pain), global health and/or QoL, and six single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the 
previous week.  Scale scores can be obtained for the multi-item scales.
The EORTC QLQ-OV28 consists of 28 items that includes a multi-item scale that 
assesses abdominal and/or gastrointestinal symptoms, peripheral neuropathy, other 
chemotherapy side effects, hormonal symptoms, body image, attitudes toward disease 
and/or treatment, and sexuality of patients with local or advanced ovarian cancer who 
receive treatment by surgery with or without chemotherapy. The EORTC QLQ-C30 and 
the QLQ-OV28 module take approximately 20 minutes to complete.
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4.5.8.2
FACT-G Single Item GP5
The FACT-G, Version 4 (see Appendix 6), is a validated and reliable 27-item 
questionnaire comprised of four subscales that measure physical (7 items), social and 
family (7 items), emotional (6 items) and functional wellbeing (7 items) and is considered 
appropriate for use with patients with any form of cancer (Cella et al. 1993; 
Webster et al. 1999).  In this study, the single item GP5 (“I am bothered by side effects 
of treatment”) from the Physical Well-Being Subscale of the FACT-G has been selected 
for individual item analysis to document the level of bothersomeness of symptoms on 
patient’s lives.  Patients will assess how true the statement “I am bothered by side 
effects of treatment” has been for them in the previous 7 days on a five-point scale (0, 
not at all; 1, a little bit; 2, somewhat; 3, quite a bit; 4, very much). The single item GP5 
from the FACT-G takes less than a minute to complete.
4.5.8.3
EuroQol 5 Dimension, 5 Level
The EQ-5D-5L is a validated, self-reported health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) 
(see Appendix 7).  There are two components to the EQ-5D-5L:  a five-item health state 
profile that assesses mobility, self-care, usual activities, pain and discomfort, and anxiety
and depression, as well as a visual analogue scale that measures health state.  
Published weighting systems allow for the creation of a single composite score of the 
patient’s health status.  The EQ-5D-5L takes approximately 3 minutes to complete and 
will be utilized in this study to inform pharmacoeconomic evaluations, and, as such,
EQ-5D-5L data will not be included in the CSR.
4.5.9
Eastern Cooperative Oncology Group Performance Status
ECOG performance status will be assessed with the use of the ECOG Performance 
Scale as previously described (Pignata et al. 2014).
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment or the attributable portion of the 
study treatment regimen (bevacizumab, placebo, paclitaxel, and/or carboplatin) if they 
experience any of the following:

Intolerable toxicity related to study treatment that includes the development of an 
immune-related adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Any adverse event that requires study treatment discontinuation per the guidelines in 
Section 5.1

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient
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
Use of an anti-cancer therapy not required per protocol

Symptomatic deterioration attributed to disease progression

Confirmed disease progression per investigator assessment according to 
RECIST v1.1

Pregnancy
For patients that have urgent/emergency surgery, bevacizumab/placebo treatment 
should be interrupted. If the patient has healed well and has had no complications after 
surgery, bevacizumab/placebo treatment can be restarted based on the investigator’s
judgment. If in doubt, the investigator should contact and discuss with the Medical 
Monitor.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will return to the clinic for a treatment discontinuation visit 30 days after the 
last dose of study drug (see Appendix 1 for additional details). The visit during which 
response assessment shows progressive disease may be used as the treatment 
discontinuation visit.  
After discontinuation of all study treatments, physical examination, CA-125 assessments, 
and tumor response data, as well as information on survival follow-up and new 
anti-cancer therapy will be collected via telephone calls, patient medical records, and/or 
clinic visits according to the schedule of activities (see Appendix 1), unless the patient 
withdraws consent specifically for follow-up and/or surveillance or the Sponsor 
terminates the study.  If a patient requests to be withdrawn from follow-up and/or 
surveillance, this request must be documented in the source documents and signed by 
the investigator.  If the patient withdraws consent from the study that includes follow-up 
and/or surveillance, the study staff may nevertheless use a public information source 
(e.g., county records) to obtain only information about survival status.
4.6.2
Patient Discontinuation from Study
Patients will return to the clinic for a study discontinuation visit within 30 days after the 
last dose of the study treatment is administered.
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure
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
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. Patients 
who withdraw from the study will not be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonization (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety profile of bevacizumab plus carboplatin and paclitaxel has been well 
documented in several clinical trials that included patients with NSCLC and OC.  The 
anticipated important safety risks for bevacizumab are outlined below.  Please refer to 
the Bevacizumab Investigator's Brochure for a complete summary of safety information.
Measures will be taken to ensure the safety of patients who participate in this study, 
which includes the use of stringent inclusion and exclusion criteria and close monitoring 
of patients during the study.  Administration of bevacizumab will be performed in a 
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monitored setting in which there is immediate access to trained personnel and adequate 
equipment and medication to manage potentially serious reactions.  All adverse events 
will be reported as described in Sections 5.25.6.
5.1.1
Risks Associated with Bevacizumab
The most common side effects associated with bevacizumab include GI perforations, 
surgery and wound-healing complications, hemorrhage (severe or fatal hemorrhage that
includes hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, 
pulmonary hemorrhage, epistaxis, and vaginal bleeding), non-gastrointestinal fistula 
formation, arterial thromboembolic events (includes cerebral infarction, TIAs, myocardial 
infarction, angina), and hypertension.
For additional details regarding the safety profile of bevacizumab, refer to the 
Bevacizumab Investigator's Brochure.
5.1.2
Risks Associated with Paclitaxel
Paclitaxel is known to cause myelosuppression, alopecia, peripheral neuropathy, 
myalgia, arthralgia, nausea, and vomiting.  Less commonly reported adverse events are 
hypersensitivity reactions, infections, bleeding, diarrhea, mucositis, liver function test 
elevations, injection-site reactions, and cardiovascular effects such as hypotension, 
bradycardia, hypertension, arrhythmias, other ECG abnormalities, syncope, and venous 
thrombosis.
For more details with regard to the safety profile of paclitaxel, refer to the prescribing 
information for paclitaxel.
5.1.3
Risks Associated with Carboplatin
Carboplatin is known to cause bone marrow suppression, which includes
myelosuppression, anemia, and thrombocytopenia.  Carboplatin-based chemotherapy is 
considered to be moderately emetogenic.  
For more details with regard to the safety profile of carboplatin, refer to the prescribing 
information for carboplatin.
5.1.4
Management of Patients Who Experience Specific 
Adverse Events
5.1.4.1
Dose Modifications, Interruptions, and Delays
In order to maintain dose-intensity and cumulative dose-delivery in this study, 
reasonable efforts will be made to minimize dose reduction and treatment delays as 
specified.  Any patient whose treatment is delayed must be evaluated on a weekly basis 
until adequate hematologic and non-hematologic parameters have been met.  No dose 
escalation is planned for this study.
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Carboplatin and paclitaxel and bevacizumab/placebo must be given on the same day; 
hence delays in carboplatin and paclitaxel should result in delay of bevacizumab/placebo 
as well, until they can all be given safely.  Alternatively, if it is not safe to proceed with 
bevacizumab/placebo, bevacizumab/placebo should be held and omitted, and treatment 
with carboplatin and paclitaxel should proceed.  There is no delay plan in the 
bevacizumab/placebo-only treatment phase. When it is not safe to proceed with 
bevacizumab/placebo, bevacizumab/placebo should be omitted.  The option to re-start 
bevacizumab/placebo in the next cycle will depend on the patient’s situation and the 
investigator’s judgment. In the event that bevacizumab/placebo is omitted for more than 
two consecutive administrations (6 weeks), restarting bevacizumab/placebo treatment 
must be discussed with the Medical Monitor. 
5.1.4.2
Management of Adverse Events Related to 
Bevacizumab/Placebo
Dose reductions of bevacizumab/placebo for adverse events are not allowed.  Criteria 
for treatment modifications and guidelines for the management of toxicities are 
summarized in Table 3.  If adverse events occur that necessitate withholding 
bevacizumab/placebo from patients, the dose will remain unchanged once treatment 
resumes.
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Table 3
Bevacizumab Dose Management for Adverse Events
Event
Action to Be Taken
Hypertension
Grade 1
(prehypertension [systolic BP 120139 mm 
Hg or diastolic BP 8089 mm Hg])
No bevacizumab dose modifications.
Consider increased BP monitoring; start 
anti-hypertensive medication if appropriate.
Grade 2
(Stage 1 hypertension [systolic BP 
140159 mm Hg or diastolic BP 
9099 mm Hg]; medical intervention 
indicated; recurrent or persistent [24 hrs]; 
symptomatic increase by >20 mm Hg 
[diastolic] or to >140/90 mm Hg if 
previously WNL; monotherapy indicated)
Withhold bevacizumab.  Start 
antihypertensive therapy.  Once blood 
pressure is 150/100 mmHg, patient may 
continue bevacizumab therapy.
Grade 3
(Stage 2 hypertension [systolic BP 
160 mm Hg or diastolic BP 100 mm Hg]; 
medical intervention indicated; more than 
one drug or more intensive therapy than 
previously used indicated)
More than one antihypertensive drug or more 
intensive therapy than previously required:  If 
not controlled to 150/100 mmHg with 
medication, discontinue bevacizumab
Grade 4
(life-threatening consequences 
[e.g., malignant hypertension, transient or 
permanent neurologic deficit, hypertensive 
crisis]; urgent intervention indicated)
Discontinue bevacizumab
Hemorrhage
Grade 1 or Grade 2
(nonpulmonary-related or nonCNS-related 
event)
No bevacizumab modifications
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Table 3
Bevacizumab Dose Management for Adverse Events (cont.)
Event
Action to Be Taken
Hemorrhage (cont.)
Grade 3
(non-pulmonary or non-brain or non-spinal 
cord hemorrhage)
Withhold bevacizumab until all of the following 
criteria are met:

The bleeding has resolved, and 
hemoglobin is stable.

There is no bleeding diathesis that would 
increase the risk of therapy.

There is no anatomic or pathologic 
condition that significantly increases the 
risk of hemorrhage recurrence.
Patients who experience a repeat Grade 3 
hemorrhagic event will be discontinued from 
bevacizumab.
Grade 4
(non-pulmonary or non-brain or non-spinal 
cord hemorrhage)
Discontinue bevacizumab
Grade 1 (pulmonary or brain or spinal cord 
hemorrhage)
Withhold bevacizumab until all of the following 
criteria are met:

The bleeding has resolved, and 
hemoglobin is stable.

There is no bleeding diathesis that would 
increase the risk of therapy.

There is no anatomic or pathologic 
condition that significantly increases the 
risk of hemorrhage recurrence.
Grade 2, Grade 3, or Grade 4
(pulmonary or brain or spinal cord 
hemorrhage)
Discontinue bevacizumab
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Table 3
Bevacizumab Dose Management for Adverse Events (cont.)
Venous thromboembolic event
Grade 1 or 2
No bevacizumab modifications
Grade 3 or asymptomatic Grade 4
If the planned duration of full-dose 
anticoagulation is 2 weeks, bevacizumab 
should be withheld until the full-dose
anticoagulation period is over
If the planned duration of full-dose 
anticoagulation is 2 weeks, bevacizumab 
may be resumed after 2 weeks of full-dose 
anticoagulation if all of the following criteria are 
met:

The patient must have an in-range INR 
(between 2 and 3) if on warfarin, low 
molecular weight heparin, or other 
anticoagulant dosing must be stable prior 
to re-initiation of the study treatment.

