A Phase 3, Randomized, Double-Blind Study of Pembrolizumab Versus Placebo in Combination With Paclitaxel With or Without Bevacizumab for the Treatment of Platinum-resistant Recurrent Ovarian Cancer (KEYNOTE-B96/ENGOT-ov65)
Phase: PHASE3
Conditions: Ovarian Cancer, Carcinoma, Ovarian Epithelial, Fallopian Tube Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT05116189 
Document Date: 
31-Jan-2024
A Phase 3, Randomized, Double-Blind Study of Pembrolizumab 
versus Placebo in Combination With Paclitaxel With or Without 
Bevacizumab for the Treatment of Platinum-resistant Recurrent 
Ovarian Cancer (KEYNOTE-B96 / ENGOT-ov65)

PRODUCT: MK-3475
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Double-Blind Study of Pembrolizumab versus 
Placebo in Combination With Paclitaxel With or Without Bevacizumab for the Treatment of 
Platinum-resistant Recurrent Ovarian Cancer (KEYNOTE-B96 / ENGOT-ov65)
Protocol Number: B96-04 / ENGOT-ov65
Compound Number: MK-3475
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT05116189
EU CT
2023-506177-35
EudraCT
2020-005027-37
JRCT
jRCT2051210184
WHO
Not applicable
UTN
Not applicable
IND
126,191
Approval Date: 31 January 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04/
Global Amendment
31-JAN-2024
To update the target number of events for the 
interim/final analyses and sample size and power 
calculations to reflect the actual PD-L1 CPS 
prevalence within the study based on blinded 
data review.
Amendment 03/
Global Amendment
22-JUN-2022
To add collection of blood samples for 
pembrolizumab PK and ADA/NAb analysis for 
participants receiving bevacizumab due to 
Health Authority request, to provide additional 
clarifications for inclusion/exclusion criteria, and 
to change the Sponsor entity name and address.
Amendment 02/
Germany-specific 
Amendment
22-DEC-2021
To clarify in the Schedule of Assessments that 
pregnancy testing is to continue in posttreatment 
for 120 days after the last dose of 
pembrolizumab/placebo or 180 days after the 
last dose of paclitaxel, docetaxel (if applicable), 
or bevacizumab (if using) and to remove the 
contraceptive language from the Germany 
country-specific appendix that was incorrectly 
included.
Amendment 01/
Japan-specific 
Amendment
13-OCT-2021
To indicate docetaxel as IMP in Japan, and 
permit a starting dose for docetaxel (if using) of 
70 mg/m2 for Japanese participants.
Original Protocol
27-JUL-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendment:
To update the target number of events for the interim/final analyses and sample size and 
power calculations to reflect the actual PD-L1 CPS prevalence within the study based on 
blinded data review.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 9.1 
Statistical 
Analysis Plan 
Summary
The target number of events for the 
interim/final analyses and sample size and 
power calculations were updated to reflect the 
actual PD-L1 CPS prevalence within the study 
based on blinded data review.
To align with new data.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Throughout
The structure of the protocol has been updated.
To comply with current industry regulations and 
guidelines. This restructuring does not affect the 
clinical or regulatory integrity of the protocol. 
All other changes and their reasons are included 
for completeness.
Title Page
The NCT number was added.
To include all available and applicable regulatory 
agency numbers.
The EU CT number was added.
See rationale for Title Page (NCT number).
The jRCT number was added.
See rationale for Title Page (NCT number).
Section 1.1 
Synopsis
Indication: The indication was updated to 
ovarian cancer recurrent.
To align with MedDRA coding.
Section 1.3 
Schedule of 
Activities
A statement referring to Table 1 and Table 2 
was added.
To correctly cite tables in text.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 1.3.1 
First Course 
Treatment
Table 1: An “X” was added to the Cycle 1 
column of the ECOG performance status row
and the related note in the comments column 
was clarified.
To accurately depict the intended collection 
timepoints.
Table 1: An “X” was added to the Cycle 1 
column of the chemistry row and the related 
note in the comments column was clarified.
See rationale for Section 1.3.1 (ECOG).
Table 1: An “X” was added to the Cycle 1 
column of the hematology row and the related 
note in the comments column was clarified.
See rationale for Section 1.3.1 (ECOG).
Table 1: An “X” was added to the Cycle 1 
column of the urinalysis (for participants 
receiving bevacizumab) row and the related 
note in the comments column was clarified.
See rationale for Section 1.3.1 (ECOG).
Section 1.3.2
Second Course 
(Retreatment)
Table 2: Details of pregnancy test requirements 
posttreatment were added to the comments 
column of the pregnancy test row.
To correct a previous erroneous omission.
Table 2: An “X” was added to the Cycle 1 
column of the urinalysis row.
See rationale for Section 1.3.2 (pregnancy test 
requirements).
Section 4.4 
Beginning and 
End-of-Study 
Definition
The description of lost to follow-up was 
replaced with a citation to Section 7.3.
To allow a participant to be considered lost to 
follow-up as appropriate for the study.
Section 5.2 
Exclusion 
Criteria
Exclusion Criterion 21: A statement referring to 
Appendix 7 was added.
See rationale for Section 1.3.2 (pregnancy test 
requirements).
Exclusion Criterion 22: A statement referring to 
Appendix 7 was added.
See rationale for Section 1.3.2 (pregnancy test 
requirements).
Section 6.1 Study 
Intervention(s)
Administered
Table 4: The descriptions for the dose 
formulations for pembrolizumab, paclitaxel, 
docetaxel, bevacizumab, and placebo were 
updated to Solution.
To align with ISO standards.
Table 4: A note regarding duration of treatment 
with paclitaxel and bevacizumab was added.
To align with the rest of the protocol.
Section 7.3 Lost 
to Follow-up
The definition for when a participant is 
considered lost to follow-up and how the 
missing data will be handled were deleted.
See rationale for Section 4.4.
Section 9.7.1 
Efficacy Interim 
Analysis
Table 11: The target number of events for the 
interim/final analyses and sample size and 
power calculations were updated to reflect the 
actual PD-L1 CPS prevalence within the study 
based on blinded data review.
See rationale for Section 9.1.
Section 9.8.1 
Progression-free 
Survival
Table 12:The target number of events for the 
interim/final analyses and sample size and 
power calculations were updated to reflect the 
actual PD-L1 CPS prevalence within the study 
based on blinded data review.
See rationale for Section 9.1.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 9.8.2 
Overall Survival
Table 13: The target number of events for the 
interim/final analyses and sample size and 
power calculations were updated to reflect the 
actual PD-L1 CPS prevalence within the study 
based on blinded data review.
See rationale for Section 9.1.
Section 9.9 
Sample Size and 
Power 
Calculations
The target number of events for the 
interim/final analyses and sample size and 
power calculations were updated to reflect the 
actual PD-L1 CPS prevalence within the study 
based on blinded data review.
See rationale for Section 9.1.
Section 10.3.2 
Definition of AE
Reference to Sponsor’s product was removed.
To align terminology throughout the protocol.
Section 10.3.5 
Recording AE 
and SAE
References to Sponsor’s product were replaced 
with study intervention.
See rationale for Section 10.3.2.
Section 10.7.5 
Japan
The Japan-specific requirement regarding the 
bevacizumab dosing regimen was updated to 
include the newly approved, 10-mg/kg Q2W 
bevacizumab dosing regimen in Japan.
To allow participants in Japan the option to 
receive either of the bevacizumab dosing 
regimens now approved for treatment of ovarian 
cancer in Japan.
The Japan-specific requirement regarding the 
docetaxel dose was updated to refer to Section 
4.3.2 instead of Section 4.3.3.
To correct a previous error.
Throughout 
document
Minor administrative, formatting, grammatical,
and/or typographical changes were made
throughout the document.
To ensure clarity and accurate interpretation of 
the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities...........................................................................................22
1.3.1
First Course Treatment ................................................................................22
1.3.2
Second Course (Retreatment) ......................................................................31
2
INTRODUCTION..........................................................................................................37
2.1
Study Rationale....................................................................................................38
2.2
Background ..........................................................................................................39
2.2.1
Pembrolizumab ............................................................................................39
2.2.1.1
Pharmaceutical and Therapeutic Background ...................................40
2.2.1.2
Preclinical and Clinical Studies .........................................................40
2.2.1.3
Ongoing Clinical Studies...................................................................40
2.2.2
Therapeutic Strategies in Platinum-resistant Ovarian Cancer .....................40
2.2.3
Immunotherapy Plus Chemotherapy in Platinum-resistant Recurrent 
Ovarian Cancer ............................................................................................42
2.2.4
Pembrolizumab and Paclitaxel in Platinum-resistant Recurrent Ovarian 
Cancer ..........................................................................................................43
2.2.5
Safety Data on the Combination of Pembrolizumab and Chemotherapy 
in Other Malignancies..................................................................................43
2.3
Benefit/Risk Assessment......................................................................................44
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................45
4
STUDY DESIGN............................................................................................................49
4.1
Overall Design......................................................................................................49
4.2
Scientific Rationale for Study Design.................................................................51
4.2.1
Rationale for Endpoints ...............................................................................51
4.2.1.1
Efficacy Endpoints.............................................................................51
4.2.1.2
Safety Endpoints................................................................................52
4.2.1.3
Patient-reported Outcomes.................................................................52
4.2.1.3.1
EORTC QLQ-C30 ...................................................................52
4.2.1.3.2
EORTC QLQ-OV28 ................................................................52
4.2.1.3.3
EQ-5D-5L ................................................................................53
4.2.1.4
Planned Exploratory Biomarker Research.........................................53
4.2.1.5
Future Biomedical Research..............................................................55
4.2.2
Rationale for the Use of Comparator/Placebo .............................................55
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4.3
Justification for Dose...........................................................................................55
4.3.1
Pembrolizumab ............................................................................................55
4.3.2
Paclitaxel......................................................................................................56
4.3.3
Bevacizumab................................................................................................56
4.3.4
Maximum Dose/Exposure for This Study ...................................................56
4.4
Beginning and End-of-Study Definition ............................................................57
4.4.1
Clinical Criteria for Early Study Termination .............................................57
5
STUDY POPULATION ................................................................................................58
5.1
Inclusion Criteria.................................................................................................58
5.2
Exclusion Criteria................................................................................................61
5.3
Lifestyle Considerations......................................................................................63
5.3.1
Meals and Dietary Restrictions....................................................................63
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................64
5.4
Screen Failures.....................................................................................................64
5.5
Participant Replacement Strategy......................................................................64
6
STUDY INTERVENTION............................................................................................65
6.1
Study Intervention(s) Administered...................................................................65
6.1.1
Treatment .....................................................................................................68
6.1.2
Second Course .............................................................................................68
6.2
Preparation/Handling/Storage/Accountability .................................................68
6.2.1
Dose Preparation..........................................................................................68
6.2.2
Handling, Storage, and Accountability........................................................69
6.3
Measures to Minimize Bias: Randomization and Blinding..............................69
6.3.1
Intervention Assignment..............................................................................69
6.3.2
Stratification.................................................................................................69
6.3.3
Blinding........................................................................................................70
6.4
Study Intervention Compliance..........................................................................70
6.5
Concomitant Therapy..........................................................................................70
6.5.1
Cautions for Use of Paclitaxel .....................................................................72
6.5.2
Cautions for Use of Docetaxel.....................................................................72
6.5.3
Rescue Medications and Supportive Care ...................................................72
6.6
Dose Modification (Escalation/Titration/Other)...............................................72
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................73
6.6.2
Dose Modification for Chemotherapy-related Toxicity ..............................79
6.6.3
Dose Modification for Bevacizumab-related Toxicity ................................80
6.7
Intervention After the End of the Study............................................................80
6.8
Clinical Supplies Disclosure................................................................................80
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6.9
Standard Policies..................................................................................................80
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................81
7.1
Discontinuation of Study Intervention...............................................................81
7.2
Participant Withdrawal From the Study...........................................................82
7.3
Lost to Follow-up .................................................................................................82
8
STUDY ASSESSMENTS AND PROCEDURES........................................................84
8.1
Administrative and General Procedures ...........................................................84
8.1.1
Informed Consent.........................................................................................84
8.1.1.1
General Informed Consent.................................................................85
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................85
8.1.2
Inclusion/Exclusion Criteria ........................................................................85
8.1.3
Participant Identification Card.....................................................................85
8.1.4
Medical History ...........................................................................................86
8.1.4.1
Ovarian Cancer History Details.........................................................86
8.1.5
Prior and Concomitant Medications Review...............................................86
8.1.5.1
Prior Medications...............................................................................86
8.1.5.2
Concomitant Medications..................................................................86
8.1.5.3
Subsequent Anticancer Treatment .....................................................87
8.1.6
Assignment of Screening Number...............................................................87
8.1.6.1
Treatment Eligibility Assessment Form ............................................87
8.1.7
Assignment of Treatment/Randomization Number.....................................87
8.1.8
Study Intervention Administration ..............................................................88
8.1.8.1
Timing of Dose Administration.........................................................88
8.1.8.1.1
Pembrolizumab/Placebo ..........................................................88
8.1.8.1.2
Paclitaxel (or Docetaxel)..........................................................88
8.1.8.1.3
Bevacizumab............................................................................89
8.1.9
Discontinuation and Withdrawal .................................................................89
8.1.9.1
Withdrawal From Future Biomedical Research ................................90
8.1.10
Participant Blinding/Unblinding..................................................................90
8.1.10.1
Nonemergency Unblinding................................................................91
8.1.11
Calibration of Equipment.............................................................................91
8.1.12
Tumor Tissue for Biomarker Status.............................................................91
8.2
Efficacy Assessments ...........................................................................................92
8.2.1
Tumor Imaging and Assessment of Disease................................................92
8.2.1.1
Initial Tumor Scans............................................................................93
8.2.1.2
Tumor Scans During the Study..........................................................93
8.2.1.3
End-of-treatment and Follow-up Tumor Scans .................................94
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8.2.1.4
Second Course (Retreatment) Tumor Scans......................................94
8.2.1.5
RECIST 1.1 Assessment of Disease..................................................95
8.2.2
Tumor Marker Assessment..........................................................................95
8.2.3
Patient-reported Outcomes...........................................................................96
8.3
Safety Assessments...............................................................................................96
8.3.1
Physical Examinations.................................................................................96
8.3.1.1
Full Physical Examination.................................................................96
8.3.1.2
Directed Physical Examination..........................................................97
8.3.2
Vital Signs....................................................................................................97
8.3.3
Electrocardiograms ......................................................................................97
8.3.4
Clinical Safety Laboratory Assessments .....................................................97
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................98
8.3.5
Pregnancy Testing........................................................................................98
8.3.6
Performance Assessments............................................................................98
8.3.6.1
Eastern Cooperative Oncology Group Performance Status...............98
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................99
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................99
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....101
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.101
8.4.4
Regulatory Reporting Requirements for SAE ...........................................102
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................102
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................102
8.4.7
Events of Clinical Interest..........................................................................103
8.5
Treatment of Overdose......................................................................................103
8.6
Pharmacokinetics...............................................................................................103
8.7
Pharmacodynamics............................................................................................104
8.8
Biomarkers .........................................................................................................104
8.8.1
Planned Genetic Analysis Sample Collection............................................104
8.9
Future Biomedical Research Sample Collection.............................................104
8.10
Medical Resource Utilization and Health Economics.....................................104
8.11
Visit Requirements.............................................................................................105
8.11.1
Screening....................................................................................................105
8.11.2
Treatment Period........................................................................................105
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................105
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8.11.4
Posttreatment Visit.....................................................................................105
8.11.4.1
End-of-Treatment Visit....................................................................105
8.11.4.2
Safety Follow-up Visit.....................................................................106
8.11.4.3
Efficacy Follow-up Visits................................................................106
8.11.4.4
Survival Follow-up Contacts ...........................................................106
8.11.5
Vital Status.................................................................................................107
9
STATISTICAL ANALYSIS PLAN ...........................................................................108
9.1
Statistical Analysis Plan Summary...................................................................108
9.2