The patient must not have had a Grade 3 
or Grade 4 hemorrhagic event while on 
anticoagulation.
Symptomatic Grade 4
Discontinue bevacizumab
Arterial thromboembolic event
(new onset, deteriorating, or unstable angina, myocardial infarction, TIA, 
cerebrovascular accident, and any other arterial thromboembolic event)
Any grade
Discontinue bevacizumab
Congestive heart failure
(left ventricular systolic dysfunction)
Grade 1 or Grade 2
No bevacizumab modifications
Grade 3
Discontinue bevacizumab
Grade 4
Discontinue bevacizumab
Proteinuria a
Grade 1
(1+ proteinuria; urinary protein 
<1.0 g/24 hrs)
No bevacizumab modifications
Grade 2
(2+ proteinuria; urinary protein 
1.03.4 g/24hrs)
For 2 dipstick, may administer bevacizumab 
and obtain 24-hr urine prior to next dose.
For 3 dipstick, obtain 24-hour urine prior to 
administration of bevacizumab, withhold 
bevacizumab for proteinuria 2 g/24 hr and 
resume when proteinuria is 2 g/24 hr. a
Grade 3 
(urinary protein 3.5 g/24 hrs)
Withhold bevacizumab.  Resume when 
proteinuria is 2 g/24 hr. a
Nephrotic syndrome
Discontinue bevacizumab
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Table 3
Bevacizumab Dose Management for Adverse Events (cont.)
Gastrointestinal perforation
Any grade
Discontinue bevacizumab
Fistula
Any grade tracheoesophageal fistula
Discontinue bevacizumab
Grade 4 fistula (other than 
tracheoesophageal)
Discontinue bevacizumab
Bowel obstruction
Grade 1
Continue patient in the study for partial 
obstruction that does not require medical 
intervention.
Grade 2
Withhold and resume at investigator/Medical 
Monitor discretion after complete resolution. 
Restart no sooner than 28 days after surgical 
intervention and complete resolution of 
post-surgical wound at investigator/Medical 
Monitor discretion.
Wound dehiscence
Any grade
(requires medical or surgical therapy)
Discontinue bevacizumab
Reversible posterior leukoencephalopathy
Any grade
(confirmed by magnetic resonance imaging)
Discontinue bevacizumab
a All proteinuria values are from 24-hour urine collection. Institutional protocols are acceptable.
Temporary suspension of bevacizumab/placebo must occur if a patient experiences a 
serious adverse event or a Grade 3 or Grade 4 adverse event as assessed by the 
investigator to be related to bevacizumab/placebo.  If the event resolves to Grade 1, 
bevacizumab/placebo may be reinitiated at the same dose level.  If 
bevacizumab/placebo is delayed due to toxicity for 42 days beyond when the next dose 
should have been given, restarting bevacizumab/placebo treatment must be discussed 
with Medical Monitor. 
The appropriate interval between the last dose of bevacizumab/placebo and major 
surgery is unknown.  Because bevacizumab has a half-life of approximately 21 days, 
elective surgery should be delayed whenever possible, but if necessary, 
bevacizumab/placebo should be withheld for 28 days prior to the procedure. 
Emergency surgery should be performed as appropriate without delay after a careful 
benefit-risk assessment. Reinitiation of bevacizumab after surgery should not occur for 
28 days, and until wounds have fully healed.  Reinitiation of bevacizumab after surgery 
requires documented approval from the Medical Monitor.
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Infusion of bevacizumab/placebo should be interrupted in patients who develop dyspnea 
or clinically significant hypotension.  Patients who experience an NCI CTCAE Grade 3 or 
Grade 4 allergic reaction and/or hypersensitivity, adult respiratory distress syndrome, or 
bronchospasm (regardless of grade level) will be discontinued from 
bevacizumab/placebo treatment.  If possible, a sample for ADA assessment will be 
collected at the time of discontinuation.
Bevacizumab/placebo infusion should be slowed to 50% or interrupted for patients who 
experience any infusion-associated symptoms not specified above.  If the infusion is 
interrupted, it may be resumed at 50% of the rate prior to the reaction after the patient’s 
symptoms have adequately resolved, and increased in 50% increments up to the full 
rate if well tolerated.  Infusions may be restarted at the full rate during the next cycle.
For guidelines on the dosing of other study drugs when bevacizumab/placebo is withheld, 
see Table 4.
5.1.4.3
Management of Adverse Events Related to 
Carboplatin/Paclitaxel
The dose for this regimen is carboplatin AUC 6 mg/mL/min with paclitaxel 175 mg/m2 on 
Day 1 for a maximum of six cycles.
Investigators should follow their institution’s administration guidelines for carboplatin and 
paclitaxel and local prescribing information for carboplatin and paclitaxel.  For further 
details of administration, preparation, and storage, refer to the pharmacy manual and 
local prescribing information for carboplatin and paclitaxel.  Carboplatin-based 
chemotherapy is considered to be highly emetogenic, and the appropriate anti-emetic 
prophylaxis should be administered.
5.1.4.3.1
Carboplatin and Paclitaxel Dose Modifications
Dose levels of carboplatin and paclitaxel are shown in Table 4.
Table 4
Dose Levels of Chemotherapy
Drug
Starting Dose Level
Dose Level 1
Dose Level 2
Carboplatin
AUC 6 mg/mL/min
AUC 5 mg/mL/min
AUC 4 mg/mL/min
Paclitaxel
175 mg/m2
135 mg/m2
110 mg/m2
AUCarea under the concentrationtime curve.
5.1.4.3.2
Hematologic Toxicity
Treatment decisions will be based on the ANC rather than total WBC.  ANC must 
be 1,500/mm3 and platelet count must be 10,0000/mm3 on Day1 of each cycle.
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5.1.4.3.2.1
Dose Modification 
Initial occurrence of dose-limiting toxicity neutropenia (DLT ANC) or dose-limiting toxicity 
thrombocytopenia (DLT PLT) will be handled according to Table 5.
DLT ANC is defined by the occurrence of febrile neutropenia or prolonged Grade 4 
neutropenia persisting for 7 days.  There will be no modifications for uncomplicated 
Grade 4 neutropenia lasting less than 7 days.  Febrile neutropenia is defined according 
to the NCI CTCAE as fever with or without clinically or microbiologically documented 
infection with ANC 1000/mm3 and fever 38.5°C.  DLT PLT is defined by any 
occurrence of Grade 4 thrombocytopenia (25,000/mm3) or bleeding associated with 
Grade 3 thrombocytopenia (25,000 to50,000/mm3).  There will be no modifications for 
uncomplicated Grade 3 thrombocytopenia.
Table 5
Modification Instructions for DLT Hematologic Toxicity
DLT 
ANC
DLT 
PLT
First Occurrence
Second Occurrence
Yes
No
Reduce carboplatin to AUC 
5 mg/mL/min (and paclitaxel to
135 mg/m2)
Add G-CSF and maintain all current drug 
doses
Yes
Yes
Reduce carboplatin to AUC 
5 mg/mL/min (and paclitaxel to
135 mg/m2)
Add G-CSF and decrease carboplatin to 
AUC 4 mg/mL/min (and paclitaxel to
110 mg/m2)
No
Yes
Reduce carboplatin to AUC 
5 mg/mL/min (and paclitaxel to
135 mg/m2)
Decrease carboplatin to AUC 4 mg/mL/min
(and paclitaxel to 110 mg/m2)
AUC area under the curve; DLT ANC dose-limiting neutropenia; DLT PLT dose-limiting 
thrombocytopenia; G-CSF granulocyte colony-stimulating factor.
All dose reduction for the first episode of DLT ANC and DLT PLT are permanent. If a 
second episode of DLT ANC and DLT PLT requiring dose reduction occurs, the doses of 
carboplatin will be reduced to AUC 4 mg/mL/min. For patients who require a third dose 
reduction, chemotherapy should be immediately discontinued.
5.1.4.3.2.2
Treatment Delay
Treatment should be delayed if either of the following occurs within 24 hours prior to 
scheduled therapy: ANC is 1500/mm3 (or 1000/mm3 if the patient is receiving or is 
planned to receive G-CSF) or the platelet count is10,0000/mm3. 
Full blood counts (including differential WBC counts) should be repeated at least weekly 
until hematological recovery has occurred.  If hematological recovery occurs within 
7 days, no dose modification is mandated.  If hematological recovery occurs in 
7 to 21 days, for an abnormal ANC, G-CSF should be added with the next cycle; for 
patients with platelet count decrease, carboplatin should be decreased one AUC unit.
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However, if the ANC and platelet counts have not recovered in 3 weeks, the patient’s 
chemotherapy should be discontinued. 
Investigators should be vigilant and alert to early and overt signs of 
myelosuppression/infection/febrile neutropenia so that these complications can be 
promptly and appropriately managed.
Patients should be made aware of these signs and encouraged to seek medical 
attention at the earliest opportunity. 
No dose reductions will be made for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines.
5.1.4.3.3
Hepatic Toxicity (Paclitaxel)
The Day 1 value should be used to determine the dose (see Table 6).
Table 6
Paclitaxel Dose Level for Different Hepatic Values
AST
Bilirubin
Paclitaxel Dose to Give
5 ULN
And
WNL
175 mg/m2
5 ULN
Or
ULN 1.5 ULN
135 mg/m2
1.5 ULN
0
AST aspartate aminotransferase; ULN upper limit of normal; WNL within normal limit.
If paclitaxel is withheld because of hepatic toxicity, carboplatin should also be withheld 
and administered when paclitaxel is resumed.  If paclitaxel is withheld, hepatic values 
must recover within 3 weeks, or the patient’s paclitaxel treatment should be discontinued.  
No dose reductions for carboplatin should be made for hepatic toxicity.
The investigator should make all efforts to exclude malignant disease progression as a 
cause of liver enzyme derangement.  All study medication should be discontinued if the 
disease under investigation has progressed.
5.1.4.3.4
Cardiovascular Toxicity (Paclitaxel)
Cardiac rhythm disturbances have occurred infrequently in patients in clinical trials with 
paclitaxel treatment; however, most patients were asymptomatic, and cardiac monitoring 
is not required.  Transient asymptomatic bradycardia has been noted in as many as 29% 
of patients.  More significant atrioventricular block has rarely been noted.  Cardiac 
events should be managed as follows:

Asymptomatic bradycardia:  Report as an adverse event.

Symptomatic arrhythmia during infusion:  Stop paclitaxel infusion and manage 
arrhythmia according to standard practice.  Paclitaxel treatment will be discontinued.  
Report as an adverse event.
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
Chest pain and/or symptomatic hypotension (90/60/mmHg or requires fluid 
replacement): Stop paclitaxel infusion.  Perform an ECG.  Give IV diphenhydramine 
and dexamethasone if hypersensitivity is considered.  Also consider epinephrine or 
bronchodilators if chest pain is not thought to be cardiac in origin.  Report as an 
adverse event.  Paclitaxel treatment will be discontinued, and cardiovascular support 
should be given as appropriate.  If appropriate, the advice of a cardiologist should 
also be sought.
5.1.4.3.5
Neurologic Toxicity (Paclitaxel)
Severe peripheral neuropathy requires reduction of one dose level in paclitaxel and 
delay in all subsequent study treatment for a maximum of 3 weeks until recovery to 
Grade 1. If peripheral neuropathy does not recover to Grade 1 by a maximum delay of 
3 weeks from the time therapy is scheduled, the patient’s chemotherapy should be 
discontinued.
5.1.4.3.6
Allergic Reaction/Hypersensitivity (Paclitaxel)
CAUTION:  Patients who had a mild to moderate hypersensitivity reaction have been 
successfully rechallenged, but the administration of prophylactic medication (see below) 
and intensive monitoring of vital signs is recommended.
In general, the occurrence of a hypersensitivity reaction to paclitaxel, carboplatin, or 
bevacizumab/placebo is not considered a DLT. Patients may be retreated at full doses 
after administration of medication to prevent hypersensitivity reactions, and adjustments 
in infusion rates should be made. However, if despite these safety measures, repeat 
attempt at infusion of the inciting drug results in a recurrent hypersensitivity reaction, the 
inciting drug should be discontinued for the remainder of the study. In the event of any 
Grade 3 or 4 allergic or infusional reaction to bevacizumab / placebo, 
bevacizumab/placebo will be permanently discontinued.  Allergic 
reaction/hypersensitivity events should be managed as follows:

Mild symptoms:  Complete paclitaxel infusion.  Supervise at bedside. 

Moderate symptoms:  Stop paclitaxel infusion.  Give IV diphenhydramine 25 to 50 
mg and IV dexamethasone 10 mg.  Resume paclitaxel infusion, after recovery of 
symptoms, at a low rate, 20 mL/hr for 15 minutes, and then 40 mL/hr for 15 minutes, 
then if no further symptoms, at full-dose rate until infusion is complete.  Report as an 
adverse event.  If symptoms recur, stop paclitaxel infusion.  Paclitaxel treatment 
should be discontinued.

Severe life-threatening symptoms:  Stop paclitaxel infusion.  Give IV
diphenhydramine and dexamethasone as above.  Add epinephrine or 
bronchodilators if indicated.  Report as an adverse event.  Paclitaxel treatment 
should be discontinued.
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5.1.4.3.7
Other Toxicities
There will be no dose modifications for alopecia, nausea, constipation, or diarrhea.  It is 
recommended that routine medical measures be employed to manage nausea, 
constipation, and diarrhea. 
Potential modifications for other non-hematologic toxicities with an impact on organ 
function of Grade 2 require discussion with the Medical Monitor or his or her designee 
except where noted below.
For any Grade 3 non-hematologic adverse event (except controllable nausea/emesis) 
considered to be at least possibly related to study treatment, study treatment should be 
held until symptoms resolve to Grade1 or better.  If a Grade 3 adverse event persists for 
more than 3 weeks or recurs after resumption of therapy, the patient may be 
discontinued from study treatment after consulting with the Medical Monitor or his or her 
designee.
For any Grade 4 non-hematologic adverse event (except controllable nausea or emesis), 
the patient may be discontinued from study treatment after consulting with the Medical 
Monitor or his or her designee.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline
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
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Grade 3 hypertension 

Grade 3 proteinuria

Any grade GI perforation, abscess, or GI fistulae

Grade 2 nonGI-related fistula or abscess

Tracheoesophageal fistula

Grade 3 wound-healing complication

Hemorrhage
Any grade CNS bleeding
Grade 2 hemoptysis
Other Grade 3 hemorrhagic event

Any grade arterial thromboembolic event

Grade 3 venous thromboembolic event

Any grade posterior reversible encephalopathy syndrome

Grade 3 congestive heart failure
These events may or may not be serious adverse events, and they may or may not be 
considered related to study medication. Regardless of relationship or severity, these 
events will be followed for 6 months after the last study treatment or until resolution.
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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After the initiation of the study treatment, all adverse events will be reported until 30 days 
after the last dose of the study treatment is administered or until the initiation of a new 
anti-cancer therapy, whichever occurs first.  Serious adverse events and adverse events 
of special interest will continue to be reported until 90 days after the last dose of the 
study treatment was administered or until the initiation of a new anti-cancer therapy, 
whichever occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
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Table 7
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also
Table 8):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
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Table 8
Causal Attribution Guidance
Is the adverse event suspected to be caused by study treatment on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained 
by the patient's clinical state, intercurrent illness, or concomitant therapies; and/or 
the adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified 
below.  
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, avoid 
ambiguous terms such as "systemic reaction."  Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient experiences 
both a local and systemic reaction to the same dose of study drug, each reaction should 
be recorded separately on the Adverse Event eCRF, with signs and symptoms also 
recorded separately on the dedicated Infusion-Related Reaction eCRF.
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5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated by 
changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
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A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)
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
Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with 
clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see
Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of ovarian, fallopian tube, or primary peritoneal cancer
should be recorded on the Death Attributed to Progressive Disease eCRF.  All other 
deaths that occur during the adverse event reporting period, regardless of relationship to 
study drug, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section 5.4.2). An independent monitoring committee will monitor the 
frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
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concept on the Adverse Event eCRF.  Generally, one such event should be reported
only.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Ovarian, Fallopian Tube, 
or Primary Peritoneal Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration, 
insertion of access device for study drug administration or the performance of an 
efficacy measurement for the study)
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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease.
The patient has not experienced an adverse event.

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
The highest dose of bevacizumab tested in human patients (20 mg/kg of body weight 
every 2 weeks administered by IV infusion) was associated with severe migraine in 
several patients.
Carboplatin was administered in Phase I studies at a dosage of up to 1600 mg/m2 by 
IV per course. At this dosage, life-threatening hematological side effects with 
granulocytopenia, thrombocytopenia, and anemia were observed in the study patients. 
See the Carboplatin Package Insert for more details.
There is no known antidote for paclitaxel overdose. Treatment should be directed at the 
primary anticipated toxicities, which consist of bone marrow suppression. See Paclitaxel 
Package Insert for more details. 
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.
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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Medical Monitor/Roche Medical Responsible:  
 M.D., Ph.D. (Primary)
Telephone No.:  
Mobile Telephone No.: 
Medical Monitor/Roche Medical Responsible:  
, M.D., M.S. (Secondary)
Telephone No.:  
Mobile Telephone No.:  
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
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calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
EDC system.  A report will be generated and sent to Roche Safety Risk Management by 
the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 90 days after the last dose 
of study treatment are provided in Section 5.6.
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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 6 months after the last 
dose of bevacizumab, paclitaxel, or carboplatin, whichever is later.  A Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study treatment and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study
treatment should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
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5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 90 days after the last 
dose of any study treatment), all deaths, regardless of cause, should be reported 
through use of the Long-Term Survival Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Bevacizumab Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Analysis populations are defined as follows:

The intent-to-treat (ITT) population is defined as all randomized patients regardless 
of whether the assigned study treatment was received.  For efficacy analyses, 
patients will be analyzed according to their randomized treatment assignment. 

Objective response rate (ORR) will be analyzed in patients in the ITT population with 
measurable disease at baseline.

The duration of response (DOR) evaluable population is defined as patients with an 
objective response.

The PRO-evaluable population is defined as patients in the ITT population with a
baseline and 1 post-baseline PRO assessment.

The safety population is defined as patients who received any amount of any 
component of the study treatments (bevacizumab, paclitaxel or carboplatin).  
Patients will be allocated to treatment arms according to the treatment they actually 
received (i.e., patients randomized to placebo chemotherapy alone who received at 
least one full or partial dose of bevacizumab will be included in the 
bevacizumabchemotherapy arm for safety).
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of study treatment.
6.1
DETERMINATION OF SAMPLE SIZE
The purpose of this study is to confirm the efficacy and safety of bevacizumab in a 
population of Chinese women with advanced ovarian, fallopian tube, and primary 
peritoneal cancers who have not received prior chemotherapy for this disease, and to 
investigate the consistency in treatment effect between Chinese patients and the 
patients in global study for the purpose of registration in China. The primary efficacy 
results will be bridged with those of the pivotal Study GOG218.
A total of approximately 100 patients will be randomized in a 1:1 ratio to either the 
bevacizumab or placebo arms of the study. The final analysis of the primary endpoint of 
PFS will be performed when approximately 56 PFS events have occurred in the ITT 
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population (56% of 100 patients), which will provide an 80% probability of demonstrating 
consistency with the global study.
The calculation is based on the following assumptions: 

Median PFS is 18.2 months for the bevacizumab arm and 12 months for the placebo 
arm (hazard ratio [HR]0.624)

Enrollment rate is 9.6 patients per month

5% yearly dropout rate
On the basis of the above assumptions, the required number of PFS events for the final
analysis is projected to occur at approximately 24 months after the first patient is 
randomized.
The study is not powered to demonstrate statistical significance of treatment benefit on 
the primary and secondary efficacy endpoints.  Because no formal hypothesis testing will 
be performed, no type I error adjustment for multiple comparisons will be made.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized by treatment arm for the ITT population.  Reasons for premature study 
withdrawal will be summarized.  Enrollment and major protocol deviations will be 
reported and summarized by treatment arm for the ITT population.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, race/ethnicity, baseline 
disease characteristics, etc.) will be summarized using means, standard deviations, 
medians, and ranges for continuous variables and proportions for categorical variables, 
as appropriate.  Summaries will be presented by treatment arm for the ITT population.
6.4
EFFICACY ANALYSES
The primary and secondary efficacy endpoints will be analyzed for the ITT population
unless specified otherwise, with patients grouped according to their assigned treatment.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is PFS, which will be assessed by the investigator using 
RECIST v1.1.  The study is not fully powered for the primary endpoint; instead 
consistency with the global pivotal study (GOG218) will be considered for the primary 
endpoint.
PFS after randomization is defined as the time from randomization to the first 
documented occurrence of disease progression or death from any cause during the 
study (whichever occurs first), as determined by the investigator according to 
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RECIST v1.1. Data for patients who have not experienced disease progression or death 
will be censored at the last tumor assessment.  Data for patients with no post-baseline 
tumor assessment will be censored at the date of randomization plus 1 day.
The primary endpoint of PFS will be analyzed between treatment and control arms
based on the stratified log-rank test. The HR of PFS in the experimental arm compared 
with the control arm will be estimated using a stratified Cox regression model, and the 95% 
CI will be provided. The stratification factors will be those used during randomization, as 
recorded in eCRF. Results from an unstratified analysis will also be presented. 
Kaplan-Meier methodology will be used to estimate median PFS for each treatment arm, 
and Kaplan-Meier curves will be constructed to provide visual descriptions of the 
difference between the treatment and control arms.
The Brookmeyer-Crowley methodology will be used to construct the 95% CI for the 
median PFS and OS for each treatment arm (Brookmeyer and Crowley 1982).
6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Overall Survival
OS is defined as the time from randomization to death from any cause. Data for patients 
who are not reported as having died at the date of analysis will be censored at the date 
when they were last known to be alive.  Data for patients who do not have post-baseline 
information will be censored at the date of randomization plus 1 day.
The methodologies detailed for the PFS analysis will be used for the OS analysis in the 
ITT population.
6.4.2.2
Objective Response Rate (ORR)
An objective response is defined as either a CR or PR, as determined by the investigator 
according to RECIST v1.1. Patients who do not meet these criteria, including patients 
without any post-baseline tumor assessment, will be considered non-responders.
ORR is defined as the proportion of patients who had an objective response.  The 
analysis population for ORR will be all patients in the ITT population with measurable 
disease at baseline.  An estimate of ORR and its 95% CI will be calculated using the 
Clopper Pearson method for each treatment arm.  CIs for the difference in ORRs 
between the two treatment arms will be determined using the normal approximation to 
the binomial distribution.
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6.4.2.3
Duration of Response
DOR will be assessed in patients who had an objective response as determined by the 
investigator by use of RECIST v1.1. DOR is defined as the time from the first 
occurrence of a documented objective response to disease progression or death from 
any cause during the study (whichever occurs first), as determined by the investigator 
according to RECIST v1.1. Patients who have not progressed and who have not died at 
the time of analysis will be censored at the time of last tumor assessment date.  DOR is 
based on a non-randomized subset of patients (specifically, patients who achieved an 
objective response), and formal hypothesis testing will not be performed for this endpoint.  
Comparisons between treatment arms will be made for descriptive purposes.  The 
methodologies detailed for the PFS analysis will be used for the DOR analysis.
6.4.2.4
Patient-Reported Disease Symptoms, Function and Health-
Related Quality of LifeEORTC Data
Patient-Reported Abdominal Pain or BloatingEORTC QLQ-OV28
The primary patient-reported outcomes endpoint of the proportion of patients in each 
arm who report a clinically meaningful improvement in patient-reported abdominal pain 
or bloating, defined as a 10-point decrease from the baseline score on each of two 
items from the EORTC QLQ-OV28 abdominal/gastrointestinal symptom scale (Items 31 
and 32), will be summarized at each post-baseline timepoint by treatment arm, with its 
95% CI, with the use of Clopper Pearson method.  The difference in proportions will be 
provided, with its 95% CI, with the use of the Hauck-Anderson method.
Prespecified subgroup analysis will also be performed in patients with ascites at baseline 
(who typically have significantly impaired HRQoL) and in patients with sufficient 
symptoms at baseline to allow detection of a 10-point improvement in a given symptom 
score. 
The definition of improvement in patient-reported abdominal pain or bloating 
(i.e., a 10-point decrease from the baseline score in QLQ-OV28 abdominal symptom 
items) is based on the standard analysis method for the EORTC QLQ-C30 that deems a 
score change of 10 points on any item or scale to be clinically meaningful (Osoba et al. 
1998; Fayers 2001a; Osoba 2002; Osoba et al. 2005; Brundage et al. 2007; Luckett et al. 
2010; Cocks et al. 2011).  Although the clinical meaningfulness of a 10-point change 
was established based on the EORTC QLQ-C30, the disease-specific modules, 
including the QLQ-OV28, were designed on the same structure using the same rating 
scale and are, therefore, applicable in this context.  Additionally, other OC studies have 
used the 10-point minimally important difference (MID) threshold for the QLQ-OV28, 
demonstrating that a change of this magnitude is significant to patients with OC while 
setting a precedent for its use and supporting its utility in this context (Richter et al. 2012; 
Brotto et al. 2016; Fagotti et al. 2016).
A sensitivity analysis will be performed to evaluate the robustness of the published 
standard threshold for meaningful change of 10-points with the use of the raw data for 
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the abdominal pain and bloating items of the EORTC QLQ-OV28.  The proportion of 
patients in each arm reporting a 1-category decrease on each of the 4-point symptom 
scales of the EORTC QLQ-OV28 abdominal symptom items (Items 31 and 32) will be 
summarized at each post-baseline timepoint by treatment arm.  All analyses of the 
abdominal symptoms single item data that involve the 10-point MID will be replicated 
with this alternate MID threshold.
Patient-Reported Function and HRQoL: EORTC QLQ-C30
For the additional secondary PRO endpoint, the proportion of patients in each arm who 
report a clinically meaningful improvement in patient-reported function and HRQoL, 
defined as a 10-point increase from the baseline score on each of the functional 
(physical, role, emotional, and social) and global health status and/or HRQoL scales of 
the EORTC QLQ-C30, will be summarized at each post-baseline timepoint by treatment 
arm as specified above.
6.4.3
Exploratory Efficacy Endpoints
6.4.3.1
Patient-Reported Disease and/or Treatment-Related 
SymptomsEORTC Data
Summary statistics (mean, standard deviation, median, and range) of absolute scores
and mean changes from the baseline will be calculated for all disease and/or 
treatment-related symptom items and subscales of the EORTC QLQ-C30 and 
QLQ-OV28 at each assessment timepoint for each arm during the administration of the 
treatment and the survival follow-up period. The mean (and 95% CI) and median of the 
absolute scores and the changes from the baseline will be reported for interval and 
continuous variables. Previously published minimally-important differences will be used 
to identify meaningful change from the baseline within each treatment group on the
disease and/or treatment-related symptoms scales (Osoba et al. 1998; Cocks et al. 
2011).
The EORTC QLQ-C30 and QLQ-OV28 data will be scored according to the 
EORTC scoring manual (Fayers et al. 2001b). In the event of incomplete data, if the 
scale has more than 50% of the constituent items completed, a pro-rated score will be 
computed that is consistent with the scoring manual and the validation papers of the 
measure.  For subscales with less than 50% of the items completed, the subscale will be 
considered missing.  PRO completion, compliance rates, and reasons for missing data 
will be summarized at each timepoint by treatment arm.
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6.4.3.2
FACT-G, Single Item GP5 Data
A descriptive analysis of absolute scores and the proportion of patients who selected 
each response option at each assessment visit by treatment arm will be reported for item
GP5 (“I am bothered by side effects of treatment”) from the FACT-G physical well-being 
subscale.  Item GP5 from Version 4 of the FACT-G questionnaire will be scored 
according to the FACIT scoring manual (Cella 1997).  PRO completion, compliance 
rates, and reasons for missing data will be summarized at each timepoint by treatment 
arm.
6.4.3.3
Health Economic Data
Health economic data, as assessed by the EQ-5D-5L, will be evaluated for patients with 
a baseline assessment and at least one post-baseline EQ-5D-5L assessment. The 
results from the health economic data analyses will be reported separately from the CSR
as they will be used in pharmacoeconomic analyses only.
6.4.4
Handling of Missing Data
For PFS, patients who are alive without a date of disease progression will be analyzed 
as censored observations on the date of the last tumor assessment.  If no post-baseline 
tumor assessment is available, PFS will be censored at the date of randomization plus 
1 day.
For OS, patients who are not reported as having died will be analyzed as censored 
observations on the date they were last known to be alive.  If no post-baseline data are 
available, OS will be censored at the date of randomization plus 1 day.
For objective response, patients without any post-baseline assessment will be 
considered non-responders.
For DOR, data for patients who have not progressed and who have not died at the time 
of analysis will be censored at the time of the last tumor assessment date.
For the PRO disease-symptom improvement, patient function and HRQoL endpoints, 
patients without a baseline assessment visit or a certain post-baseline assessment visit 
will be considered non-responders and will not be included in the analysis.
6.5
SAFETY ANALYSES
Safety analyses will be performed on the safety-evaluable population, which is defined 
as patients who received any amount of any component of the study treatments 
(bevacizumab, paclitaxel or carboplatin).  Patients will be allocated to treatment arms 
according to the treatment they actually received (i.e., patients randomized to 
placebochemotherapy alone who received at least one full or partial dose of 
bevacizumab will be included in the bevacizumabchemotherapy arm for safety).
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Drug exposure will be summarized to include treatment duration, number of doses, and 
dose intensity.
Verbatim description of adverse events will be mapped to MedDRA thesaurus terms and 
graded according to NCI CTCAE v4.0.  All adverse events occurring during or after the 
first study drug dose will be summarized by treatment arm and NCI CTCAE grade.  In 
addition, serious adverse events, severe adverse events (Grade 3), adverse events of 
special interest, and adverse events leading to study drug discontinuation or interruption 
will be summarized accordingly.  Multiple occurrences of the same event will be counted 
once at the maximum severity.
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data will be summarized by treatment arm and grade.
Changes in vital signs will be summarized by treatment arm.
Deaths reported during the study treatment period and those reported during the 
follow-up period after study treatment completion and discontinuation will be 
summarized by treatment arm.
6.6
INTERIM ANALYSIS
There will be no planned interim analysis.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Other electronic data will be sent directly 
to the Sponsor, using the Sponsor’s standard procedures to handle and process the 
electronic transfer of these data.  eCRFs and correction documentation will be 
maintained in the EDC system’s audit trail.  System backups for data stored by the 
Sponsor and records retention for the study data will be consistent with the Sponsor’s 
standard procedures.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.
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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
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7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test results, 
and medication inventory records, must be retained by the Principal Investigator for at 
least 15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures like optional tumor and plasma samples (see Section 4.5.6).  The 
investigator or authorized designee will explain to each patient the objectives, methods, 
and potential risks associated with each optional procedure.  Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time for any 
reason.  A separate, specific signature will be required to document a patient's 
agreement to participate in optional procedures.  Patients who decline to participate will 
not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
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8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor
will provide clinical operations management, data management, and medical monitoring.
Approximately 16 sites countrywide will participate to enroll approximately 100 patients.
Enrollment will occur through an IxRS.  
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details). 
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For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective CSR.  In addition, for all clinical trials in patients involving an IMP for 
which a marketing authorization application has been filed or approved in any country, 
the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).
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10.
REFERENCES
Aabo K, Adams M, Adnitt P, et al. Chemotherapy in advanced ovarian cancer: four 
systematic meta-analyses of individual patient data from 37 randomised trials. 
Advanced Ovarian Cancer Trialists' Group. Br J Cancer 1998;78:147987.
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:36576.
American Cancer Society. Survival rates for ovarian cancer, by stage [ resource on the 
Internet]. 2014 [updated 2016 Feb 04; cited 2016 Aug 22]. Available from: 
http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-
survival-rates.
Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in 
ovarian cancer. N Engl J Med 2006;354:3443.
Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based 
treatment regimens in advanced-stage ovarian cancer: a phase III trial of the 
Gynecologic Cancer Intergroup. J Clin Oncol 2009;27:141925. [Erratum: J Clin 
Oncol 2009;27:2305.]
Borgstrom P, Gold DP, Hillan KJ, et al. Importance of VEGF for breast cancer 
angiogenesis in vivo: implications from intravital microscopy of combination 
treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. 
Anticancer Res 1999;19:420314.
Brookmeyer, Ron, and John Crowley. "A confidence interval for the median survival 
time." Biometrics (1982):2941.
Brooks R, The EuroQol Group. EuroQol: the current state of play. Health Policy 
1996;37:5372.
Brotto L, Brundage M, Hoskins P, et al. Randomized study of sequential 
cisplatin-topotecan/carboplatin-paclitaxel versus carboplatin-paclitaxel: effects on 
quality of life. Support Care Cancer 2016;24:124149. 
Brundage M, Osoba D, Bezjak A, et al. Lessons learned in the assessment of 
health-related quality of life: selected examples from the National Cancer Institute 
of Canada Clinical Trials Group. J Clin Oncol 2007;25:507881.
Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary 
treatment of ovarian cancer. N Engl J Med 2011;365:247383.
Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: Prospective evaluation 
of a simple formula based on renal function. J Clin Oncol 1989;7:14856.
Protocol Number: 
 Report Number: 
Clinical Study Report: bevacizumab - F. Hoffmann-La Roche Ltd
YO40268
1105854
108


Bevacizumab—F. Hoffmann-La Roche Ltd
94/Protocol YO40268, Version 3
Cella D. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) 
measurement system. Version 4. Evanston: Center on Outcomes, Research and 
Education (CORE), Evanston Northwestern Healthcare and Northwestern 
University, 1997.
Cella D, Paul D, Yount S, et al. What are the most important symptom targets when 
treating advanced cancer? A survey of providers in the National Comprehensive 
Cancer Network (NCCN). Cancer Invest 2003;21:52635.
Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy 
(FACT) scale: Development and validation of the general measure. Journal of
Clinical Oncology 1993;11(3):5709.
Chan JK, Brady MF, Penson RT, et al. Weekly vs. every-3-week paclitaxel and 
carboplatin for ovarian cancer. N Engl J Med 2016;374:73848.
Chen, Wanqing, et al. "Cancer statistics in China, 2015." CA: a cancer journal for 
clinicians 66.2 (2016):11532.
Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16:3141.
Cocks K. King MT, Velikova G, et al. Evidence-based guidelines for determination of 
sample size and interpretation of the European Organization for the Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 
2011;29:8996.
Cull A, Howat S, Greimel E, et al. Development of a European Organization for 
Research and Treatment of Cancer questionnaire module to assess the quality of 
life of ovarian cancer patients in clinical trials: a progress report. Eur J Cancer 
2001;37:4753.
Dieras V, Guastalla JP, Ferrero JM, Cure H, Weber B, Winckel P et al. A multicenter 
phase II study of cisplatin and docetaxel (Taxotere) in the first-line treatment of 
advanced ovarian cancer: a GINECO study. Cancer Chemother Pharmacol 
2004;53:48995.
Donovan KA, Donovan HS, Cella D, et al. Recommended patient-reported core set of 
symptoms and quality-of-life domains to measure in ovarian cancer treatment trials. 
J Natl Cancer Inst 2014;106:dju128.
du Bois A. Treatment of advanced ovarian cancer. Eur J Cancer 2001;37 (Suppl 9):S17.
du Bois A, Weber B, Rochon J, et al. Addition of epirubicin as a third drug to carboplatin-
paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively 
randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft 
Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe 
d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens. J Clin Oncol 
2006;24:112735.
Protocol Number: 
 Report Number: 
Clinical Study Report: bevacizumab - F. Hoffmann-La Roche Ltd
YO40268
1105854
109


Bevacizumab—F. Hoffmann-La Roche Ltd
95/Protocol YO40268, Version 3
Ebell MH, Culp MB, Radke TJ. A systematic review of symptoms for the diagnosis of
ovarian cancer. Am J Prev Med 2016;50:38494.
EuroQol Group. EuroQola new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199208.
Fagotti A, Ferrandina G, Vizielli G, et al. Phase III randomised clinical trial comparing 
primary surgery versus neoadjuvant chemotherapy in advanced epithelial ovarian 
cancer with high tumour load (SCORPION trial): final analysis of peri-operative 
outcome. Eur J Cancer 2016;59:2233.
Fayers PM. Interpreting quality of life data: population-based reference data for the
EORTC QLQ-C30. Eur J Cancer 2001a;37:13314.
Fayers P, Aaronson N, Bjordal K, et al. on behalf of the EORTC Quality of Life Group. 
The EORTC QLQ-C30 scoring manual. 3rd ed. Brussels: European Organisation 
for Research and Treatment of Cancer; 2001b.
Ferlay J, Soerjomataram I, Ervik M, et al. International Agency for Research on Cancer: 
Cancer Incidence and Mortality Worldwide, IARC CancerBase No. 11 
[resource on the Internet]. 2013. Available from: http://globocan.iarc.fr.
Friedlander ML, King MT. Patient-reported outcomes in ovarian cancer clinical trials. 
Ann Oncol 2013;24:x648.
Goff BA. Ovarian cancer: screening and early detection. Obstet Gynecol Clin No Am 
2012;39:18394.
Goff BA, Mandel LS, Melancon CH, et al. Frequency of symptoms of ovarian cancer in 
women presenting to primary care clinics. JAMA 2004;291:270512.
Greimel E, Bottomley A, Cull A, et al. An international field study of the reliability and 
validity of a disease-specific questionnaire module (the QLQ-OV28) in assessing 
the quality of life of patients with ovarian cancer. Eur J Cancer 2003;39:14028.
Han, Kelong, et al. "Population pharmacokinetics of bevacizumab in cancer patients with 
external validation." Cancer chemotherapy and pharmacology 78.2 (2016): 341-
351.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736.
Herzog TJ, Alvarez RD, Secord A, et al. SGO guidance document for clinical trial 
designs in ovarian cancer: a changing paradigm. Gynecol Oncol 2014;135:37.
Hoskins P, Vergote I, Cervantes A, et al. Advanced ovarian cancer: phase III 
randomized study of sequential cisplatin-topotecan and carboplatin-paclitaxel vs. 
carboplatinpaclitaxel. J Natl Cancer Inst 2010;102:154756.
Jain RK. Normalizing tumour vasculature with anti-angiogenic therapy: a new paradigm 
for combination therapy. Nat Med 2001;7:9879.
Protocol Number: 
 Report Number: 
Clinical Study Report: bevacizumab - F. Hoffmann-La Roche Ltd
YO40268
1105854
110