Responsibility for Analyses/In-house Blinding ...............................................110
9.3
Hypotheses/Estimation ......................................................................................110
9.4
Analysis Endpoints.............................................................................................111
9.5
Analysis Populations..........................................................................................112
9.5.1
Efficacy Analysis Populations...................................................................112
9.5.2
Safety Analysis Populations ......................................................................112
9.5.3
PRO Analysis Populations.........................................................................112
9.6
Statistical Methods.............................................................................................112
9.6.1
Statistical Methods for Efficacy Analyses.................................................113
9.6.1.1
Progression-Free Survival................................................................113
9.6.1.2
Overall Survival...............................................................................114
9.6.1.3
Analysis Strategy for Key Efficacy Variables.................................115
9.6.2
Statistical Methods for Safety Analyses ....................................................116
9.6.3
Statistical Methods for PRO Analyses.......................................................117
9.6.4
Demographic and Baseline Characteristics ...............................................118
9.7
Interim Analyses ................................................................................................118
9.7.1
Efficacy Interim Analysis ..........................................................................119
9.7.2
Safety Interim Analysis..............................................................................120
9.8
Multiplicity .........................................................................................................120
9.8.1
Progression-free Survival...........................................................................121
9.8.2
Overall Survival.........................................................................................123
9.8.3
Safety Analyses..........................................................................................125
9.9
Sample Size and Power Calculations ...............................................................125
9.10
Subgroup Analyses.............................................................................................126
9.11
Compliance (Medication Adherence)...............................................................127
9.12
Extent of Exposure.............................................................................................127
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................128
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......128
10.1.1
Code of Conduct for Clinical Trials...........................................................128
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10.1.2
Financial Disclosure...................................................................................131
10.1.3
Data Protection...........................................................................................132
10.1.3.1
Confidentiality of Data ....................................................................132
10.1.3.2
Confidentiality of Participant Records.............................................132
10.1.3.3
Confidentiality of IRB/IEC Information..........................................132
10.1.4
Committees Structure.................................................................................133
10.1.4.1
Executive Oversight Committee......................................................133
10.1.4.2
External Data Monitoring Committee .............................................133
10.1.4.3
Scientific Advisory Committee (SAC)............................................133
10.1.5
Publication Policy......................................................................................133
10.1.6
Compliance with Study Registration and Results Posting Requirements .134
10.1.7
Compliance with Law, Audit, and Debarment ..........................................134
10.1.8
Data Quality Assurance .............................................................................135
10.1.9
Source Documents .....................................................................................135
10.1.10
Study and Site Closure...............................................................................136
10.2
Appendix 2: Clinical Laboratory Tests............................................................137
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................139
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................139
10.3.2
Definition of AE ........................................................................................139
10.3.3
Definition of SAE ......................................................................................140
10.3.4
Additional Events Reported in the Same Manner as SAE.........................141
10.3.5
Recording AE and SAE .............................................................................141
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................145
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................146
10.5
Appendix 5: Contraceptive Guidance..............................................................147
10.5.1
Definitions..................................................................................................147
10.5.2
Contraception Requirements......................................................................148
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................149
10.7
Appendix 7: Country-specific Requirements..................................................153
10.7.1
China..........................................................................................................153
10.7.2
Germany.....................................................................................................153
10.7.3
Ireland ........................................................................................................154
10.7.4
Italy ............................................................................................................154
10.7.5
Japan ..........................................................................................................154
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10.7.6
United Kingdom.........................................................................................155
10.8
Appendix 8: 2014 Federation of Gynecology and Obstetrics (FIGO) 
Ovarian, Fallopian Tube, and Peritoneal Cancer Staging System................156
10.9
Appendix 9: Abbreviations ...............................................................................157
11
REFERENCES.............................................................................................................163
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LIST OF TABLES
Table 1
First Course Treatment – Study Schedule of Activities...............................22
Table 2
Second Course Retreatment - Study Schedule of Activities........................31
Table 3
Adequate Organ Function Laboratory Values .............................................60
Table 4
Study Interventions......................................................................................66
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...........................................................................74
Table 6
Pembrolizumab Monotherapy, Coformulations or IO Combinations 
Infusion Reaction Dose Modification and Treatment Guidelines ...............................78
Table 7
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................................100
Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS.................114
Table 9
Analysis Strategy for Key Efficacy Variables...........................................115
Table 10
Analysis Strategy for Safety Parameters....................................................117
Table 11
.....................................119
Table 12
 
....................................................................................................................122
Table 13
..........123
Table 14
Protocol-required Safety Laboratory Assessments....................................137
CCI
CCI
CCI
CCI
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LIST OF FIGURES
Figure 1
Study Diagram .............................................................................................21
Figure 2
Multiplicity Diagram for Type I Error Control..........................................121
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-Blind Study of Pembrolizumab versus 
Placebo in Combination With Paclitaxel With or Without Bevacizumab for the Treatment of 
Platinum-resistant Recurrent Ovarian Cancer (KEYNOTE-B96 / ENGOT-ov65)
Short Title: Pembrolizumab/placebo plus paclitaxel with or without bevacizumab for 
platinum-resistant recurrent ovarian cancer
Acronym: KEYNOTE-B96
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Throughout this protocol, the term Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 refers to the modification of RECIST 1.1 to include a maximum of 10 target lesions and a 
maximum of 5 target lesions per organ. Refer to Section 4.2.1.1 for additional details.
In female participants with platinum-resistant recurrent ovarian cancer who have received 
≤2 prior lines of therapy:
Primary Objective
Primary Endpoint
To compare pembrolizumab plus paclitaxel 
with or without bevacizumab to placebo 
plus paclitaxel with or without 
bevacizumab, with respect to progression-
free survival (PFS) per RECIST 1.1 as 
assessed by the investigator
Hypothesis (H1): pembrolizumab plus 
paclitaxel with or without bevacizumab is 
superior to placebo plus paclitaxel with or 
without bevacizumab, with respect to PFS 
per RECIST 1.1 as assessed by the 
investigator for participants with 
programmed cell death ligand 1 (PD-L1) 
positive tumors (Combined Positive Score 
[CPS] ≥1)
Hypothesis (H2): pembrolizumab plus 
paclitaxel with or without bevacizumab is 
superior to placebo plus paclitaxel with or 
without bevacizumab, with respect to PFS 
per RECIST 1.1 as assessed by the 
investigator for all participants
PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
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Secondary Objectives
Secondary Endpoints
To compare pembrolizumab plus paclitaxel 
with or without bevacizumab to placebo 
plus paclitaxel with or without 
bevacizumab, with respect to overall 
survival (OS)
Hypothesis (H3): Pembrolizumab plus 
paclitaxel with or without bevacizumab is 
superior to placebo plus paclitaxel with or 
without bevacizumab, with respect to OS 
for participants with PD-L1 positive tumors 
(CPS ≥1)
Hypothesis (H4): Pembrolizumab plus 
paclitaxel with or without bevacizumab is 
superior to placebo plus paclitaxel with or 
without bevacizumab, with respect to OS 
for all participants
OS: The time from randomization to death 
due to any cause
To compare pembrolizumab plus paclitaxel 
with or without bevacizumab to placebo 
plus paclitaxel with or without 
bevacizumab, with respect to PFS per 
RECIST 1.1 by blinded independent central 
review (BICR) for participants with PD-L1 
positive tumors (CPS ≥1) and all 
participants
PFS
To evaluate the safety and tolerability of 
pembrolizumab in combination with 
paclitaxel with or without bevacizumab
-Adverse events (AEs)
-Study treatment discontinuation due to AEs
To compare pembrolizumab plus paclitaxel 
with or without bevacizumab to placebo 
plus paclitaxel with or without 
bevacizumab, with respect to Global Health 
Status/Quality of Life (GHS/QoL) score 
using the European Organisation for 
Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire 
Core 30 (QLQ-C30) and abdominal and 
gastrointestinal (GI) symptoms using the 
EORTC Ovarian Cancer-Specific Quality of 
Life Questionnaire (QLQ-OV28) 
abdominal/GI symptom scale for 
participants with PD-L1 positive tumors 
(CPS ≥1) and all participants
Change from baseline and time to 
deterioration (TTD) of the QoL and 
symptom scores from the GHS/QoL scale 
(items 29 and 30) of the EORTC QLQ-C30 
and the abdominal/GI symptom scale (items 
31 to 36) of the EORTC QLQ-OV28
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Ovarian cancer recurrent
Population
Participants with platinum-resistant 
recurrent ovarian cancer who have received 
≤2 prior lines of therapy
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects
Investigator
Outcomes Assessor
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 65 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Extension Portion of the Study in China: 
The study may remain open longer than 65 
months to complete an extension portion of 
the study in China.
Number of Participants:
Approximately 616 eligible participants are expected to be randomized to 1 of 2 treatment 
arms as described in Section 6.3.1. Crossover between treatment arms is not permitted.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/Treatment 
Period
Use
Arm 1
Pembrolizumab 
(MK-3475)
25 mg/mL
400 mg
IV Infusion
Q6W for 18 cycles
Test Product
Arm 1
Paclitaxel
Variable
80 mg/m2
IV Infusion
Days 1, 8, 15 of each 
Q3W cycle until 
disease progression 
or prohibitive toxicity
Background 
Treatment
Arm 1
Docetaxel (in 
place of 
paclitaxel, only 
after Sponsor 
consultation)
Variable
75 mg/m2
IV Infusion
Q3W until disease 
progression or 
prohibitive toxicity
Background 
Treatment
Arm 1
Bevacizumab (if 
using)
25 mg/mL
10 mg/kg
IV Infusion
Optional, Q2W until 
disease progression 
or prohibitive toxicity
Background 
Treatment
Arm 2
Placebo
Normal Saline 
or Dextrose
0 mg/mL
IV Infusion
Q6W for 18 cycles
Placebo
Arm 2
Paclitaxel
Variable
80 mg/m2
IV Infusion
Days 1, 8, 15 of each 
Q3W cycle until 
disease progression 
or prohibitive toxicity
Background 
Treatment
Arm 2
Docetaxel (in 
place of 
paclitaxel, only 
after Sponsor 
consultation)
Variable
75 mg/m2
IV Infusion
Q3W until disease 
progression or 
prohibitive toxicity
Background 
Treatment
Arm 2
Bevacizumab (if 
using)
25 mg/mL
10 mg/kg
IV Infusion
Optional, Q2W until 
disease progression 
or prohibitive toxicity
Background 
Treatment
Abbreviations: IV=intravenous; QW=weekly; Q2/3/6W=every 2/3/6 weeks.
The unit dose strength for background treatment may vary depending on market availability.
Pembrolizumab/placebo may be administered for a maximum of 18 Q6W cycles. Paclitaxel and bevacizumab may continue 
until disease progression, prohibitive toxicity, other protocol-defined reasons for discontinuation, or the participant has 
received the maximum duration (if applicable) per the respective approved labels or local practice.
Paclitaxel-related toxicities should be managed according to local practice and institutional guidelines with supportive care 
measures, dose interruptions and reductions before consideration of discontinuation, if clinically appropriate. Docetaxel (75
mg/m2 Q3W) may be considered for participants who experience either a severe hypersensitivity reaction to paclitaxel or an 
adverse event requiring discontinuation of paclitaxel only after consultation with the Sponsor. Refer to Appendix 7 for 
country-specific requirements.