Bevacizumab—F. Hoffmann-La Roche Ltd
96/Protocol YO40268, Version 3
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. 
Qual Life Res 2013;22:171727.
Kabbinavar FF, Wong JT, Ayala RE, et al. The effect of antibody to vascular endothelial 
growth factor and cisplatin to the growth of lung tumours in nude mice. Proc Am 
Assoc Cancer Res 1995;36:Abstract 488.
Karam A, Ledermann J A, Kim JW, et al. Fifth Ovarian Cancer Consensus Conference 
of the Gynecologic Cancer InterGroup: first-line interventions. Annals of Oncology 
2017;28:71117.
Katsumata N, Yasuda M, Isonishi S et al. Long-term results of dosedense paclitaxel and 
carboplatin versus conventional paclitaxel and carboplatin for treatment of 
advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 
3016): a randomised, controlled, open-label trial. Lancet Oncol 2013;14:1020–26.
Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in 
combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 
3, open-label, randomised controlled trial. Lancet 2009;374:13318.
Kehoe S. Response after 3 cycles of first-line platinum chemotherapy in advanced 
ovarian cancer: An analysis of the neoadjuavant arm of CHORUS [abstract]. 
Gynecol Oncol 2016;141:abstract 1.
Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced 
angiogenesis suppresses tumour growth in vivo. Nature 1993;362:8414.
Ledermann JA, Raja FA, Fotopoulou C, et al. Newly-diagnosed and relapsed epithelial 
ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment 
and follow-up. Ann Oncol 2013;24:vi2432.
Luckett T, King M, Butow P, et al. Assessing health-related quality of life in gynecologic 
oncology: a systematic review of questionnaires and their ability to detect clinically 
important differences and change. Int J Gynecol Cancer 2010;20:66484.
Matsuo K, Ahn EH, Prather CP, et al. Patient-reported symptoms and survival in 
ovarian cancer. Int J Gynecol Cancer 2011;21:155565.
McGuire WP III, Markman M. Primary ovarian cancer chemotherapy: current standards 
of care. Br J Cancer 2003;89:S3-8. 
McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared 
with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. 
N Engl J Med Jan 4 1996;334:16.
National Cancer Institute. SEER cancer statistics review 1975-2013 [resource on the 
internet]. 2016. Available from: 
http://seer.cancer.gov/csr/1975_2013/results_merged/sect_21_ovary.pdf.
Protocol Number: 
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[NCCN] National Comprehensive Cancer Network. Clinical practice guidelines in 
oncology: Ovarian cancer including fallopian tube cancer and primary peritoneal 
Cancer [resource on the internet]. 2017. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
Olson SH, Mignone L, Nakraseive C, et al. Symptoms of ovarian cancer. Obstet Gynecol 
2001;98:2127.
Osoba D. A taxonomy of the uses of health-related quality-of-life instruments in cancer 
care and the clinical meaningfulness of the results. Med Care 
2002;40(6 Suppl):III31–8.
Osoba D, Bezjak A, Brundage M, et al. Analysis and interpretation of health-related 
quality-of-life data from clinical trials: basic approach of The National Cancer 
Institute of Canada Clinical Trials Group. Eur J Cancer 2005;41:2807.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:13944.
Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel 
compared with cisplatin and paclitaxel in patients with optimally resected Stage III 
ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 
2003;21:3194200.
Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. 
N Engl J Med 2011;365:248496.
Pfisterer J, du BA, Wagner U, Quaas J, Blohmer JU, Wallwiener D et al. Docetaxel and 
carboplatin as first-line chemotherapy in patients with advanced gynecological 
tumors. A phase I/II trial of the Arbeitsgemeinschaft Gynakologische Onkologie 
(AGO-OVAR) Ovarian Cancer Study Group. Gynecol.Oncol 2004; 92:94956.
Pfisterer J, Weber B, Reuss A, et al. Randomized phase III trial of topotecan following 
carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a 
gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer 
Inst 2006;98:103645.
Piccart MJ, Bertelsen K, James K, et al. Randomised intergroup trial of cisplatin-
paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial 
ovarian cancer: three-year results. J Natl Cancer Inst May 3 2000;92:699708.
Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a week versus 
every 3 weeks in patients with advanced ovarian cancer (MITO-7): A randomised, 
multicentre, open-label, Phase III trial. Lancet Oncol 2014;15:396405.
Richter R, Oskay-Oezcelik G, Chekerov R, et al. Health-related quality of life during 
sequential chemotherapy with carboplatin followed by weekly paclitaxel in 
advanced ovarian cancer: a multicenter phase II study of the North Eastern 
German Society of Gynecological Oncology. Anticancer Res 2012;32:39676.
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Rose PG, Blessing JA, Ball HG, Hoffman J, Warshal D, DeGeest K et al. A phase II 
study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a 
Gynecologic Oncology Group study. Gynecol Oncol 2003;88:1305.
Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the response to 
treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 2004;96:48788.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:730.
Sopik V, Iqbal J, Rosen B, et al. Why have ovarian cancer mortality rates declined? 
Part II. Case-fatality. Gynecol Oncol 2015;138:7506.
Stuart GC, Kitchener H, Bacon M, et al. 2010 Gynecologic Cancer InterGroup (GCIG) 
consensus statement on clinical trials in ovarian cancer: report from the Fourth 
Ovarian Cancer Consensus Conference. Int J Gynecol Cancer 2011;21:7505.
Tsai CM, Au JS, Chang GC, et al, Safety and efficacy of first-line bevacizumab with 
chemotherapy in Asian patients with advanced nonsquamous NSCLC: results from 
the phase IV MO19390 (SAiL) study. J Thorac Oncol 2011;6:10927.
Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R et al. Phase III
randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line
chemotherapy for ovarian carcinoma. J Natl Cancer Inst 2004;96:168291.
Vergote I, Tropé CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in 
Stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:94353.
Vorobiof DA, Rapoport BL, Chasen MR, Cohen GL, Mahomed R, Karime M. Phase II 
clinical trial of carboplatin and docetaxel in patients with metastatic ovarian cancer: 
active combination with low incidence of peripheral neuropathy. Int J Gynecol 
Cancer 2003;13:2879.
Warren RS, Yuan H, Matli MR, et al. Regulation by vascular endothelial growth factor of 
human colon cancer tumourigenesis in a mouse model of experimental liver 
metastasis. J Clin Invest 1995;95:178997.
Webster K, Odom L, Peterman A, et al. The functional assessment of chronic illness 
therapy (FACIT) measurement system: validation of version 4 of the core 
questionnaire. Quality Life Res 1999;8:604.
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Appendix 1
Schedule of Activities
Observations and Tests
Pre-Treatment
Chemotherapy (Cycles 16) and 
Bevacizumab/Placebo 
(Cycles 26) a
Bevacizumab/  
Placebo Only (Cycle
7 through 
Discontinuation) a
Study 
Completion/Early 
Termination 
Visit a
Post-Treatment a
Day 28 to 1
Weekly
Every 
Course
Every 
Other 
Course
Every 
Course
Every 
Other 
Course
Within 30 days 
of the last dose 
of the study 
treatment
Every 3 Months 
for 2 Years, 
Every 6 Months 
for 3 Years, Then 
Annually
Informed consent 
x
History and physical 
examination
x b
x c, d
x c, d
x
ECOG PS
x
x
x
x
Vital signs
x b
x e
x c
x c
Hematology f
x g
x
x
x
Urinalysis
x h
x i
x i
x
Serum chemistry j
x g
x
x
x
Serum pregnacy test (for 
women of childbearing 
potential)
x g
As clinically indicated
PT/INR, aPTT
x g
x k
x k
x l
Audiogram
x m
ECG
x b
As clinically indicated
Radiographic disease 
assessment
x b, n
x d, o
x d, o
x p
x o
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Observations and Tests
Pre-Treatment
Chemotherapy (Cycles 16) and 
Bevacizumab/Placebo 
(Cycles 26) a
Bevacizumab/  
Placebo Only (Cycle
7 through 
Discontinuation) a
Study 
Completion/Early 
Termination 
Visit a
Post-Treatment a
Day 28 to 1
Weekly
Every 
Course
Every 
Other 
Course
Every 
Course
Every 
Other 
Course
Within 30 days 
of the last dose 
of the study 
treatment
Every 3 Months 
for 2 Years, 
Every 6 Months 
for 3 Years, Then 
Annually
HIV, HBV, HCV 
serology q
x
Serum CA-125 level
x b, r
x c, s
x c, s
x
EORTC QLQ-C30, QLQ-
OV28, and EQ-5D-5L t
x
x
x
x
FACT-G and the single 
item GP5 t
Starting at 
Cycle 4
x
x
x
Adverse events u
x g
x
x
x
x
x
Concomitant medications
x v
x
x
x
x
Incision check
x
x w
Bevacizumab/placebo 
administration
x x
x
Paclitaxel administration
x
Carboplatin 
administration
x
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aPTTactivated partial thromboplastin time; CA-125cancer antigen 125; CTcomputed tomography; ECOG PSEastern Cooperative Oncology 
Group Performance Status; EORTCEuropean Organization for Research and Treatment of Cancer; EQ-5D-5LEuroQol 5 Dimension, 5-Level 
Questionnaire; FACT-G GP5Functional Assessment of Cancer Therapy–General; HBcAbhepatitis B core antibody; HBsAbhepatitis B surface 
antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; INRInternational Normalized Ratio; MRImagnetic 
resonance imaging; QLQ-OV28Quality of Life Questionnaire Ovarian Cancer Module 28; QLC-C30Quality of Life Questionnaire Core 30; 
PROpatient-reported outcome; PTprothrombin time; RECIST Response Evaluation Criteria in Solid Tumors.
a Each cycle is 21 days. Study drug administration occurs on Day 1 (3 days) of each cycle.  All other events and assessments during the study 
treatment must occur within 3 days prior to the administration.  The end of the study treatment or early discontinuation visit should occur within 
30 days after the last dose of the study treatment is administered.  The post-treatment follow up visits will occur every 3 months (14 days) for 
the first 2 years after the end of study treatment or early discontinuation visit, then every 6 months (14 days) for 3 years, and then annually.
b Must be performed within 28 days prior to start of study treatment.
c Within 1 week before and as close to the beginning of the next applicable course as possible.
d Patients who do not experience disease progression, including those who will discontinue study treatment, need to be followed in a consistent 
fashion to monitor tumor status.  Therefore, the schedule of tumor assessment by physical examination, CA-125 monitoring, and imaging should 
be conducted according to the timeline shown per the study calendar.
e Vital signs should be assessed at least weekly during the first cycle of bevacizumab/placebo therapy.  During the time between treatments, vital 
sign assessments may be performed at home by the patient at the investigator’s discretion, and the investigator or study nurse are responsible 
for obtaining the results from the patient.
f
Hematology should include hemoglobin, hematocrit, platelet count, red blood cell count, and WBC count with differential (neutrophils). Additional 
hematologic assessments may be performed as clinically indicated or per local practice.
g Must be obtained within 14 days prior to start of study treatment.
h Within 7 days before treatment.
i
Does not need to be repeated on Day 1 if tests are performed within 7 days before Day 1 (start of study treatment).
j
Serum chemistry includes sodium, potassium, glucose, blood urea nitrogen (BUN), creatinine, albumin, bilirubin, AST, ALT, and ALP.
k For patients on prophylactic or therapeutic anticoagulation with warfarin, PT/INR should be monitored before each treatment.  Treatment should 
be withheld for PT INR of 1.5 on prophylactic warfarin or greater than the therapeutic range if patient is on full-dose warfarin.
l
When clinically indicated.
m For patients with a history of hearing loss; an audiogram should be repeated as clinically indicated.
n An initial CT or MRI scan of at least the chest, abdomen, and pelvis is required to establish a postsurgical baseline for the extent of residual 
disease within 28 days prior to randomization (Scan 1). A CT/MRI scan of the neck and/or head may also be performed if necessary.
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o Follow-up radiographic assessment of disease.  In the absence of RECIST-defined disease progression, imaging using the same modality and
encompassing the same field as in the initial pre-treatment evaluation should be repeated with the following schedule, regardless of whether or
not the patient has measurable disease on initial CT or MRI scan and regardless of the treatment cycle:
Scans 2 and 3:  Every 9 weeks (5 days) from the date of randomization during the concurrent treatment phase
Scans 4, 5, 6, and 7:  Every 12 weeks (5 days) in the maintenance phase (the first scan in the maintenance phase is performed 12 weeks
after the last scan during the concurrent treatment phase)
After the completion of all protocol therapy, every 3 months (14 days) for 2 years, then every 6 months (14 days) for 3 years.  CT scans or
MRIs after 5 years of survival follow-up may be done as clinically indicated.
During or after completion of all study treatment, as clinically indicated at any time for clinical suspicion of progressive disease, including rising
serum CA-125 levels, not meeting criteria for disease progression.  Imaging assessments as part of this protocol should be discontinued if
RECIST-defined disease progression is confirmed according to guidelines.
Patients with no RECIST-defined disease progression who are early discontinued from study treatment before Cycle 6 (including Cycle 6),
Scans 2 and 3:  Every 9 weeks (5 days) from the date of randomization; the following tumor assessments should be conducted every
3 months (14 days) after the study completion/early termination visit for 2 years, then every 6 months (14 days) for 3 years.  CT scans
or MRIs after 5 years of survival follow-up may be done as clinically indicated.
Patients with no RECIST-defined disease progression who are early discontinued from study treatment after Cycle 6, the following tumor
assessments should be conducted every 3 months (14 days) after the study completion/early termination visit for 2 years, then every
6 months (14 days) for 3 years.  CT scans or MRIs after 5 years of survival follow-up may be done as clinically indicated.
p If not performed within 28 days prior to the treatment discontinuation visit.
q HBsAg, HBsAb, HBcAb, and HCV Ab serology and HIV testing are required at screening. If a patient has a negative HBsAg test and a positive
total HBcAb test at screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a 
positive HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection.
r
Baseline pre-chemotherapy value is required.  When available, also include pre-surgical value.
s PFS will be assessed using RECIST, Version 1.1.  CA-125 elevation alone will not be used to define progressive disease.  However, CA-125 
levels will be collected as described in the schedule of activities to enable further analysis.
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t
All PRO questionnaires must be completed in their entirety by the patient at the investigational site at the start of the clinic visit before discussion 
of the patient’s health state, laboratory test results, or health records, before the administration of the study treatment, and/or prior to the 
performance of any other study assessments (e.g., scans) that could bias the patient’s responses.
The EORTC QLQ-C30, QLQ-OV28, and EQ-5D-5L questionnaires must be administered and completed by patients in that order at the
following assessment timepoints:  baseline, defined as prior to Cycle 1 (3 days); prior to Cycle 4 of chemotherapy (3 days); prior to Cycle 7
(3 days); prior to Cycle 13 (3 days); prior to Cycle 22 (3 days); at the end of treatment or discontinuation visit within 30 days of the
administration of the last dose of study treatment; after the treatment completion visit, every 3 months ( 14 days) for the first year of the
survival follow-up period; every 6 months ( 14 days) for the second year of the survival follow-up period; and every year ( 14 days) for the
final 3 years of the survival follow-up period.
The single-item GP5 from the FACT-G questionnaire will be the final PRO measure to be administered and must be completed by patients
beginning at the Cycle 4, Day 1 visit; and then at all other assessment timepoints listed above along with the other PRO questionnaires.
u All serious adverse events and adverse events of special interest, regardless of their relationship to the study drug, will be reported until 90 days 
after the last dose of the study drug is administered or the initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, 
regardless of the relationship to the study drug, will be reported until 30 days after the last dose of the study drug is administered or the initiation 
of new anti-cancer therapy, whichever occurs first.  After this period, the investigator should report any serious adverse events that are believed 
to be related to prior study drug treatment.
v Concomitant medications need to be collected 7 days prior to starting study treatment.
w Patients with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are eligible, but require 
weekly wound examinations until complete closure.
x Bevacizumab/placebo is initiated at Cycle 2 rather than at Cycle 1.
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Appendix 2
Response Evaluation Criteria in Solid Tumors (RECIST), V 1.1: 
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
Measurability of Tumor at Baseline
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.
a)
Measurable Tumor Lesions
Tumor Lesions:  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm).  At baseline and 
follow-up, only the short axis will be measured and followed. See also notes below on 
“Baseline Documentation of Target and Non-Target Lesions” for information on lymph 
node measurement.
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.
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b)
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter10 mm or 
pathological lymph nodes with short axis10 but15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
c)
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques for measuring bone lesions.  However, 
these techniques can be used to confirm the presence or disappearance of 
bone lesions.

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques, such as 
CT or MRI, can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable
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Target Lesions:  Specifications by Methods of Measurements 
d)
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
e)
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions:  Clinical lesions will only be considered measurable when they are 
superficial and10 mm in diameter as assessed using calipers (e.g., skin nodules).  For 
the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested.
Chest X-Ray:  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV
contrast because of allergy or renal insufficiency, the decision as to whether a non-
contrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline 
and during the study should be guided by the tumor type under investigation and the 
anatomic location of the disease.  For patients who develop contraindications to contrast 
after baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed should also be based on the tumor type 
and the anatomic location of the disease, and should be optimized to allow for 
comparison with the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, 
the patient should be considered not evaluable from that point forward.  Care must be 
taken in measurement of target lesions on a different modality and interpretation of 
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non-target disease or new lesions, since the same lesion may appear to have a different 
size using a new modality.
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology:  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.
Tumor Response Evaluation
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above.
Baseline Documentation of Target and Non-Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to 
a maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and be representative of all involved organs, but in addition should 
lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
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reported as two dimensions in the plane in which the image is obtained (for CT this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with short axis10 mm 
but15 mm) should be considered non-target lesions. Nodes that have a short axis 
of 10 mm are considered non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters. If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
Response Criteria
f)
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  Disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters
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
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
g)
Special Notes on the Assessment of Target Lesions
Lymph Nodes:  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to10 mm on study. This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if complete response (CR) criteria are met, since a normal lymph node is defined 
as having a short axis of10 mm.
Target Lesions That Become Too Small to Measure:  During the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and below measurable limit (BML) should 
be ticked.  (BML is equivalent to a “less than” sign.) (Note:  It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when 
normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned in this circumstance as well 
and BML should also be ticked).
To reiterate, however, if the radiologist is able to provide an actual measure, it should be 
recorded, even if it is below 5 mm, and in that case BML should not be ticked.
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Lesions That Split or Coalesce on Treatment:  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion.
h)
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only
qualitatively at the timepoints specified in the protocol.

Complete response:  Disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level

All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

Progressive disease:  Unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
i)
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease:  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease:  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.
The same general concepts apply here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
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can be applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in non-measurable disease 
is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable 
lesion). Examples include an increase in a pleural effusion from “trace” to “large” or an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.”  If unequivocal progression is 
seen, the patient should be considered to have had overall PD at that point. While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial.
j)
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
CR. For example, necrosis of a liver lesion may be reported on a CT scan report as a
“new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)
While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly, possible “new” disease). New lesions on the 
basis of FDG-PET imaging can be identiﬁed according to the following algorithm: 
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1.
A negative FDG-PET scan at baseline with a positive3 FDG-PET scan during the 
study is a sign of PD based on a new lesion. 
2.
In the case of no FDG-PET scan at baseline and a positive FDG-PET scan during 
the study:
If the positive FDG-PET scan during the study corresponds to a new site of 
disease conﬁrmed by CT, this will be considered PD.
If the positive FDG-PET scan during the study is not conﬁrmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine whether 
there is truly progression occurring at that site (if so, the date of PD will be the 
date of the initial abnormal FDG-PET scan).
If the positive FDG-PET scan during the study corresponds to a preexisting site 
of disease on CT that is not progressing on the basis of the anatomic images, 
this will not be considered PD. 
Evaluation of Response
k)
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.
                                           
3 A “positive” FDG-PET scan lesion means one that is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation-corrected image.
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Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST), V 1.1: 
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Table 1
Timepoint Response:  Patients with Target Lesions
(with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial
response; SDstable disease.
Table 2
Timepoint Response:  Patients with Non-Target 
Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
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l)
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response.  This would most likely happen in 
the case of PD. For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression. Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that timepoint.
m) Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1 and 2.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
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In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion.
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Appendix 3
CA-125 Response and Progression Evaluation Criteria
CA-125 RESPONSE
Guidelines for using CA-125 response have been developed (Rustin 2004).  Patients 
should have a pretreatment CA-125 of at least twice the upper limit of normal (ULN) in 
order to be considered for CA-125 response.  In those patients, a CA-125 response 
would be obtained the moment the CA-125 is reduced by 50% and this should be 
confirmed with a consecutive CA-125 assessment not earlier than 28 days after the 
previous one, with however the date of the first 50% reduction to be the reference date 
for the CA-125 response.
CA-125 PROGRESSIVE INCREASE
CA-125 progressive increase will be defined on the basis of a progressive serial 
elevation of serum CA-125 according to the following criteria:

Patients with elevated CA-125 levels pre-treatment and normalization of CA-125 
must show evidence of CA-125 2the ULN on two occasions at least 1 week apart 
or

Patients with elevated CA-125 pre-treatment that never normalizes must show 
evidence of CA-125 2times the nadir value on two occasions at least 1 week
apart or

Patients with CA-125 in the normal range pretreatment must show evidence of 
CA-125 2times the upper normal limit on two occasions at least 1 week apart
Elevated values must be confirmed by two separate measurements obtained at least 1
week apart.  A progressive increase in CA-125 levels will be assigned the date of the 
first measurement that meets the criteria as noted.
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Appendix 4
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire
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Appendix 4: European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire
Bevacizumab—F. Hoffmann-La Roche Ltd
118/Protocol YO40268, Version 3
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Appendix 5
Quality of Life Questionnaire Ovarian Cancer Module 28
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Appendix 5: Quality of Life Questionnaire Ovarian Cancer Module 28
Bevacizumab—F. Hoffmann-La Roche Ltd
120/Protocol YO40268, Version 3
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Appendix 6
Patient Questionnaire FACT-G Single Item GP5
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Appendix 7
Patient Questionnaire EuroQol 5 Dimension, 5-Level 
Questionnaire
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SAP_001.pdf: 
 
Official Title: 
A Phase III Trial of Carboplatin and Paclitaxel Plus Placebo Versus 
Carboplatin and Paclitaxel Plus Concurrent and Extended 
Bevacizumab in Chinese Women With Newly Diagnosed, Previously 
Untreated, Stage III or Stage IV Epithelial Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer 
NCT Number: 
NCT03635489 
Document Date: 
SAP Version 1: 04-December-2020 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Bevacizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan YO40268
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III TRIAL OF CARBOPLATIN AND PACLITAXEL 
PLUS PLACEBO VERSUS CARBOPLATIN AND 
PACLITAXEL PLUS CONCURRENT AND EXTENDED 
BEVACIZUMAB IN CHINESE WOMEN WITH NEWLY 
DIAGNOSED, PREVIOUSLY UNTREATED, STAGE III OR 
STAGE IV EPITHELIAL OVARIAN, FALLOPIAN TUBE, OR
PRIMARY PERITONEAL CANCER
PROTOCOL NUMBER:
YO40268
STUDY DRUG:
Bevacizumab (RO4876646)
VERSION NUMBER:
1
IND NUMBER:
113807
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
 Ph.D.
DATE FINAL:
See electronic date stamp below
Date and Time(UTC)        Reason for Signing
Name
04-Dec-2020 09:09:24
Company Signatory
Protocol Number: 
 Report Number: 
Clinical Study Report: bevacizumab - F. Hoffmann-La Roche Ltd
YO40268
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Bevacizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan YO40268
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 4
2.
STUDY DESIGN........................................................................................... 4
2.1
Study Objectives...................................................................... 5
2.2
Protocol Synopsis.................................................................... 7
2.3
Outcome Measures ................................................................. 7
2.4
Determination of Sample Size ................................................. 7
3.
STUDY CONDUCT....................................................................................... 8
3.1
Randomization......................................................................... 8
4.
STATISTICAL METHODS ............................................................................ 8
4.1
Analysis Populations ............................................................... 8
4.2
Analysis of Study Conduct....................................................... 9
4.3
Analysis of Treatment Group Comparability ............................ 9
4.4
Efficacy Analysis...................................................................... 9
4.4.1
Primary Efficacy Endpoint........................................................ 9
4.4.2
Secondary Efficacy Endpoints............................................... 10
4.4.2.1
Overall Survival ..................................................................... 10
4.4.2.2
Objective Response Rate (ORR)........................................... 10
4.4.2.3
Duration of Response............................................................ 11
4.4.2.4
Patient-Reported Disease Symptoms, Function 
and Health-Related Quality of Life -- EORTC 
Data....................................................................................... 11
4.4.3
Exploratory Efficacy Endpoints.............................................. 12
4.4.3.1
Patient-Reported Disease and/or Treatment-
Related Symptoms - EORTC Data ........................................ 12
4.4.3.2
FACT-G, Single Item GP5 Data............................................. 12
4.4.3.3
Health Economic Data: EQ-5D-5L......................................... 13
4.4.4
Sensitivity Analyses............................................................... 13
4.4.4.1
Impact of Missing Scheduled Tumor 
Assessments on Primary PFS Analysis................................. 13
4.4.4.2
Impact of Non−Protocol-Specified anti-Cancer 
Therapy on Primary PFS Analysis......................................... 13
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Bevacizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan YO40268
4.4.4.3
Impact of Demographics, Baseline 
Characteristics and Ovarian Cancer History on 
Primary PFS Analysis............................................................ 13
4.4.5
Subgroup Analyses ............................................................... 14
4.5
Safety Analyses..................................................................... 14
4.5.1
Exposure of Study Medication............................................... 14
4.5.2
Adverse Events ..................................................................... 14
4.5.3
Laboratory Data..................................................................... 15
4.5.4
Vital Signs and ECOG Performance Status........................... 15
4.6
Missing Data.......................................................................... 15
4.7
Interim analysis...................................................................... 15
5.
REFERENCES ........................................................................................... 16
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints..................................... 6
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 5
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 18
Appendix 2
Schedule of Assessments........................................................... 26
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Bevacizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan YO40268
1.
BACKGROUND
This Statistical Analysis Plan (SAP) describes the planned analyses and statistical 
methods of Study YO40268 (BevFLOC).
The analyses outlined in this SAP will supersede those specified in the protocol.
Please refer to Section 1 of the Study Protocol for more details about bevacizumab and 
the study rationale of Study YO40268.
2.
STUDY DESIGN
This is a Phase III, double-blind, two-arm, randomized study designed to evaluate the 
efficacy and safety of bevacizumab administered with paclitaxel plus carboplatin 
compared with placebo administered with paclitaxel plus carboplatin in Chinese patients 
with newly diagnosed, previously untreated International Federation of Gynecology and 
Obstetrics (FIGO) Stage III with any gross (macroscopic or palpable) residual disease or 
FIGO Stage IV epithelial ovarian, fallopian tube, or primary peritoneal cancer. 
100 patients are randomized.
More details about the study design could be found in Appendix 1, Protocol Synopsis.
Figure 1 illustrates the study design.
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6/Statistical Analysis Plan YO40268
Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
bevacizumab versus placebo in 
combination with 
paclitaxelcarboplatin
PFS after randomization, defined as the time from
randomization to the first occurrence of disease 
progression or death from any cause during the 
study (whichever occurs first), as determined by the 
investigator according to RECIST v1.1
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
bevacizumab versus placebo in 
combination with 
paclitaxelcarboplatin
OS after randomization, defined as the time from 
randomization to death from any cause
ORR, defined as a CR or PR, as determined by the 
investigator according to RECIST v1.1 for patients 
with measurable residual disease after primary 
surgery
DOR, defined for patients who had an OR and 
defined as the time from the first occurrence of a 
documented OR to disease progression, as 
determined by the investigator according to 
RECIST v1.1 or death from any cause, whichever 
occurs first for patients with measurable residual 
disease after primary surgery
To evaluate patient-reported 
abdominal symptoms of OC 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin, as measured 
by two items from the Abdominal/GI 
Symptom Scale of the EORTC QLQ-
OV28
Clinically meaningful improvement in patient-
reported abdominal pain or bloating, defined as a 
10-point decrease from the baseline score on 
either of the two items (Items 31 and 32) of the 
EORTC QLQ-OV28 Abdominal/GI Symptom Scale
To evaluate patient-reported 
outcomes (PROs) of function and 
health-related quality of life (HRQoL) 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Clinically meaningful improvement in patient-
reported function and HRQoL, defined as a 10-
point increase from the baseline score on each of 
the function (physical, role, emotional, social) and 
global health status/HRQoL scales of the EORTC 
QLQ-C30
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate PROs of 
disease/treatment-related symptoms 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Mean and mean changes from the baseline score 
in disease and/or treatment-related symptoms by 
assessment timepoint and between treatment arms 
as assessed by all symptom items and/or scales of 
the EORTC QLQ-C30 and QLQ-OV28
To evaluate any treatment burden 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Proportion of patients reporting each response 
option at each assessment timepoint by treatment 
arm for item GP5 from the FACT-G (“I am bothered 
by side effects of treatment.”)
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7/Statistical Analysis Plan YO40268
Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objectives 
(cont.)
Corresponding Endpoints (cont.)
To evaluate and compare between 
treatment arms patients' health utility, 
as measured by the EQ-5D-5L to 
generate utility scores for use in 
economic models for reimbursement
Health utility scores of the EQ-5D-5L questionnaire
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
bevacizumab versus placebo in 
combination with 
paclitaxelcarboplatin
Occurrence and severity of adverse events, with 
severity determined according to NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical laboratory 
test results
CR complete response; DOR duration of response; EORTC European Organization for 
Research and Treatment of Cancer; EQ-5D-5LEuroQol 5 Dimension, 5-Level Questionnaire, 
FACT-GFunctional Assessment of Cancer Therapy–General; GIgastrointestinal; 
HRQoL health-related quality of life; NCI CTCAE National Cancer Institute Common 
Terminology Criteria for Adverse Events; OC ovarian cancer; OR objective response; 
ORRobjective response rate; OS overall survival; PFS progression-free survival; 
PR partial response; PRO patient-reported outcome; QLQ-C30 Quality of Life 
Questionnaire Core 30; QLQ-OV28 Quality of Life Questionnaire Ovarian Cancer Module 28; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1.
2.2
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedules of 
Assessments in Appendix 2.
2.3
OUTCOME MEASURES
See the Protocol Synopsis in Appendix 1 for a description of the primary outcome 
measures.
2.4
DETERMINATION OF SAMPLE SIZE
The primary efficacy results will be bridged with those of the pivotal Study GOG218.
A total of approximate 100 patients will be randomized in a 1:1 ratio to either the 
bevacizumab or placebo arms of the study. The final analysis of the primary endpoint of 
progression free survival (PFS) will be performed when approximately 56 PFS events
have occurred in the intent to treat (ITT) population (56% of 100 patients), which will 
provide an 80% probability of demonstrating consistency with the global study.
The calculation is based on the following assumptions: 

Median PFS is 18.2 months for the bevacizumab arm and 12 months for the 
placebo arm (hazard ratio [HR]0.624)
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
Enrolment rate is 9.6 patients per month

5% yearly dropout rate
On the basis of the above assumptions, the required number of PFS events for the final 
analysis is projected to occur at approximately 24 months after the first patient is 
randomized.
The study is not powered to demonstrate statistical significance of treatment benefit on 
the primary and secondary efficacy endpoints.  Because no formal hypothesis testing will 
be performed, no type I error adjustment will be made.
3.
STUDY CONDUCT
3.1
RANDOMIZATION 
Randomization will be performed centrally using an interactive voice/Web response 
system (IxRS) that uses stratified block randomization.  After screening, patients who 
meet all eligibility criteria will be randomized in a 1:1 ratio to one of two treatment 
groups:  bevacizumab or placebo.
Randomization to treatment allocation will be stratified by:

FIGO stage and debulking status (Stage III optimally debulked vs. Stage III 
suboptimally debulked vs. Stage IV) and

Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 vs. 1 or 2)
Stratification factors will ensure balance of these strong prognostic factors across 
treatment arms and facilitate unbiased estimate of treatment effect in subgroups based 
on disease severity and performance status.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
Analysis populations are defined as follows:

The ITT population is defined as all randomized patients regardless of whether the 
assigned study treatment was received.  For efficacy analyses, patients will be 
analyzed according to their randomized treatment assignment. 