The use of bevacizumab is optional and may be administered to eligible participants at the investigator’s discretion. Use of 
bevacizumab must be decided before randomization as it is a stratification factor. Refer to Section 8.1.8.1.3 for additional 
information on use of bevacizumab and biosimilars. Refer to Appendix 7 for country-specific requirements.
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Other current or former name(s) or alias(es) for study intervention(s) are as follows:
MK-3475.
Total Number 
of Intervention 
Groups/Arms
2
Duration of 
Participation
Each participant will participate in the study from the time that the 
participant provides documented informed consent through the final 
protocol-specified contact.
After a screening phase of up to 28 days, each participant will be 
assigned to receive study intervention until one of the conditions for 
discontinuation of study intervention is met.
Participants who complete study intervention after receiving 18
administrations of pembrolizumab/placebo (18 Q6W 400 mg infusions), 
and participants who attain a complete response and stop study 
intervention may be eligible for up to 9 additional administrations of
Q6W pembrolizumab (approximately 1 year) upon experiencing disease 
progression.
After the end of treatment, each participant will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy.
Participants who discontinue for reasons other than radiographic disease 
progression will have posttreatment follow-up imaging for disease status 
until any of the conditions for discontinuation of imaging are met.
All participants will be followed for overall survival until death, 
withdrawal of consent, or the end of the study.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 9.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Diagram
Abbreviations: CPS=combined positive score; ECOG PS =Eastern Cooperative Oncology Group Performance 
Status; EU=European Union; OS=overall survival; PARPi=poly(adenosine-ribose) polymerase inhibitor; 
PD-1=programmed cell death 1; PD-L1=programmed cell death 1 ligand 1; PFS=progression-free survival; 
Q2/3/6/9/12W=every 2/3/6/9/12 weeks; ROW=Rest of World; US=United States.
Pembrolizumab/placebo may only be administered for 18 Q6W cycles. Paclitaxel and/or bevacizumab may 
continue until disease progression, prohibitive toxicity, other protocol-defined reason for discontinuation or the 
participant has received the maximum duration (if applicable) per the respective approved label or local 
practice.
a
Paclitaxel-related toxicities should be managed according to local practice and institutional guidelines with 
supportive care measures, dose interruptions and reductions before consideration of discontinuation, if
clinically appropriate. Docetaxel (75 mg/m2 Q3W) may be considered for participants who experience either 
a severe hypersensitivity reaction to paclitaxel or an adverse event requiring discontinuation of paclitaxel 
only after consultation with the Sponsor. Refer to Appendix 7 for country-specific requirements.
b
The use of bevacizumab is optional and may be administered to eligible participants at the investigator’s 
discretion. Use of bevacizumab must be decided before randomization as it is a stratification factor. Refer to 
Appendix 7 for country-specific requirements.
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1.3
Schedule of Activities
The schedules of activities for First Course Treatment and Second Course Retreatment are presented in Table 1 and Table 2, 
respectively.
1.3.1
First Course Treatment
Table 1
First Course Treatment – Study Schedule of Activities
Period
Screen-
ing
Study Intervention (Q6W Cycles)a
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8+
DC
Safety 
follow-upb
Efficacy 
follow-upc
Survival 
follow-upd
Note: Window for pembrolizumab/placebo 
and bevacizumab (if applicable) dosing is ±3 
days. Window for paclitaxel dosing is ±1 day, 
except on C1D1, which has a window of +3 
days.
Scheduling Window
-28 d
to
-1 d
+3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3 d
30 d after 
last dose 
(+7 d)
Q9W or 
Q12W
(±7 d)
Q12W
(± 7 d)
Administrative Procedures
Informed consent
X
Rescreened participants do not need to provide 
additional documented consent if original 
consent was obtained more than 28 days before 
C1, unless required per local regulations.
Treatment beyond initial radiographic disease 
progression per RECIST 1.1 requires an 
additional consent.
Informed Consent for 
Future Biomedical 
Research (optional)
X
Participant may participate in main study 
without signing Future Biomedical Research 
consent.
Participant ID Card
X
X
Distribute at screening and add the 
randomization number at the time of 
randomization
Eligibility Assessment 
(Inclusion / Exclusion)
X
Screening procedures may be performed on the 
date of randomization as long as they are 
performed before randomization.
Demographics
X
Medical History
X
Ovarian Cancer 
History Details
X
Collect disease details including histology, prior 
treatments, and surgery. 
Prior BRCA status
X
Record local results if performed/available.
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Period
Screen-
ing
Study Intervention (Q6W Cycles)a
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8+
DC
Safety 
follow-upb
Efficacy 
follow-upc
Survival 
follow-upd
Note: Window for pembrolizumab/placebo 
and bevacizumab (if applicable) dosing is ±3 
days. Window for paclitaxel dosing is ±1 day, 
except on C1D1, which has a window of +3 
days.
Scheduling Window
-28 d
to
-1 d
+3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3 d
30 d after 
last dose 
(+7 d)
Q9W or 
Q12W
(±7 d)
Q12W
(± 7 d)
Prior HRD status
X
Record local results if performed/available.
Review FIGO (2014) 
Staging from Initial 
Diagnosis
X
Refer to Appendix 8.
Prior / Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Record medications taken within 28 days before 
the start of study intervention.
Record concomitant medications at every visit 
that study intervention is administered. 
Concomitant medications will be recorded for 
30 days after last dose. All concomitant 
medications administered during SAEs or ECIs 
are to be recorded. 
Treatment Eligibility 
Assessment 1 Form 
for Bevacizumab 
X
The investigator must record whether or not 
bevacizumab is selected and, if applicable, 
document the justification for adding 
bevacizumab to SOC paclitaxel before
randomization.
Treatment Eligibility 
Assessment 2 Form 
for Bevacizumab
X
The investigator must record whether or not 
bevacizumab is selected and, if applicable, 
document the reason why bevacizumab was not 
selected before randomization.
Randomization 
(via IRT)
X
First dose of study intervention may be 
administered up to 3 days after randomization.
Register Visit in IRT
X
X
X
X
X
X
X
X
X
X
Each time drug is dispensed, IRT is to be 
contacted.
Subsequent 
Anticancer Treatment
X
X
X
X
Participants should be contacted by telephone to 
monitor new anticancer treatment if there is no 
corresponding clinic visit.
Date of Progression 
on Subsequent 
Anticancer Treatment
X
X
X
Participants will be followed for PFS2.  
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Period
Screen-
ing
Study Intervention (Q6W Cycles)a
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8+
DC
Safety 
follow-upb
Efficacy 
follow-upc
Survival 
follow-upd
Note: Window for pembrolizumab/placebo 
and bevacizumab (if applicable) dosing is ±3 
days. Window for paclitaxel dosing is ±1 day, 
except on C1D1, which has a window of +3 
days.
Scheduling Window
-28 d
to
-1 d
+3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3 d
30 d after 
last dose 
(+7 d)
Q9W or 
Q12W
(±7 d)
Q12W
(± 7 d)
Survival Information 
(Vital Status)
X
After investigator-determined disease 
progression or start of new anticancer treatment.
In addition, on Sponsor request, participants may 
be contacted for survival status at any time 
during the course of the study.
Clinical Assessments
Adverse Event 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
Report AEs at every visit that study intervention 
is administered through 30 days after the last 
dose of study intervention. Report SAEs through 
90 days after the last dose of study intervention, 
or 30 days after the last dose if participant 
initiates a new anticancer treatment, whichever 
is earlier.
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
Perform within 3 days before randomization. If 
ECOG PS is performed on the day of 
randomization, it should be performed before 
randomization.
After C1D1, perform on Day 1 of every 
pembrolizumab/placebo cycle (Q6W) and 
chemotherapy cycle (Q3W).
Complete Physical 
Examination
X
X
Symptom-directed 
Physical Examination
X
X
X
X
X
X
X
X
X
If a complete physical examination is performed 
within 3 days before randomization, a symptom-
directed physical examination is not required at 
C1D1.
Assess more frequently as clinically indicated.
Vital Signs 
(temperature, blood 
pressure, respiratory 
rate, pulse rate, 
weight, height [height 
- screening only])
X
X
X
X
X
X
X
X
X
X
X
Assess during screening and before treatment at 
the start of every pembrolizumab/placebo cycle 
(Q6W) and chemotherapy cycle (Q3W). In case 
of dose interruption or missed dose, assess 
before restarting treatment. 
Assess more frequently as clinically indicated.
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Period
Screen-
ing
Study Intervention (Q6W Cycles)a
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8+
DC
Safety 
follow-upb
Efficacy 
follow-upc
Survival 
follow-upd
Note: Window for pembrolizumab/placebo 
and bevacizumab (if applicable) dosing is ±3 
days. Window for paclitaxel dosing is ±1 day, 
except on C1D1, which has a window of +3 
days.
Scheduling Window
-28 d
to
-1 d
+3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3 d
30 d after 
last dose 
(+7 d)
Q9W or 
Q12W
(±7 d)
Q12W
(± 7 d)
Blood Pressure 
(Additional 
Assessments Required 
for Participants 
Receiving 
Bevacizumab)
Measure blood pressure before each 
bevacizumab administration (Q2W).