Objective response rate (ORR) will be analyzed in patients in the ITT population 
with measurable disease at baseline. For duration of response (DOR), only patients 
with an objective response will be included.

The patient-reported outcomes (PRO)-evaluable population is defined as patients in 
the ITT population with a baseline and 1 post-baseline PRO assessment.

The safety population is defined as patients who received any amount of any 
component of the study treatments (bevacizumab, placebo, paclitaxel or 
carboplatin).  Patients will be allocated to treatment arms according to the treatment 
they actually received (i.e., patients randomized to placebochemotherapy alone 
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who received at least one full or partial dose of bevacizumab will be included in the 
bevacizumabchemotherapy arm for safety).
4.2
ANALYSIS OF STUDY CONDUCT
Study enrollment, patient disposition, reasons for discontinuation from the study will be 
summarized for the ITT population. Reason for treatment discontinuation will be 
summarized for the safety population.
Protocol deviations, including violations of inclusion/exclusion criteria and major 
deviations during study conduct will be reported and summarized by treatment arm.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographics, baseline disease characteristics, and ovarian cancer (OC) history will be
summarized by treatment arm. Descriptive baseline summaries of continuous data will 
present the group mean, standard deviation, median, ranges and inter-quartile ranges, 
as appropriate. Descriptive baseline summaries of discrete data will present the
category counts as frequencies and percentages.
Previous and concurrent diseases and medications will be summarized. Subsequent 
anti-cancer therapy will be summarized.
4.4
EFFICACY ANALYSIS
The primary and secondary efficacy endpoints will be analyzed for the ITT population
unless specified otherwise, with patients grouped according to their assigned treatment.
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is PFS, which will be assessed by the investigator using 
Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1).  Consistency with the 
global pivotal study (GOG218) will be considered for the primary endpoint.
PFS after randomization is defined as the time from randomization to the first 
documented occurrence of disease progression or death from any cause during the 
study (whichever occurs first), as determined by the investigator according to 
RECIST v1.1.  Data for patients who have not experienced disease progression or death 
will be censored at the last tumor assessment.  Data for patients with no post-baseline 
tumor assessment will be censored at the date of randomization plus 1 day.
The stratification factors used for randomization are FIGO stage and debulking status, 
and ECOG PS (Section 3.1).  The number of patients in each stratum will be examined 
once recruitment is completed but before unblinding and efficacy analyses are 
performed. If any strata levels are deemed to be too small with limited number of PFS 
events, the robust stratified analyses cannot be conducted due to the potential risk of 
over-stratification (Akazawa et al. 1997). Therefore, judging from their clinical relevance,
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the following rule will be applied to decide which stratification factor(s) to be dropped
when conducting the analyses.
If the smallest stratum contains less than 5 PFS events, drop ECOG PS. If the smallest 
stratum still contains less than 5 PFS events after ECOG PS is dropped, further drop 
FIGO stage and debulking status and use unstratified analyses as the primary analyses.
The following analyses will be performed for PFS endpoint:

The HR will be estimated using a stratified Cox regression model. 95% confidence 
interval (CI) for the HR will be provided. Unstratified HR and its 95% CI will also be 
provided.

Kaplan-Meier methodology will be used to estimate median PFS for each treatment
arm and to construct survival curves for each treatment arm. The
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the
median PFS for each treatment arm (Brookmeyer and Crowley 1982).

The stratified log-rank test will also be performed. 
4.4.2
Secondary Efficacy Endpoints
4.4.2.1
Overall Survival
Overall survival (OS) is defined as the time from randomization to death from any cause.  
Data for patients who are not reported as having died at the date of analysis will be 
censored at the date when they were last known to be alive.  Data for patients who do 
not have post-baseline information will be censored at the date of randomization1 day.
The methodologies detailed for the PFS analysis will be used for the OS analysis in the 
ITT population, except that only unstratified analysis will be provided due to the lower
number of OS events anticipated.
4.4.2.2
Objective Response Rate (ORR)
An objective response (OR) is defined as either a complete response (CR) or partial
response (PR) as determined by the investigator according to RECIST v1.1. The 
analysis for ORR will include patients in the ITT population with measurable disease at 
baseline. Patients, who do not meet these criteria, including patients without any 
post-baseline tumor assessment, will be considered non-responders.
ORR is defined as the proportion of patients who had an objective response. A 
confirmation after the first occurrence of an objective response is not required in the 
analysis. An estimate of ORR and its 95% CI will be calculated using the 
Clopper-Pearson method for each treatment arm.  CIs for the difference in ORRs 
between the two treatment arms will be determined using the normal approximation to 
the binomial distribution.
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4.4.2.3
Duration of Response
DOR will be assessed in patients who had an objective response as determined by the 
investigator according to RECIST v1.1.  DOR is defined as the time from the first 
occurrence of a documented objective response (unconfirmed CR or PR) to disease 
progression or death from any cause during the study (whichever occurs first), as 
determined by the investigator according to RECIST v1.1.  Patients who have not 
progressed and who have not died at the time of analysis will be censored at the time of 
last tumor assessment date. If no tumor assessments were performed after the date of 
the first occurrence of the objective response (unconfirmed CR or PR), patient will be 
censored at the date of the first occurrence of the objective response1 day.
DOR is based on a non-randomized subset of patients (specifically, patients who 
achieved an objective response).  Comparisons between treatment arms will be made 
for descriptive purposes.  The methodologies detailed for the PFS analysis will be used 
for the DOR analysis except that the analysis will not be stratified.
4.4.2.4
Patient-Reported Disease Symptoms, Function and 
Health-Related Quality of Life -- EORTC Data
Patient-Reported Abdominal Pain or Bloating -- EORTC QLQ-OV28
The primary patient-reported outcomes endpoint of the proportion of patients in each 
arm who report a clinically meaningful improvement in patient-reported abdominal pain 
or bloating, defined as a10-point decrease from the baseline score on each of two 
items from the European Organization for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire Ovarian Cancer Module 28 (QLQ-OV28)
abdominal/gastrointestinal symptom scale (Items 31 and 32), will be summarized at 
each post-baseline timepoint by treatment arm, with its 95% CI, with the use of 
Clopper-Pearson method.  The difference in proportions will be provided, with its 95% 
CI, with the use of the Hauck-Anderson method.
Pre-specified subgroup analysis will also be performed in patients with ascites at 
baseline (who typically have significantly impaired health-related quality of life [HRQoL]) 
and in patients with sufficient symptoms at baseline to allow detection of a 10-point
improvement in a given symptom score.
The definition of improvement in patient-reported abdominal pain or bloating 
(i.e., a10-point decrease from the baseline score in QLQ-OV28 abdominal symptom 
items) is based on the standard analysis method for the EORTC QLQ-C30 that deems a 
score change of 10 points on any item or scale to be clinically meaningful 
(Osoba et al. 1998; Fayers 2001a; Osoba 2002; Osoba et al. 2005; 
Brundage et al. 2007; Luckett et al. 2010; Cocks et al. 2011).  Although the clinical 
meaningfulness of a 10-point change was established based on the EORTC QLQ-C30, 
the disease-specific modules, including the QLQ-OV28, were designed on the same 
structure using the same rating scale and are, therefore, applicable in this context.  
Additionally, other OC studies have used the 10-point minimally important difference 
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(MID) threshold for the QLQ-OV28, demonstrating that a change of this magnitude is 
significant to patients with OC while setting a precedent for its use and supporting its 
utility in this context (Richter et al. 2012; Brotto et al. 2016; Fagotti et al. 2016).
Patient-Reported Function and HRQoL: EORTC QLQ-C30
For the additional secondary PRO endpoint, the proportion of patients in each arm who 
report a clinically meaningful improvement in patient-reported function and HRQoL, 
defined as a10-point increase from the baseline score on each of the functional 
(physical, role, emotional, and social) and global health status/QoL scales of the EORTC 
QLQ-C30, will be summarized at each post-baseline timepoint by treatment arm as
specified above.
All EORTC QLQ-OV28 and QLQ-C30 data will be scored according to the EORTC 
scoring manual (Fayers et al. 2001b). PRO completion, compliance rates, and reasons 
for missing data will be summarized at each timepoint by treatment arm. For the PRO 
disease-symptom improvement, patient function and HRQoL endpoints, patients without 
a baseline assessment visit or at least one post-baseline assessment visit for the 
calculated scale of interest will be considered non-responders and will not be included in 
the analysis.
4.4.3
Exploratory Efficacy Endpoints
4.4.3.1
Patient-Reported Disease and/or Treatment-Related
Symptoms - EORTC Data
Summary statistics (mean and 95% CI, standard deviation, median, and range) of 
absolute scores and mean changes from the baseline will be calculated for all disease
and/or treatment-related symptom items and subscales of the EORTC QLQ-C30 and 
QLQ-OV28 at each assessment timepoint for each arm during the administration of the 
treatment and the survival follow-up period. The mean (and 95% CI) and median of the 
absolute scores and the changes from the baseline will be reported for interval and 
continuous variables. Previously-published minimally-important differences will be used 
to identify meaningful change from the baseline within each treatment group on the
disease and/or treatment-related symptoms scales (Osoba et al. 1998;
Cocks et al. 2011).
In the event of incomplete data, if the scale has more than 50% of the constituent items 
completed, a pro-rated score will be computed that is consistent with the scoring manual
and the validation papers of the measure.  For subscales with less than 50% of the items 
completed, the subscale will be considered missing.
4.4.3.2
FACT-G, Single Item GP5 Data
A descriptive analysis of absolute scores and the proportion of patients who selected
each response option at each assessment visit by treatment arm will be reported for item
GP5 (“I am bothered by side effects of treatment”) from the Functional Assessment of 
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Cancer Therapy–General (FACT-G) physical well-being subscale.  Item GP5 from 
Version 4 of the FACT-G questionnaire will be scored according to the FACIT scoring 
manual (Cella 1997).  PRO completion, compliance rates, and reasons for missing data 
will be summarized at each timepoint by treatment arm.
4.4.3.3
Health Economic Data: EQ-5D-5L
Health economic data from the EuroQol 5 Dimension, 5-Level Questionnaire (EQ-5D-5L)
measure will be used in pharmacoeconomic analyses only and not presented in the 
Clinical Study Report.
4.4.4
Sensitivity Analyses
Statistical methodologies that are analogous to those methodologies used in the primary 
analysis of PFS as specified in Section 4.4.1 will be applied for sensitivity analyses.
4.4.4.1
Impact of Missing Scheduled Tumor Assessments on Primary 
PFS Analysis
If a patient missed two or more consecutive assessments scheduled immediately prior to 
the date of disease progression per RECIST v1.1 or death in any treatment arm, the 
following two sensitivity analyses may be performed: 

Patients who missed two or more consecutive assessments scheduled immediately 
prior to the date of disease progression per RECIST v1.1 or death will be censored 
at the last tumor assessment prior to the first missed visit. 

Patients who missed two or more consecutive assessments scheduled immediately 
prior to the date of disease progression per RECIST v1.1 or death will be counted 
as having progressed on the date of the first of these missing assessments. 
4.4.4.2
Impact of Non−Protocol-Specified anti-Cancer Therapy on 
Primary PFS Analysis
Patients who received non−protocol-specified anti-cancer therapy before a PFS event 
will be censored at the last tumor assessment date before they received 
non−protocol-specified anti-cancer therapy in PFS analyses that may be performed for 
the comparisons between treatment arms. 
4.4.4.3
Impact of Demographics, Baseline Characteristics and Ovarian 
Cancer History on Primary PFS Analysis
In order to further evaluate if the baseline variables exert any potential confounding 
effect on the estimation of PFS HR, adjusted PFS HR will be estimated by fitting 
multivariate Cox regression models including important baseline variables, i.e., age, 
FIGO stage and debulking status, ECOG PS and histological grade. Other 
demographics or baseline characteristics might also be included if clinically relevant.
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4.4.5
Subgroup Analyses
To assess the consistency of the study PFS results, results in subgroups will be 
examined. The following subgroups will be considered: 

Demographics 

Baseline prognostic characteristics (e.g., FIGO stage and debulking status, ECOG 
PS etc.)
Summaries of PFS, including unstratified HRs estimated from Cox proportional hazards 
models, will be displayed for each level of the categorical variables in a forest plot
(Lewis and Clarke 2001). Kaplan-Meier estimates of median PFS will be produced 
separately for each level of the categorical variables for the comparisons between 
treatment arms.
4.5
SAFETY ANALYSES
All safety analyses will be performed on the safety population, i.e., all patients who 
receive any dose of study medication (see Section 4.1).
Safety will be assessed through study treatment exposures, summaries of adverse 
events (AEs), changes in laboratory test results and changes in vital signs, and will be 
presented by treatment arm.  Non-overlapping visit windows will be assigned to post-
baseline assessments.
4.5.1
Exposure of Study Medication
Study drug exposure, including but not limited to treatment duration, number of cycles, 
dose intensity, and total cumulative dose will be summarized for each treatment arm with 
descriptive statistics. The number of missed doses will also be displayed.
4.5.2
Adverse Events
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms and graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 4.0 
(NCI CTCAE v4.0).  Adverse events, occurring on or after the first dose of study 
treatment will be summarized by mapped term, appropriate thesaurus level, and 
NCI CTCAE grade regardless of relationship to study drug, as assessed by the 
investigator.  For each patient, if multiple incidences of the same AEs occur, the 
maximum severity reported will be used in the summaries.
Summary tables including but not limited to the following will be provided:

AEs

Serious Adverse Events (SAEs)

AEs leading to study treatment discontinuation 

AEs leading to dose reduction or interruption
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
Treatment-related AEs

Severe adverse events (Grade3)

AEs leading to death

AEs by highest NCI CTCAE Grade

Sponsor-defined AESI
Multiple occurrences of the same event will be counted once at the maximum severity.  
All listings of AEs will include all AEs with onset on or after the first study drug treatment 
up to the data cutoff date.
All deaths and causes of death will be summarized by treatment arm as well.
4.5.3
Laboratory Data
Laboratory data will be classified according to NCI CTCAE v4.0 and will be summarized 
descriptively over time including change from baseline.  Highest NCI CTCAE grade 
post-baseline will also be reported and shift tables from baseline to worst value during 
the study post-baseline will be presented.  
A Hy’s law analysis will be provided.  The potential Hy’s law quadrant is defined as the 
occurrence of either of the following:

Treatment-emergent ALT or AST3upper limit of normal (ULN) (or baseline value 
if baseline value was above the ULN) in combination with total bilirubin2ULN (of 
which35% is direct bilirubin).