12-lead ECG
X
Additional ECGs may be performed as clinically 
indicated.
Laboratory Assessments for Eligibility and Safety
HIV / HBV / HCV 
Eligibility Testing
X
Required only when mandated by local health 
authority.
Refer to Appendix 7 for country-specific
requirements.
Urine or Serum
Pregnancy Test -
WOCBP Only
X
X
X
WOCBP require a negative pregnancy test 
within either 24 hours (urine) or 72 hours 
(serum) before the first dose of study 
intervention.
A pregnancy test must be performed every 
month during study treatment. Pregnancy testing 
should continue in posttreatment until 120 days 
after last dose of pembrolizumab/placebo and 
180 days after last dose of paclitaxel, docetaxel 
(if applicable) and bevacizumab (if using).
More frequent pregnancy testing may be 
performed if required by local regulations or if 
clinically indicated. Refer to Appendix 7 for 
country-specific requirements.
Home pregnancy tests are acceptable when a 
scheduled visit does not occur within the month 
(per local regulation), but the site must make 
monthly telephone contact with the participant to 
determine the results of the pregnancy test.
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Period
Screen-
ing
Study Intervention (Q6W Cycles)a
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8+
DC
Safety 
follow-upb
Efficacy 
follow-upc
Survival 
follow-upd
Note: Window for pembrolizumab/placebo 
and bevacizumab (if applicable) dosing is ±3 
days. Window for paclitaxel dosing is ±1 day, 
except on C1D1, which has a window of +3 
days.
Scheduling Window
-28 d
to
-1 d
+3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3 d
30 d after 
last dose 
(+7 d)
Q9W or 
Q12W
(±7 d)
Q12W
(± 7 d)
Serum FSH -
WONCBP only
X
Only required for postmenopausal women with 
<12 months amenorrhea and not currently on 
HRT or hormonal contraception (see Appendix 
5). Confirmation with 2 FSH measurements in 
the postmenopausal range is required.
PT/INR and 
aPTT/PTT
X
Perform within 7 days before randomization. 
Perform more frequently if clinically indicated.
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Perform within 7 days before randomization. 
After C1D1, perform within 72 hours before 
treatment on Day 1 of every pembrolizumab/ 
placebo cycle (Q6W) and chemotherapy cycle 
(Q3W). In case of dose interruption or missed 
dose, assess before restarting treatment.
Perform more frequently if clinically indicated.
Hematology
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (for 
participants not 
receiving 
bevacizumab)
X
X
X
X
X
X
X
Perform within 7 days before randomization. 
After C1, perform within 72 hours before 
treatment on Day 1 every 2 pembrolizumab/ 
placebo cycles starting with C2 (ie, C2, 4, 6
etc.).
Perform more frequently if clinically indicated.
Urinalysis (for 
participants receiving 
bevacizumab)
X
X
X
X
X
X
X
X
X
X
X
Perform within 7 days before randomization. 
After C1D1, perform within 72 hours before 
every bevacizumab administration (Q2W). In 
case of dose interruption or missed dose, assess 
before restarting treatment.
Perform more frequently if clinically indicated.
T3 or FT3, plus FT4 
and TSH
X
X
X
X
X
X
X
X
X
X
Perform within 7 days before randomization.
Perform within 72 hours before treatment on 
Day 1 of every cycle starting with C2 (if 
unavailable, results may be reviewed after 
dosing).
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Period
Screen-
ing
Study Intervention (Q6W Cycles)a
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8+
DC
Safety 
follow-upb
Efficacy 
follow-upc
Survival 
follow-upd
Note: Window for pembrolizumab/placebo 
and bevacizumab (if applicable) dosing is ±3 
days. Window for paclitaxel dosing is ±1 day, 
except on C1D1, which has a window of +3 
days.
Scheduling Window
-28 d
to
-1 d
+3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3 d
30 d after 
last dose 
(+7 d)
Q9W or 
Q12W
(±7 d)
Q12W
(± 7 d)
Study Intervention Administration
Pembrolizumab 
(MK-3475) or placebo 
(Q6W)
X
X
X
X
X
X
X
X
Maximum of 18 cycles. Window for 
pembrolizumab/placebo dosing is ±3 days.
Pembrolizumab: 400 mg by IV
Placebo: normal saline or dextrose by IV.
Paclitaxele 
(Q3W - D1, D8, D15)
80 mg/m2 by IV QW until disease progression, 
prohibitive toxicity, or other protocol-defined 
reason for discontinuation. Window for 
paclitaxel dosing is ±1 day, except on C1D1, 
which has a window of +3 days. 
Refer to Section 6.1 for treatment requirements.
Bevacizumab -
optional
(Q2W)
10 mg/kg by IV Q2W until disease progression, 
prohibitive toxicity, or other protocol-defined 
reason for discontinuation. Bevacizumab use 
must be selected in IRT before randomization as 
it is a stratification factor. Window for 
bevacizumab dosing is ±3 days.
Refer to Section 6.1 for treatment requirements.
Refer to Appendix 7 for country-specific 
requirements.
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Period
Screen-
ing
Study Intervention (Q6W Cycles)a
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8+
DC
Safety 
follow-upb
Efficacy 
follow-upc
Survival 
follow-upd
Note: Window for pembrolizumab/placebo 
and bevacizumab (if applicable) dosing is ±3 
days. Window for paclitaxel dosing is ±1 day, 
except on C1D1, which has a window of +3 
days.
Scheduling Window
-28 d
to
-1 d
+3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3 d
30 d after 
last dose 
(+7 d)
Q9W or 
Q12W
(±7 d)
Q12W
(± 7 d)
Efficacy Assessments
Tumor Scans –
Chest, Abdomen, and 
Pelvis
X
X
X
Baseline tumor scans must be obtained within 
28 days before randomization.
Postrandomization scans will be performed 
Q9W (±7 d) through Week 54 and Q12W (±7 d) 
thereafter. All time points are calculated from 
the date of randomization. Scan timing should 
follow calendar days and should not be adjusted 
for delays in cycle starts.
Tumor scans are required at EOT if previous 
scans were performed more than 4 weeks before
EOT. If required, EOT scans must be performed 
before the start of new anticancer treatment.
Unscheduled scans may be performed as 
clinically indicated.
Bone Scan
X
Required at baseline within 28 days before 
randomization for participants with a history of 
bone metastases and/or who are clinically 
symptomatic. On-study bone scans should be 
performed if clinically indicated or to confirm 
CR (if other lesions indicate CR and bone
lesions existed at baseline). 
Brain Scan
X
Required at baseline within 28 days before 
randomization for participants with a history of 
brain metastases (to confirm stability) or who 
are clinically symptomatic (to rule out brain 
metastases). On-study brain scans should be 
performed if clinically indicated or to confirm 
CR (if other lesions indicate CR and brain 
lesions existed at baseline).
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Period
Screen-
ing
Study Intervention (Q6W Cycles)a
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8+
DC
Safety 
follow-upb
Efficacy 
follow-upc
Survival 
follow-upd
Note: Window for pembrolizumab/placebo 
and bevacizumab (if applicable) dosing is ±3 
days. Window for paclitaxel dosing is ±1 day, 
except on C1D1, which has a window of +3 
days.
Scheduling Window
-28 d
to
-1 d
+3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3 d
30 d after 
last dose 
(+7 d)
Q9W or 
Q12W
(±7 d)
Q12W
(± 7 d)
CA-125
X
X
X
Perform within 7 days before randomization.
Sample to be collected at the time of each
scheduled tumor scan (±14 days of scheduled 
scan). An optional sample may be collected at
the time of unscheduled scan at the
investigator’s discretion. Additional assessments 
may be performed if clinically indicated (eg, 
suspected progression).
All CA-125 testing will be performed locally.
Health-Related Quality of Life (HRQoL)
EORTC QLQ-C30
X
X
X
X
X
X
X
X
X
X
Administer PROs in the order shown before 
performing any procedures, assessments, and 
treatment. 
Collect at every cycle that 
pembrolizumab/placebo is scheduled to be 
administered (ie, Q6W) until completion or 
discontinuation. Continue to collect PROs Q6W 
if the participant discontinues 
pembrolizumab/placebo but continues 
chemotherapy and/or bevacizumab. 
EORTC QLQ-OV28
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
Blood and Tissue Sample Collection for Biomarker, Pharmacokinetic, and Immunogenicity Analyses
Archival or Newly 
Obtained Tissue 
Collection
X
Prospective analysis of PD-L1 status is required 
before randomization.
Blood for Genetic 
Analysis
X
Collect before administration of first dose of 
study intervention.
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Period
Screen-
ing
Study Intervention (Q6W Cycles)a
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8+
DC
Safety 
follow-upb
Efficacy 
follow-upc
Survival 
follow-upd
Note: Window for pembrolizumab/placebo 
and bevacizumab (if applicable) dosing is ±3 
days. Window for paclitaxel dosing is ±1 day, 
except on C1D1, which has a window of +3 
days.
Scheduling Window
-28 d
to
-1 d
+3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3
d
±3 d
30 d after 
last dose 
(+7 d)
Q9W or 
Q12W
(±7 d)
Q12W
(± 7 d)
Blood for ctDNA 
Analysis
X
X*
X
X
X
X†
X
Collect before administration of first dose of 
study intervention. Collect at C1D1, C2D1, 
C2D22, C4D1, C6D1, C7D1. 
*Collect at both C2D1 and C2D22.
†Collect at C9D1 and C10D1. After C10D1, 
collect at D1 of Q12W (C12, C14, C16, C18).
Collect at EOT. An optional sample may be 
collected at the time of unscheduled visit at the
investigator’s discretion.
Blood for 
Pembrolizumab PK
X
X
X
Collect up to 72 hours before 
pembrolizumab/placebo administration at C1D1, 
C2D1, C5D1 (only applicable for participants 
receiving bevacizumab enrolled after approval 
of Amendment 03).
Blood for 
Pembrolizumab 
ADA/NAb
X
X
X
Abbreviations: ADA=antidrug antibodies; AE=adverse event; aPTT=activated partial thromboplastin time; BRCA=breast cancer gene; C=cycle; CA-125=cancer antigen-125; 
ctDNA=circulating tumor DNA; d/D=day; DC=discontinuation; ECG=electrocardiogram; ECI=event of clinical interest; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-
C30=European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-OV28=European Organisation for Research and Treatment of 
Cancer Ovarian Cancer-Specific Quality of Life Questionnaire; EOT=end of treatment; EQ-5D-5L=European Quality of Life Five-dimension Five-level Scale Questionnaire; FBR=future 
biomedical research; FIGO=International Federation of Gynecology and Obstetrics; FSH=follicle-stimulating hormone; FT3=free triiodothyronine; FT4=free thyroxine; HBV=hepatitis B 
virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HRD=homologous recombination deficiency; HRQoL=health-related quality of life; HRT=hormone replacement 
therapy; ID=identification; INR=International Normalized Ratio; IRT=interactive response technology; IV=intravenous; NAb=neutralizing antibodies; PD-L1=programmed cell death ligand 
1; PFS2=progression-free survival after next-line treatment; PK=pharmacokinetic; PRO=patient-reported outcome; PT=prothrombin time; PTT=partial thromboplastin time; 
Q2/3/6/9/12/24W=every 2/3/6/9/12/24 weeks; QW=once weekly; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; SOC=standard of care; 
T3=triiodothyronine; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential.
a.
Pembrolizumab/placebo may only be administered for 18 Q6W cycles. Paclitaxel and/or bevacizumab may continue until disease progression, prohibitive toxicity, other protocol-defined 
reason for discontinuation or the participant has received the maximum duration (if applicable) per the respective approved label or local practice. 
b. If the End-of-Treatment Visit occurs ≥30 days from last dose of study intervention, a separate Safety Follow-up Visit is not required. 
c.
Participants should continue tumor scans Q9W (±7 d) through Week 54 and Q12W (±7 d) thereafter until investigator-assessed radiographic disease progression per RECIST 1.1, the 
start of a new anticancer treatment, withdrawal of consent, pregnancy, or death. Tumor scan timepoints will be calculated from the date of randomization for the duration of the study.
d. Survival Follow-up Visit will be performed by telephone.
e.
Paclitaxel-related toxicities should be managed according to local practice and institutional guidelines with supportive care measures, dose interruptions, and reductions before 
consideration of discontinuation, if clinically appropriate. Docetaxel (75 mg/m2 Q3W) may be considered for participants who experience either a severe hypersensitivity reaction to 
paclitaxel or an AE requiring discontinuation of paclitaxel only after consultation with the Sponsor. Refer to Appendix 7 for country-specific requirements.
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1.3.2
Second Course (Retreatment)
Second Course retreatment with pembrolizumab is only available to participants who meet the criteria in Section 6.1.2. If eligible, 
these participants may be able to receive 9 additional Q6W, 400 mg administrations of pembrolizumab.
Table 2
Second Course Retreatment - Study Schedule of Activities
Period
Second Course Phase (Retreatment) Q6W Cycles
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8
C9
DC
Safety 
follow-
upa
Efficacy 
follow-upb
Survival 
follow-
upc
If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
Safety Follow-up Visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the Safety Follow-
up Visit should be performed.
Scheduling 
Window
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
30 d 
after last 
dose 
(+ 7 d)
Q12W 
(±7 d)
Q12W
(± 7 d)
Administrative Procedures
Inclusion/
Exclusion
X
Prior/
Concomitant 
Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications will be 
recorded for 30 days after last dose. 
All concomitant medications 
administered during SAEs or ECIs 
are to be recorded.  
Subsequent 
Anticancer 
Treatment
X
X
X
X
All anticancer treatment will be 
recorded until time of death or 
termination of survival follow-up.
Participants should be contacted by 
telephone to monitor new anticancer 
treatment if there is no 
corresponding clinic visit.
Date of 
Progression on 
Subsequent 
Anticancer 
Treatment
X
X
X
Participants will be followed for 
PFS2.
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Period
Second Course Phase (Retreatment) Q6W Cycles
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8
C9
DC
Safety 
follow-
upa
Efficacy 
follow-upb
Survival 
follow-
upc
If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
Safety Follow-up Visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the Safety Follow-
up Visit should be performed.
Scheduling 
Window
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
30 d 
after last 
dose 
(+ 7 d)
Q12W 
(±7 d)
Q12W
(± 7 d)
Survival 
Information 
(Vital Status)
X
After investigator-determined 
disease progression or start of new 
anticancer treatment. In addition, on 
Sponsor request, participants may be 
contacted for survival status at any 
time during the course of the study.
Study Intervention Administration
Pembrolizumab 
(MK-3475)
X
X
X
X
X
X
X
X
X
Pembrolizumab 400 mg by IV Q6W 
Efficacy Assessments
Tumor Scans –
Chest, Abdomen, 
and Pelvis
X
X
Tumor scans to be performed within 
28 days before restarting treatment 
in Second Course and then Q12W 
(±7 d) from the start of Second 
Course retreatment until disease 
progression. Scan timing should 
follow calendar days and should not 
be adjusted for delays in cycle starts.
Tumor scans are required at EOT if 
previous scans were performed 
more than 4 weeks before EOT. 
Unscheduled scans may be 
performed as clinically indicated.
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Period
Second Course Phase (Retreatment) Q6W Cycles
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8
C9
DC
Safety 
follow-
upa
Efficacy 
follow-upb
Survival 
follow-
upc
If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
Safety Follow-up Visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the Safety Follow-
up Visit should be performed.
Scheduling 
Window
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
30 d 
after last 
dose 
(+ 7 d)
Q12W 
(±7 d)
Q12W
(± 7 d)
Bone Scan
Only for participants with a history 
of bone metastases or who are 
clinically symptomatic.
A bone scan is required before 
restarting treatment in the Second 
Course, only if the previous scan 
was not performed within 28 days of 
restarting treatment, and thereafter if 
clinically indicated or to confirm CR 
(if other lesions indicate CR and 
bone lesions existed at baseline).
Brain Scan
Only for participants with a history 
of protocol-eligible treated brain 
metastases and/or who are clinically 
symptomatic, a brain scan will be 
required within 28 days of restarting 
treatment in Second Course and 
thereafter if clinically indicated or to 
confirm CR (if other lesions indicate 
CR and brain lesions existed at 
baseline).
CA-125
X
X
Sample to be collected at the time of 
each tumor scan (±14 days of 
scheduled scan). An optional sample 
may be collected at the time of 
unscheduled scan at the 
investigator’s discretion. Additional 
assessments may be performed if 
clinically indicated (eg, suspected 
progression).
All CA-125 testing will be 
performed locally.
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Period
Second Course Phase (Retreatment) Q6W Cycles
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8
C9
DC
Safety 
follow-
upa
Efficacy 
follow-upb
Survival 
follow-
upc
If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
Safety Follow-up Visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the Safety Follow-
up Visit should be performed.
Scheduling 
Window
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
30 d 
after last 
dose 
(+ 7 d)
Q12W 
(±7 d)
Q12W
(± 7 d)
Clinical Assessments
Adverse Event
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
Report all AEs through 30 days after 
the last dose of study intervention. 
Report SAEs through 90 days after 
the last dose of study intervention, 
or 30 days after the last dose if 
participant initiates a new anticancer 
treatment, whichever is earlier.
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
Perform within 7 days before
starting Second Course retreatment
and on Day 1 of each treatment
cycle starting at C2.
Complete 
Physical 
Examination
X
X
Symptom-
directed Physical 
Examination
X
X
X
X
X
X
X
X
X
Assess more frequently as clinically 
indicated.
Vital Signs 
(temperature, 
blood pressure, 
respiratory rate, 
pulse rate, 
weight, height 
[height -
screening only])
X
X
X
X
X
X
X
X
X
X
X
Assess before pembrolizumab is 
administered in each cycle.
12-lead ECG
X
An ECG is required before
restarting treatment only if it was 
not already completed within 28 
days previously.
Additional ECGs may be performed 
as clinically indicated.