Treatment-emergent ALT or AST3ULN (or baseline value if baseline value was 
above the ULN) in combination with clinical jaundice.
4.5.4
Vital Signs and ECOG Performance Status
Vital signs outside normal limits among subjects without abnormality at baseline will be 
summarized in the safety population. Change of ECOG PS from baseline to worst value 
will be summarized in the ITT population.
4.6
MISSING DATA
The handling of missing data is summarized in Section 4.4 for each endpoint.
4.7
INTERIM ANALYSIS
There will be no planned interim analysis for PFS. 
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5.
REFERENCES
Akazawa K, Nakamura T, Palesch Y. Power of Logrank Test and Cox Regression Model 
in Clinical Trials with Heterogeneous Samples. Statistics in Medicine 
1997;16:583-97.
Brookmeyer, Ron, and John Crowley. "A confidence interval for the median survival 
time." Biometrics 1982:2941.
Brotto L, Brundage M, Hoskins P, et al. Randomized study of sequential 
cisplatin-topotecan/carboplatin-paclitaxel versus carboplatin-paclitaxel: effects on 
quality of life. Support Care Cancer 2016;24:124149.
Brundage M, Osoba D, Bezjak A, et al. Lessons learned in the assessment of 
health-related quality of life: selected examples from the National Cancer Institute 
of Canada Clinical Trials Group. J Clin Oncol 2007;25:507881.
Cella D. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) 
measurement system. Version 4. Evanston: Center on Outcomes, Research and 
Education (CORE), Evanston Northwestern Healthcare and Northwestern 
University, 1997.
Cocks K. King MT, Velikova G, et al. Evidence-based guidelines for determination of 
sample size and interpretation of the European Organization for the Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 
2011;29:8996.
Fagotti A, Ferrandina G, Vizielli G, et al. Phase III randomised clinical trial comparing 
primary surgery versus neoadjuvant chemotherapy in advanced epithelial ovarian 
cancer with high tumour load (SCORPION trial): final analysis of peri-operative 
outcome. Eur J Cancer 2016;59:2233.
Fayers P, Aaronson N, Bjordal K, et al. on behalf of the EORTC Quality of Life Group. 
The EORTC QLQ-C30 scoring manual. 3rd ed. Brussels: European Organisation 
for Research and Treatment of Cancer; 2001b.
Fayers PM. Interpreting quality of life data: population-based reference data for the
EORTC QLQ-C30. Eur J Cancer 2001a;37:13314.
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:1479−80.
Luckett T, King M, Butow P, et al. Assessing health-related quality of life in gynecologic 
oncology: a systematic review of questionnaires and their ability to detect clinically 
important differences and change. Int J Gynecol Cancer 2010;20:66484.
Osoba D, Bezjak A, Brundage M, et al. Analysis and interpretation of health-related 
quality-of-life data from clinical trials: basic approach of The National Cancer 
Institute of Canada Clinical Trials Group. Eur J Cancer 2005;41:2807.
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Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health 
related quality-of-life scores. J Clin Oncol 1998;16:13944.
Osoba D. A taxonomy of the uses of health-related quality-of-life instruments in cancer 
care and the clinical meaningfulness of the results. Med Care 
2002;40(6 Suppl):III31–8.
Richter R, Oskay-Oezcelik G, Chekerov R, et al. Health-related quality of life during 
sequential chemotherapy with carboplatin followed by weekly paclitaxel in 
advanced ovarian cancer: a multicenter phase II study of the North Eastern 
German Society of Gynecological Oncology. Anticancer Res 2012;32:39676.
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Appendix 1
Protocol Synopsis
TITLE:
A PHASE III TRIAL OF CARBOPLATIN AND PACLITAXEL PLUS 
PLACEBO VERSUS CARBOPLATIN AND PACLITAXEL PLUS 
CONCURRENT AND EXTENDED BEVACIZUMAB, IN CHINESE
WOMEN WITH NEWLY DIAGNOSED, PREVIOUSLY 
UNTREATED, STAGE III OR STAGE IV, EPITHELIAL OVARIAN, 
FALLOPIAN TUBE OR PRIMARY PERITONEAL CANCER
PROTOCOL NUMBER:
YO40268
VERSION NUMBER:
3
EUDRACT NUMBER:
To be determined
IND NUMBER:
113807
NCT NUMBER:
NCT03635489
TEST PRODUCT:
Bevacizumab (RO4876646)
PHASE:
Phase III
INDICATION:
Stage III or Stage IV Epithelial Ovarian, Fallopian Tube, or Primary 
Peritoneal Cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of bevacizumab compared with placebo in 
combination with paclitaxel and carboplatin in Chinese patients with newly diagnosed, 
previously untreated FIGO Stage III with any gross (macroscopic or palpable) residual disease 
or FIGO Stage IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.
Specific objectives and corresponding endpoints for the study are outlined in the table below.
In this protocol, "study treatment" refers to the combination of treatments assigned to patients 
as part of this study (i.e., bevacizumab/placebo plus paclitaxel and carboplatin).
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
bevacizumab versus placebo in 
combination with paclitaxelcarboplatin
PFS after randomization, defined as the time from
randomization to the first occurrence of disease 
progression or death from any cause during the study 
(whichever occurs first), as determined by the 
investigator according to RECIST v1.1
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Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
bevacizumab versus placebo in 
combination with paclitaxelcarboplatin
OS after randomization, defined as the time from 
randomization to death from any cause
ORR, defined as a CR or PR, as determined by the 
investigator according to RECIST v1.1 for patients 
with measurable residual disease after primary 
surgery
DOR, defined for patients who had an OR and 
defined as the time from the first occurrence of a 
documented OR to disease progression, as 
determined by the investigator according to 
RECIST v1.1 or death from any cause, whichever 
occurs first for patients with measurable residual 
disease after primary surgery
To evaluate patient-reported 
abdominal symptoms of OC 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin, as measured 
by two items from the Abdominal/GI
Symptom Scale of the EORTC 
QLQ-OV28
Clinically meaningful improvement in 
patient-reported abdominal pain or bloating, defined 
as a 10-point decrease from the baseline score on 
either of the two items (Items 31 and 32) of the 
EORTC QLQ-OV28 Abdominal/GI Symptom Scale
To evaluate patient-reported 
outcomes (PROs) of function and 
health-related quality of life (HRQoL) 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Clinically meaningful improvement in 
patient-reported function and HRQoL, defined as a 
10-point increase from the baseline score on each 
of the function (physical, role, emotional, social) and 
global health status/HRQoL scales of the EORTC 
QLQ-C30
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate PROs of 
disease/treatment-related symptoms 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Mean and mean changes from the baseline score in 
disease and/or treatment-related symptoms by 
assessment timepoint and between treatment arms 
as assessed by all symptom items and/or scales of 
the EORTC QLQ-C30 and QLQ-OV28
To evaluate any treatment burden 
associated with bevacizumab versus 
placebo in combination with 
paclitaxelcarboplatin
Proportion of patients reporting each response 
option at each assessment timepoint by treatment 
arm for item GP5 from the FACT-G (“I am bothered 
by side effects of treatment.”)
To evaluate and compare between 
treatment arms patients' health utility, 
as measured by the EQ-5D-5L to 
generate utility scores for use in 
economic models for reimbursement
Health utility scores of the EQ-5D-5L questionnaire
Protocol Number: 
 Report Number: 
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Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
bevacizumab versus placebo in 
combination with 
paclitaxelcarboplatin
Occurrence and severity of adverse events, with 
severity determined according to NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical laboratory 
test results
CR complete response; DOR duration of response; EORTC European Organization for 
Research and Treatment of Cancer; GIgastrointestinal; HRQoL health-related quality of life; 
NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events; 
OC ovarian cancer; OR objective response; OS overall survival; PFS progression-free 
survival; PR partial response; PRO patient-reported outcome; QLQ-C30 Quality of Life 
Questionnaire Core 30; QLQ-OV28 Quality of Life Questionnaire Ovarian Cancer Module 28; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1.
Study Design
Description of Study
This is a Phase III, double-blind, two-arm, randomized study designed to evaluate the efficacy 
and safety of bevacizumab administered with paclitaxel plus carboplatin compared with placebo 
administered with paclitaxel plus carboplatin in Chinese patients with newly diagnosed, 
previously untreated FIGO Stage III with any gross (macroscopic or palpable) residual disease 
or FIGO Stage IV epithelial ovarian, fallopian tube, or primary peritoneal cancer.  Approximately 
100 patients are expected to be randomized. 
A patient-signed Informed Consent Form will be obtained before any study-specific procedures 
are undertaken. 
After informed consent is obtained, patients who meet the eligibility criteria will be randomized in 
a 1:1 ratio to the bevacizumab and carboplatin plus paclitaxel arm or the placebo and 
carboplatin plus paclitaxel arm.  Re-screening for any reason is not allowed.
Randomization will be stratified according to the following factors:  FIGO stage and debulking 
status (Stage III optimally debulked versus Stage III suboptimally debulked versus Stage IV) 
and Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1 or 2).
Patients will receive a maximum of six cycles of carboplatin/paclitaxel with either bevacizumab 
or placebo. Patients whose disease has not progressed after six cycles of chemotherapy with 
either bevacizumab or placebo will continue treatment with either bevacizumab or placebo until 
disease progression, unacceptable toxicity, or a maximum of 22 cycles, whichever occurs first. 
The details of each treatment arm are described below.
Number of Patients
Approximately 100 patients are expected to be enrolled in this study.
Target Population
The target population is patients with newly diagnosed, previously untreated, FIGO Stage III 
with any gross (macroscopic or palpable) residual disease or FIGO Stage IV epithelial ovarian, 
fallopian tube, or primary peritoneal cancer.
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment
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
A histologic diagnosis of EOC, peritoneal primary carcinoma, or fallopian tube cancer, FIGO 
Stage III with any gross (macroscopic or palpable) residual disease or FIGO Stage IV 
defined surgically at the completion of initial abdominal surgery and with appropriate tissue 
available for histologic evaluation
Patients with Stage III cancer for which the largest maximal diameter of any residual 
tumor implant at the completion of this initial surgery is no greater than 1 cm will be 
defined as having “optimally debulked” tumors.  All others will be defined as 
“suboptimally debulked” tumors.  Measurable disease on postoperative imaging 
studies is not required for eligibility.

Patients with the following histologic epithelial cell types are eligible:  serous 
adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, 
undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, 
transitional cell carcinoma, malignant Brenner tumor, or adenocarcinoma not otherwise 
specified

ECOG Performance Status 0, 1, or 2

Life expectancy of at least 12 weeks

Adequate hematological function indicated by all of the following:
−
ANC 1.5 109/L (ANC is not to be induced or supported by granulocyte colony-
stimulating factors [G-CSFs])
−
Platelet count 100 109/L (without transfusion)
−
Hemoglobin 9.0 g/dL:  Patients may receive RBC transfusions to attain this value. 

Adequate liver function indicated by all of the following: 
−
Serum bilirubin 1.5 the institutional upper limit of normal (ULN)
Patients with known Gilbert disease who have serum bilirubin level 3 ULN 
may be enrolled in the study.
−
AST, ALT, and alkaline phosphatase (ALP) 2.5 ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5 ULN
Patients with documented liver or bone metastases:  ALP 5 ULN

Adequate renal function indicated by all of the following: 
−
Serum creatinine (Scr) 1.5 ULN or calculated creatinine clearance (Ccr) 50 mL/min
−
Urinalysis for proteinuria 2unless a 24-hour urine protein 1 g is demonstrated

Blood coagulation parameters:  prothrombin time (PT) such that the international
normalized ratio (INR) is 1.5 (or an in-range INR, usually between 2 and 3, if a patient was 
on a stable dose of therapeutic warfarin for management of venous thrombosis, including 
pulmonary thromboembolus) and activated partial thromboplastin time (aPTT) is
1.5 ULN.  The use of full-dose oral or parenteral anticoagulants is permitted as long as 
the INR or aPTT is within therapeutic limits (according to the medical standard of the 
enrolling institution), and the patient has been on a stable dose of anticoagulants for at least 
2 weeks prior to randomization.

Neurologic function:  neuropathy (sensory and motor) of the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 1 or better

Enrollment between 1 and 12 weeks after initial surgery is performed for the combined 
purpose of diagnosis, staging, and cytoreduction
Patients with measurable and non-measurable disease are eligible.  Patients may or 
may not have cancer-related symptoms.

Patients in this trial may receive ovarian estrogen with or without progestin replacement 
therapy as indicated at the lowest effective dose(s) for control of menopausal symptoms at 
any time, but not progestins for management of anorexia during study treatment or prior to 
disease progression
Protocol Number: 
 Report Number: 
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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% per year 
during the treatment period and for at least 6 months after the last dose of bevacizumab, 
paclitaxel, or carboplatin, whichever is later.  Women must refrain from donating eggs 
during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries, fallopian tubes, and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the completion of PRO questionnaires
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Current diagnosis of borderline epithelial ovarian tumor or recurrent invasive epithelial 
ovarian, primary peritoneal, or fallopian tube cancer treated with surgery only (such as 
patients with Stage IA or IB low-grade epithelial ovarian or fallopian tube cancers)
Patients with a prior diagnosis of a borderline tumor that was surgically resected and 
who subsequently developed unrelated, new invasive epithelial ovarian, peritoneal 
primary, or fallopian tube cancer are eligible, provided that they have not received prior 
chemotherapy for any ovarian tumor.

Prior radiotherapy to any portion of the abdominal cavity or pelvis 
Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, 
provided that it was completed more than 3 years prior to randomization and the 
patient remains free of recurrent or metastatic disease.

Prior chemotherapy for any abdominal or pelvic tumor, including neoadjuvant chemotherapy 
for ovarian, primary peritoneal, or fallopian tube cancer.  
Patients may have received prior adjuvant chemotherapy for localized breast cancer, 
provided that it was completed more than 3 years prior to randomization and that the 
patient remains free of recurrent or metastatic disease. 

Any prior targeted therapy (including, but not limited to, vaccines, antibodies, or tyrosine 
kinase inhibitors) or hormonal therapy for management of their epithelial ovarian or 
peritoneal primary cancer 

Synchronous primary endometrial cancer, or a history of primary endometrial cancer unless 
all of the following conditions are met:  
−
Stage not greater than Stage IB
−
No more than superficial myometrial invasion, without vascular or lymphatic invasion
−
No poorly differentiated subtypes, including papillary serous, clear cell, or other FIGO 
Grade 3 lesions

With the exception of nonmelanoma-related skin cancers and other specific malignancies 
as noted above, patients with other invasive malignancies who had (or have) any evidence 
of the other cancer present within the last 5 years or whose previous cancer treatment 
contraindicates study treatment

Prior or current treatment with any anti-angiogenic, including bevacizumab. 

Treatment with any other investigational agent or previous participation in another clinical 
trial within 30 days prior to randomization in this study.
Protocol Number: 
 Report Number: 
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
Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive 
hepatitis B surface antigen (HBsAg) test result at screening, with the following exception:
Patients with a past or resolved HBV infection, defined as having a negative HBsAg 
test result and a positive total hepatitis B core antibody (HBcAb) test result at 
screening, are eligible for the study if HBV DNA is negative or undetectable.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test 
result and a positive HCV RNA test result at screening

A positive test result for HIV

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Current or recent (within 10 days prior to randomization) use of aspirin (325 mg/day) or 
other non-steroidal anti-inflammatory agents known to inhibit platelet function  

Serious non-healing wounds, ulcers, or bone fractures  
This includes history of abdominal fistula, GI perforation, or intra-abdominal abscess 
within 28 days prior to randomization.  Patients with granulating incisions healing by 
secondary intention with no evidence of fascial dehiscence or infection are eligible but 
require weekly wound examinations.