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Period
Second Course Phase (Retreatment) Q6W Cycles
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8
C9
DC
Safety 
follow-
upa
Efficacy 
follow-upb
Survival 
follow-
upc
If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
Safety Follow-up Visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the Safety Follow-
up Visit should be performed.
Scheduling 
Window
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
30 d 
after last 
dose 
(+ 7 d)
Q12W 
(±7 d)
Q12W
(± 7 d)
Laboratory Assessments
Urine or Serum
Pregnancy Test -
WOCBP Only
X
X
WOCBP require a negative 
pregnancy test within either
24 hours (urine) or 72 hours (serum) 
before starting Second Course 
retreatment.
A pregnancy test must be performed 
every month during Second Course 
treatment. Pregnancy testing should 
continue in posttreatment until 
120 days after last dose of 
pembrolizumab and 180 days after 
the last dose of paclitaxel, docetaxel 
(if applicable) and bevacizumab (if 
using) in first course treatment, if 
applicable.
More frequent pregnancy testing 
may be performed if required by 
local regulations or if clinically 
indicated.
Refer to Appendix 7 for 
country-specific requirements.
Home pregnancy tests are 
acceptable when a scheduled visit 
does not occur within the month 
(per local regulation), but the site 
must make monthly telephone 
contact with the participant to 
determine the results of the 
pregnancy test.
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Period
Second Course Phase (Retreatment) Q6W Cycles
EOT
Posttreatment
Comments
Cycle
C1
C2
C3
C4
C5
C6
C7
C8
C9
DC
Safety 
follow-
upa
Efficacy 
follow-upb
Survival 
follow-
upc
If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
Safety Follow-up Visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the Safety Follow-
up Visit should be performed.
Scheduling 
Window
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
±3 d
30 d 
after last 
dose 
(+ 7 d)
Q12W 
(±7 d)
Q12W
(± 7 d)
PT/INR and 
aPTT/PTT
X
Perform within 7 days before 
starting Second Course retreatment. 
Additional testing to be conducted 
as clinically indicated.
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Perform within 7 days before
starting Second Course retreatment. 
Perform within 72 hours before 
treatment on Day 1 of every cycle 
starting with Second Course C2.
Perform more frequently as 
clinically indicated.
Hematology
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Perform within 7 days before
starting Second Course retreatment.
After C1, perform within 72 hours 
before treatment on Day 1 every 2 
cycles starting with C2 (ie, C2, 4, 6, 
8).
T3 or FT3, plus 
FT4 and TSH
X
X
X
X
X
X
X
X
X
X
X
Perform within 7 days before
starting Second Course retreatment, 
then within 72 hours before 
treatment every cycle.
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; C=cycle; CA-125=cancer antigen-125; d=day; DC=discontinuation; ECG=electrocardiogram; 
ECI=events of clinical interest; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; FT3=free triiodothyronine; FT4=free thyroxine; INR=International 
Normalized Ratio; IV=intravenous; PFS2=progression-free survival after next-line treatment; PT=prothrombin time; PTT=partial thromboplastin time; Q6W= every 6 weeks; 
Q12W=every 12 weeks; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
a.
If the End-of-Treatment Visit occurs ≥30 days from last dose of study intervention, a separate Safety Follow-up Visit is not required. 
b. Participants should continue tumor scans Q12W (±7 d) until investigator-assessed radiographic disease progression per RECIST 1.1, the start of a new anticancer treatment, 
withdrawal of consent, pregnancy, or death. Tumor scan timepoints will be calculated from the start of Second Course retreatment.
c.
Survival Follow-up Visit will be performed by telephone. 
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2
INTRODUCTION
OC is the 20th most common cancer, with an estimated 295,414 new cases diagnosed 
worldwide, yet it is the eighth primary cause of cancer-related death for women, with 
approximately 184,799 deaths in 2018 [Bray, F., et al 2018]. In the US, the estimated 
numbers of new cases and deaths occurring in 2020 are 21,750 and 13,940, respectively 
[Siegel, R. L., et al 2020], while in Europe, the estimated number of new cases and deaths 
from OC in 2018 were 67,800 and 44,600, respectively [Ferlay, J., et al 2018]. The 5-year 
survival rate for patients with OC is only about 48% [Siegel, R. L., et al 2020]. OC is 
typically diagnosed in advanced stages (FIGO Stage III-IV) [Matulonis, U. A., et al 2016]; 5-
year survival in patients with distant disease is 29%, compared with 92% for patients with 
localized disease [Siegel, R. L., et al 2020].
OC is currently divided into several histologic subtypes that differ in genetic composition 
and clinical characteristics, for which increasingly tailored treatments are now used. In the
2014 World Health Organization classification guidelines, epithelial OC comprises serous 
(high- and low-grade), endometrioid, clear cell, mucinous, carcinosarcoma, and malignant 
Brenner tumors histologic subtypes. High-grade serous carcinoma is the most frequently 
diagnosed subtype of OC [Matulonis, U. A. 2018]. Irrespective of stages, patients with low-
grade serous and endometrioid show the best survival rates. In localized and regional stages, 
the poorest survival rates are detected for carcinosarcoma and malignant Brenner tumors, but 
in distant stage, the worst prognoses are observed in mucinous, clear cell and carcinosarcoma 
[Lan, A. 2019].
Until recently, treatment options for patients with newly diagnosed OC were cytoreductive 
surgery with either adjuvant or neoadjuvant chemotherapy (most likely platinum- and 
taxane-based) or chemotherapy alone [National Comprehensive Cancer Network 2020]. 
While most patients achieve a complete remission after the combination of cytoreductive 
surgery and chemotherapy, the majority (>80%) will recur [Matulonis, U. A., et al 2016]. 
The addition of the antiangiogenic agent bevacizumab to carboplatin plus paclitaxel, 
followed by bevacizumab alone, is a standard option in patients eligible to receive 
bevacizumab with newly diagnosed advanced OC [Burger, R. A., et al 2011] [Ledermann, J. 
A., et al 2013]. Treatment decisions in subsequent lines of therapy are less defined. Factors 
that affect treatment decisions include the duration of response to the previous chemotherapy, 
number of lines of chemotherapy, molecular signature, histological subtype, and residual 
toxic effects from previous therapies [Alvarez, R. D., et al 2016].
PARP inhibitors have ultimately changed the way that patients with OC are treated. Different 
PARP inhibitors have obtained US FDA and/or EMA approval in OC in different settings. 
Early studies have shown significant efficacy for PARP inhibitors in patients with germline 
BRCA1/2 mutations. It has also become evident that BRCA wild-type patients with other 
defects in the homologous recombination repair pathway benefit from this treatment 
[Boussios, S., et al 2019]. Recently olaparib in combination with bevacizumab was approved 
in the US as maintenance treatment for patients with OC who are in response to first-line 
platinum-based chemotherapy and whose cancer is associated with HRD positive status 
[Ray-Coquard, I., et al 2019] [U.S. Prescribing Information 2021]. Niraparib was also 
approved as maintenance treatment for OC patients who are in response to first-line 
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platinum-based chemotherapy regardless of BRCA or HRD status [Gonzalez-Martin, A., et al
2019] [U.S. Prescribing Information 2021a].
Patients with platinum-sensitive relapsed OCs (where disease progression occurs ≥6 months 
after the last dose of platinum-based chemotherapy) may initially be managed with different 
treatments such as chemotherapies and targeted therapies, if indicated. However, almost all 
patients will ultimately relapse. Patients who experience relapse during chemotherapy 
(ie, have platinum-refractory disease) or those who experience relapse within 6 months of 
completing the last platinum therapy (ie, have platinum-resistant disease) typically have low 
response rates to subsequent chemotherapy (<20%), a median PFS of 3 to 4 months, and a 
median OS in the range of 12 to 15 months [Pujade-Lauraine, E., et al 2019].
Several chemotherapeutic treatment options are globally approved and available for patients 
with PRROC including PLD, topotecan, cyclophosphamide, gemcitabine, docetaxel, and 
paclitaxel. The sequential use of single-agent therapy with a nonplatinum compound is 
considered standard [Pujade-Lauraine, E., et al 2019]. The major goals of therapy in this 
setting are to improve disease symptoms and prolong survival, while minimizing treatment 
toxicity. Weekly administration of paclitaxel has shown the highest response rate in 
platinum-resistant cancers [Markman, M., et al 2006], with less neurotoxicity than the 
standard Q3W regimen. The AURELIA study showed that the addition of bevacizumab to 
single-agent chemotherapy (weekly paclitaxel, PLD, or topotecan) significantly improved 
PFS and ORR in patients with PRROC [Pujade-Lauraine, E., et al 2014], leading to approval 
of bevacizumab in combination with paclitaxel, topotecan, and PLD for the treatment of 
second-line and third-line PRROC. Weekly paclitaxel plus bevacizumab was the most active 
of the combination regimens in the AURELIA study [Poveda, A. M., et al 2015], and is thus 
considered an ideal option, although only approximately 30% of patients with PRROC are 
eligible for bevacizumab treatment. Given the high toxicity with the current SOC 
chemotherapeutic regimens, limited activity in radiological/biochemical response, and no 
clear improvement in OS [Bogani, G., et al 2020], there remains an urgent requirement for 
novel therapies to be identified for women with platinum-resistant disease.