Active bleeding or pathologic conditions that carry high risk of bleeding, such as known 
bleeding disorder, coagulopathy, or tumor involving major vessels 

History or evidence upon physical examination of CNS disease, including primary brain 
tumor, seizures not controlled with standard medical therapy, any brain metastases, or 
history of cerebrovascular accident (CVA; stroke), transient ischemic attack (TIA), or 
subarachnoid hemorrhage within 6 months of the first date of treatment on this study 

History of hypertensive crisis or hypertensive encephalopathy

Patients with clinically significant cardiovascular disease; this includes the following:
−
Uncontrolled hypertension, defined as systolic 150 mmHg or diastolic 90 mmHg
−
Myocardial infarction or unstable angina 6 months prior to randomization
−
New York Heart Association (NYHA) Class II or greater congestive heart failure (CHF)
−
Serious cardiac arrhythmia requiring medication (This does not include asymptomatic, 
atrial fibrillation with controlled ventricular rate.)
−
NCI CTCAE Grade 2 peripheral vascular disease (at least brief [ 24 hours] episodes 
of ischemia managed non-surgically and without permanent deficit)
−
History of CVA within 6 months prior to randomization

Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human 
or humanized antibodies

Have known sensitivity to any component of paclitaxel

Patients scheduled to undergo an invasive procedure as defined below: 
Major surgical procedure within 28 days prior to the first date of bevacizumab/placebo 
therapy (Cycle 2) or anticipated during the course of the study.  This includes, but is 
not limited to, abdominal surgery prior to disease progression, such as colostomy or 
enterostomy reversal, interval or secondary cytoreductive surgery, or second-look 
surgery. 
Core biopsy or other minor surgical procedures performed within 7 days prior to the 
anticipated first dose of bevacizumab/placebo therapy, with the following exception:  
The interval of time between placement of a central vascular access device (CVAD) 
(e.g., Port-A-Cath®) and the first dose of bevacizumab for a patient must be no shorter 
than 2 days with a well-healed incision 
Protocol Number: 
 Report Number: 
Clinical Study Report: bevacizumab - F. Hoffmann-La Roche Ltd
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
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 6 months after the last dose of bevacizumab, paclitaxel, or carboplatin, whichever is 
later
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to randomization.

Patients with clinical symptoms or signs of GI obstruction and who require parenteral 
hydration and/or nutrition

Evidence of any other disease, neurologic or metabolic dysfunction, physical examination 
finding, or laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of any of the study drugs, puts the patient at higher risk for 
treatment-related complications, or may affect the interpretation of study results

Requirement for treatment with any medicinal product that contraindicates the use of any of 
the study drugs, may interfere with the planned treatment, affects patient compliance, or 
puts the patient at high risk for treatment-related complications

History or evidence of thrombotic disorders within the last 6 months prior to randomization
End of Study
The end of the study period is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for PFS analysis or safety follow-up is 
completed by the last patient, whichever occurs later.  Additionally, the Sponsor may decide to 
terminate the study at any time.
Investigational Medicinal Products
The investigational medicinal product (IMP) for this study is bevacizumab.
Test Product (Investigational Drug)
Patients in the bevacizumab and chemotherapy arm will receive bevacizumab and 
paclitaxel/carboplatin combination therapy as follows:

Chemotherapy:
−
Paclitaxel 175 mg/m2 IV over 3 hours on Day 1
−
Carboplatin area under the concentrationtime curve (AUC) 6 IV administered 
over 30 minutes on Day 1 of each cycle

Bevacizumab:  Bevacizumab 15 mg/kg IV on Day 1 of Cycle 2 Q3W starting at Cycle 2 until 
disease progression, unacceptable toxicity, a maximum of 21 cycles, or withdrawal,
whichever occurs first
Each chemotherapy cycle is to be repeated Q3W until disease progression, unacceptable
toxicity, a maximum of six cycles, or withdrawal, whichever comes first.
Paclitaxel will be the first drug of the regimen to be administered to patients in each cycle in 
both arms, followed by carboplatin and then bevacizumab.
Comparator
Patients in the placebo and chemotherapy arm will receive placebo and paclitaxel/carboplatin 
combination therapy as follows: 

Chemotherapy:
−
Paclitaxel 175 mg/m2 IV over 3 hours on Day 1
−
Carboplatin AUC 6 mg/mL/min IV over 30 minutes on Day 1

Placebo:  Placebo IV on Day 1 Q3W starting at Cycle 2 until disease progression, 
unacceptable toxicity, a maximum of 21 cycles, or withdrawal, whichever occurs first
Each chemotherapy cycle will be repeated Q3W until disease progression, unacceptable 
toxicity, a maximum of six cycles, or withdrawal, whichever comes first. 
Paclitaxel will be the first drug of the regimen to be administered in each cycle in both arms, 
followed by carboplatin and then placebo.
Protocol Number: 
 Report Number: 
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Non-Investigational Medicinal Products
Carboplatin and paclitaxel are the non-investigational medicinal products (NIMPs) for this study.  
Sites will obtain and utilize commercially available carboplatin and paclitaxel.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is PFS, which will be assessed by the investigator using 
RECIST v1.1.  The study is not fully powered for the primary endpoint; instead consistency with 
the global pivotal study (GOG218) will be considered for the primary endpoint.
PFS after randomization is defined as the time from randomization to the first documented 
occurrence of disease progression or death from any cause during the study (whichever occurs 
first), as determined by the investigator according to RECIST v1.1.  Data for patients who have 
not experienced disease progression or death will be censored at the last tumor assessment.  
Data for patients with no post-baseline tumor assessment will be censored at the date of 
randomization plus 1 day.
The primary endpoint of PFS will be analyzed between treatment and control arms based on the 
stratified log-rank test.  The HR of PFS in the experimental arm compared with the control arm 
will be estimated using a stratified Cox regression model, and the 95% CI will be provided.  The 
stratification factors will be those used during randomization, as recorded in eCRF.  Results 
from an unstratified analysis will also be presented.  Kaplan-Meier methodology will be used to 
estimate median PFS for each treatment arm, and Kaplan-Meier curves will be constructed to 
provide visual descriptions of the difference between the treatment and control arms.
The Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median PFS 
and OS for each treatment arm.
Determination of Sample Size  
The purpose of this study is to confirm the efficacy and safety of bevacizumab in a population of 
Chinese women with advanced ovarian, fallopian tube, and primary peritoneal cancers who 
have not received prior chemotherapy for this disease, and to investigate the consistency in 
treatment effect between Chinese patients and the patients in global study for the purpose of 
registration in China.  The primary efficacy results will be bridged with those of the pivotal 
Study GOG218.
A total of approximately 100 patients will be randomized in a 1:1 ratio to either the bevacizumab 
or placebo arms of the study.  The final analysis of the primary endpoint of PFS will be 
performed when approximately 56 PFS events have occurred in the ITT population (56% of 100 
patients), which will provide an 80% probability of demonstrating consistency with the global 
study.
Interim Analyses
There will be no planned interim analysis.
Protocol Number: 
 Report Number: 
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Appendix 2
Schedule of Assessments
Observations and Tests
Pre-Treatment
Chemotherapy (Cycles 16) and 
Bevacizumab/Placebo 
(Cycles 26) a
Bevacizumab/  
Placebo Only (Cycle
7 through 
Discontinuation) a
Study 
Completion/Early 
Termination 
Visit a
Post-Treatment a
Day 28 to 1
Weekly
Every 
Course
Every 
Other 
Course
Every 
Course
Every 
Other 
Course
Within 30 days 
of the last dose 
of the study 
treatment
Every 3 Months 
for 2 Years, 
Every 6 Months 
for 3 Years, Then 
Annually
Informed consent 
x
History and physical 
examination
x b
x c, d
x c, d
x
ECOG PS
x
x
x
x
Vital signs
x b
x e
x c
x c
Hematology f
x g
x
x
x
Urinalysis
x h
x i
x i
x
Serum chemistry j
x g
x
x
x
Serum pregnacy test (for 
women of childbearing 
potential)
x g
As clinically indicated
PT/INR, aPTT
x g
x k
x k
x l
Audiogram
x m
ECG
x b
As clinically indicated
Protocol Number: 
 Report Number: 
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Appendix 2
Schedule of Assessments (cont.)
Observations and Tests
Pre-Treatment
Chemotherapy (Cycles 16) and 
Bevacizumab/Placebo 
(Cycles 26) a
Bevacizumab/  
Placebo Only (Cycle
7 through 
Discontinuation) a
Study 
Completion/Early 
Termination 
Visit a
Post-Treatment a
Day 28 to 1
Weekly
Every 
Course
Every 
Other 
Course
Every 
Course
Every 
Other 
Course
Within 30 days 
of the last dose 
of the study 
treatment
Every 3 Months 
for 2 Years, 
Every 6 Months 
for 3 Years, Then 
Annually
Radiographic disease 
assessment
x b, n
x d, o
x d, o
x p
x o
HIV, HBV, HCV 
serology q
x
Serum CA-125 level
x b, r
x c, s
x c, s
x
EORTC QLQ-C30, QLQ-
OV28, and EQ-5D-5L t
x
x
x
x
FACT-G and the single 
item GP5 t
Starting at 
Cycle 4
x
x
x
Adverse events u
x g
x
x
x
x
x
Concomitant medications
x v
x
x
x
x
Incision check
x
x w
Bevacizumab/placebo 
administration
x x
x
Paclitaxel administration
x
Carboplatin 
administration
x
Protocol Number: 
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Appendix 2
Schedule of Assessments (cont.)
aPTTactivated partial thromboplastin time; CA-125cancer antigen 125; CTcomputed tomography; ECOG PSEastern Cooperative Oncology 
Group Performance Status; EORTCEuropean Organization for Research and Treatment of Cancer; EQ-5D-5LEuroQol 5 Dimension, 5-Level 
Questionnaire; FACT-G GP5Functional Assessment of Cancer Therapy–General; HBcAbhepatitis B core antibody; HBsAbhepatitis B surface 
antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; INRInternational Normalized Ratio; MRImagnetic 
resonance imaging; QLQ-OV28Quality of Life Questionnaire Ovarian Cancer Module 28; QLC-C30Quality of Life Questionnaire Core 30; 
PROpatient-reported outcome; PTprothrombin time; RECIST Response Evaluation Criteria in Solid Tumors.
a Each cycle is 21 days.  Study drug administration occurs on Day 1 (3 days) of each cycle.  All other events and assessments during the study 
treatment must occur within 3 days prior to the administration.  The end of the study treatment or early discontinuation visit should occur within 
30 days after the last dose of the study treatment is administered.  The post-treatment follow up visits will occur every 3 months (14 days) for 
the first 2 years after the end of study treatment or early discontinuation visit, then every 6 months (14 days) for 3 years, and then annually.
b Must be performed within 28 days prior to start of study treatment.
c Within 1 week before and as close to the beginning of the next applicable course as possible.
d Patients who do not experience disease progression, including those who will discontinue study treatment, need to be followed in a consistent 
fashion to monitor tumor status.  Therefore, the schedule of tumor assessment by physical examination, CA-125 monitoring, and imaging should 
be conducted according to the timeline shown per the study calendar.
e Vital signs should be assessed at least weekly during the first cycle of bevacizumab/placebo therapy.  During the time between treatments, vital 
sign assessments may be performed at home by the patient at the investigator’s discretion, and the investigator or study nurse are responsible 
for obtaining the results from the patient.
f
Hematology should include hemoglobin, hematocrit, platelet count, red blood cell count, and WBC count with differential (neutrophils). Additional 
hematologic assessments may be performed as clinically indicated or per local practice.
g Must be obtained within 14 days prior to start of study treatment.
h Within 7 days before treatment.
i
Does not need to be repeated on Day 1 if tests are performed within 7 days before Day 1 (start of study treatment).
j
Serum chemistry includes sodium, potassium, glucose, blood urea nitrogen (BUN), creatinine, albumin, bilirubin, AST, ALT, and ALP.
k For patients on prophylactic or therapeutic anticoagulation with warfarin, PT/INR should be monitored before each treatment.  Treatment should 
be withheld for PT INR of 1.5 on prophylactic warfarin or greater than the therapeutic range if patient is on full-dose warfarin.
l
When clinically indicated.
m For patients with a history of hearing loss; an audiogram should be repeated as clinically indicated.
n An initial CT or MRI scan of at least the chest, abdomen, and pelvis is required to establish a postsurgical baseline for the extent of residual 
disease within 28 days prior to randomization (Scan 1).  A CT/MRI scan of the neck and/or head may also be performed if necessary.
Protocol Number: 
 Report Number: 
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Appendix 2
Schedule of Assessments (cont.)
o Follow-up radiographic assessment of disease.  In the absence of RECIST-defined disease progression, imaging using the same modality and 
encompassing the same field as in the initial pre-treatment evaluation should be repeated with the following schedule, regardless of whether or 
not the patient has measurable disease on initial CT or MRI scan and regardless of the treatment cycle:
Scans 2 and 3:  Every 9 weeks (5 days) from the date of randomization during the concurrent treatment phase
Scans 4, 5, 6, and 7:  Every 12 weeks (5 days) in the maintenance phase (the first scan in the maintenance phase is performed 12 weeks 
after the last scan during the concurrent treatment phase)
After the completion of all protocol therapy, every 3 months (14 days) for 2 years, then every 6 months (14 days) for 3 years.  CT scans or 
MRIs after 5 years of survival follow-up may be done as clinically indicated.
During or after completion of all study treatment, as clinically indicated at any time for clinical suspicion of progressive disease, including rising 
serum CA-125 levels, not meeting criteria for disease progression.  Imaging assessments as part of this protocol should be discontinued if 
RECIST-defined disease progression is confirmed according to guidelines. 
Patients with no RECIST-defined disease progression who are early discontinued from study treatment before Cycle 6 (including Cycle 6), 
Scans 2 and 3:  Every 9 weeks (5 days) from the date of randomization; the following tumor assessments should be conducted every 
3 months (14 days) after the study completion/early termination visit for 2 years, then every 6 months (14 days) for 3 years.  CT scans 
or MRIs after 5 years of survival follow-up may be done as clinically indicated.
Patients with no RECIST-defined disease progression who are early discontinued from study treatment after Cycle 6, the following tumor 
assessments should be conducted every 3 months (14 days) after the study completion/early termination visit for 2 years, then every 
6 months (14 days) for 3 years.  CT scans or MRIs after 5 years of survival follow-up may be done as clinically indicated.
p If not performed within 28 days prior to the treatment discontinuation visit. 
q HBsAg, HBsAb, HBcAb, and HCV Ab serology and HIV testing are required at screening. If a patient has a negative HBsAg test and a positive
total HBcAb test at screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection.  If a patient has a 
positive HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection.
r
Baseline pre-chemotherapy value is required.  When available, also include pre-surgical value.
s PFS will be assessed using RECIST, Version 1.1.  CA-125 elevation alone will not be used to define progressive disease.  However, CA-125 
levels will be collected as described in the schedule of activities to enable further analysis.
t
All PRO questionnaires must be completed in their entirety by the patient at the investigational site at the start of the clinic visit before discussion 
of the patient’s health state, laboratory test results, or health records, before the administration of the study treatment, and/or prior to the 
performance of any other study assessments (e.g., scans) that could bias the patient’s responses.
The EORTC QLQ-C30, QLQ-OV28, and EQ-5D-5L questionnaires must be administered and completed by patients in that order at the 
following assessment timepoints:  baseline, defined as prior to Cycle 1 (3 days); prior to Cycle 4 of chemotherapy (3 days); prior to Cycle 7 
Protocol Number: 
 Report Number: 
Clinical Study Report: bevacizumab - F. Hoffmann-La Roche Ltd
YO40268
1105854
29


Bevacizumab—F. Hoffmann-La Roche Ltd
30/Statistical Analysis Plan YO40268
Appendix 2
Schedule of Assessments (cont.)
(3 days); prior to Cycle 13 (3 days); prior to Cycle 22 (3 days); at the end of treatment or discontinuation visit within 30 days of the 
administration of the last dose of study treatment; after the treatment completion visit, every 3 months ( 14 days) for the first year of the 
survival follow-up period; every 6 months ( 14 days) for the second year of the survival follow-up period; and every year ( 14 days) for the 
final 3 years of the survival follow-up period.
The single-item GP5 from the FACT-G questionnaire will be the final PRO measure to be administered and must be completed by patients 
beginning at the Cycle 4, Day 1 visit; and then at all other assessment timepoints listed above along with the other PRO questionnaires.
u All serious adverse events and adverse events of special interest, regardless of their relationship to the study drug, will be reported until 90 days 
after the last dose of the study drug is administered or the initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, 
regardless of the relationship to the study drug, will be reported until 30 days after the last dose of the study drug is administered or the initiation 
of new anti-cancer therapy, whichever occurs first.  After this period, the investigator should report any serious adverse events that are believed 
to be related to prior study drug treatment.
v Concomitant medications need to be collected 7 days prior to starting study treatment.
w Patients with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are eligible, but require 
weekly wound examinations until complete closure.
x
Bevacizumab/placebo is initiated at Cycle 2 rather than at Cycle 1.
Protocol Number: 
 Report Number: 
Clinical Study Report: bevacizumab - F. Hoffmann-La Roche Ltd
YO40268
1105854
30