2.1
Study Rationale
Several clinical studies have shown efficacy of immune checkpoint inhibitors (anti-CTLA-4 
antibody, anti-PD-1 antibody and/or anti-PD-L1 antibody) in patients with various types of 
solid malignancies, with response rates of 5.9% to 20.0% in OC [Hamanishi, J., et al 2016]. 
In KEYNOTE-100, pembrolizumab monotherapy elicited modest antitumor efficacy (ORR 
of 8.0%), but a durable activity in mostly heavily pretreated patients with advanced recurrent 
OC (including those with platinum-refractory, resistant, and sensitive disease). 
KEYNOTE-100 showed a trend toward higher ORR with increasing PD-L1 CPS. In the 
“training set” used to establish CPS cutoff points, ORR was 2.9% in patients with CPS <1 
(n=34), 16.9% in patients with CPS ≥1 (n=59), and 30.0% in patients with CPS ≥10 (n=20), 
while in the total population (training + confirmation sets; N=376), ORR was 5.0% for 
CPS <1 (n=141), 10.2% for CPS ≥1 (n=197), and 17.1% for CPS ≥10 (n=82) [Matulonis, U. 
A., et al 2019]. Toxicities in KEYNOTE-100 were consistent with other single-agent 
pembrolizumab studies. 
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In JAVELIN Ovarian 200, the prevalence of PD-L1+ patients was 58% [Pujade-Lauraine, E., 
et al 2019a], which is similar to CPS ≥1 in KEYNOTE-100. In the avelumab + PLD arm, the 
ORR was 18.5% (95% CI: 11.1, 27.9) in the PD-L1+ subgroup and 3.4% (95% CI: 0.4, 11.9) 
for the PD-L1− subgroup. In PD-L1+ patients, the median PFS with the combination was 
longer than with avelumab alone, indicating a potential role of PD-L1 status as predictor of 
clinical benefit.
The combination of chemotherapy and immune checkpoint blockade may be a rational 
approach for the treatment of recurrent OC; PD-L1 is over-expressed in OC; women with 
tumor-infiltrating lymphocytes have improved survival, and there is evidence of preclinical 
synergy when these 2 types of agents are combined. Pembrolizumab has a nonoverlapping 
toxicity profile with chemotherapy, and combination therapy has shown promising activity in 
recurrent OC, improving both ORR and PFS (see Section 2.2.3). 
There may be additional synergistic activity between antiangiogenic therapy (bevacizumab, 
lenvatinib) and immunotherapy [Tartour, E., et al 2011]. A study of pembrolizumab + 
bevacizumab + cyclophosphamide in recurrent OC is described in Section 2.2.3. The 
combination of pembrolizumab + lenvatinib has shown promising antitumor activity and 
manageable toxicity in various advanced solid tumors, including an ORR of 32% and DCR 
of 74% as forth-line therapy in patients with OC [Lwin, Z., et al 2020]. Further clinical
studies for combination therapies of PD-1 inhibitors with chemotherapies, targeted molecular 
drugs for solid tumors, PARPi, focal radiation therapy and the other cancer immunotherapies 
such as cancer-specific vaccines or immune modulators are currently ongoing.
Based on this rationale, and the high unmet need in patients with PRROC, the present study 
has been designed to compare the combination of pembrolizumab and the preferred SOC 
regimen (weekly paclitaxel with or without bevacizumab) with the SOC regimen alone in 
participants with PRROC who have received no more than 2 prior lines of systemic therapy. 
Due to the rapidly evolving landscape, a future approval of an immune checkpoint inhibitor
in combination with other therapies in frontline OC cannot be ruled out, and such participants 
may benefit from the combination of pembrolizumab + paclitaxel + bevacizumab. Therefore, 
participants with prior exposure to anti-PD-1 or anti-PD-L1 will be eligible for this study.
2.2
Background
2.2.1
Pembrolizumab
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across several indications. For more details on specific 
indications refer to the IB.
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2.2.1.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer, hepatocellular carcinoma, malignant melanoma, and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling on engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. After T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, 
J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which 
PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 
2005] [Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in OC.
2.2.1.2
Preclinical and Clinical Studies
Refer to the pembrolizumab IB for a summary of preclinical and clinical study data.
2.2.1.3
Ongoing Clinical Studies
Refer to the pembrolizumab IB for a summary of ongoing clinical study data.
2.2.2
Therapeutic Strategies in Platinum-resistant Ovarian Cancer
Preferred chemotherapeutic options for PRROC include paclitaxel, docetaxel, PLD, 
topotecan, and gemcitabine [National Comprehensive Cancer Network 2020]. There is 
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evidence that (at equivalent dose intensity) weekly paclitaxel in patients with PRROC leads 
to better tolerance compared with the 3-weekly regimen, without compromising efficacy, and 
it has gained widespread use globally as a standard treatment [Rosenberg, P., et al 2002]. 
Weekly paclitaxel (80 mg/m2/week) showed an ORR of 20.9% (2 CRs, 8 PRs) among 48 
patients with platinum and paclitaxel-resistant ovarian and primary peritoneal cancers in a 
Gynecologic Oncology Group study. SAEs were relatively uncommon with 21% and 4% of 
patients experiencing Grade 2 and 3 neuropathy, respectively, and Grade 3 fatigue noted in 
8% [Markman, M., et al 2006]. A higher ORR was observed in another study of weekly 
paclitaxel (80 mg/m2) for up to 24 weeks in patients with recurrent platinum-resistant 
epithelial OC; 44% of patients had a PR and 9% had a CR, with median PFS of 6.1 months 
(95% CI: 3.81, 8.39) and median OS of 10.4 months (95% CI: 8.49, 12.38). Five patients 
(15%) reported Grade 3/4 neurotoxicity at the end of 12 weeks. No dose reduction or 
treatment delay was required and no significant hematologic toxicity was observed[Le, T., et 
al 2006]. It should be noted that response was evaluated using standard RECIST criteria in 
the former study, and both standard RECIST criteria and CA-125 in the latter study.
Bevacizumab substantially improves efficacy in PRROC compared with chemotherapy 
alone, and is approved for use in eligible patients with PRROC in combination with 
paclitaxel, topotecan, or PLD. The AURELIA study showed that adding bevacizumab 
(10 mg/kg Q2W) to chemotherapy (paclitaxel 80 mg/m2 Days 1, 8, 15, and 22 Q4W, 
topotecan 4 mg/m2 on Days 1, 8, and 15 Q4W or 1.25 mg/m2 on Days 1 to 5 Q3W, or PLD 
40 mg/m2 Day 1 Q4W) significantly improved PFS and ORR [Pujade-Lauraine, E., et al 
2014]. The largest treatment effect on ORR was observed in the paclitaxel cohort (53.3% vs 
30.2%; difference, 23.1%; 95% CI: 1.7, 44.5%), followed by the topotecan cohort (17.0% vs 
0.0%; difference, 17.0%; 95% CI: 5.1, 28.9%), with a less pronounced effect in the PLD 
cohort (13.7% vs 7.8%; difference, 5.9%; 95% CI: -7.2, 19.0%) [Poveda, A. M., et al 2015]. 
PFS HRs were 0.46 (95% CI: 0.30, 0.71) in the paclitaxel cohort (median, 10.4 vs 3.9 
months), 0.57 (95% CI: 0.39, 0.83) for PLD (median 5.4 vs 3.5 months favoring 
bevacizumab-containing therapy), and 0.32 (95% CI: 0.21, 0.49) for topotecan (median 5.8 
vs 2.1 months, respectively). The median duration of therapy was 3 cycles (range: 1 to 17 
cycles) in the chemotherapy arm versus 6 cycles (range: 1 to 24 cycles) in the combination 
arm, reflecting the substantially longer PFS in the combination arm. Grade ≥2 hypertension 
and proteinuria were more common with the combination than with chemotherapy alone. 
However, there were no new safety signals. GI perforation occurred in 2.2% of bevacizumab-
treated patients [Pujade-Lauraine, E., et al 2014].
PARP inhibitors have also shown significant efficacy in relapsed OC patients with germline 
BRCA1/2 mutations who have been treated with ≥2 prior lines of chemotherapy and in 
patients whose cancer is associated with HRD that were treated with ≥3 prior lines of 
chemotherapy [U.S. Prescribing Information 2020] [U.S. Prescribing Information 2020a]. In 
KEYNOTE-162, niraparib in combination with pembrolizumab was tolerable, and showed 
promising antitumor activity for patients with ovarian carcinoma who have limited treatment 
options regardless of platinum status, biomarker status, or prior treatment with bevacizumab 
[Konstantinopoulos, P. A., et al 2019].
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2.2.3
Immunotherapy Plus Chemotherapy in Platinum-resistant Recurrent Ovarian 
Cancer
Multiple studies are exploring the augmentation of chemotherapy efficacy and ways to 
overcome drug resistance by combining standard chemotherapy with immunotherapy. In the 
3-arm, randomized JAVELIN Ovarian 200 study, avelumab alone or in combination with 
PLD did not provide a statistically significant improvement in PFS or OS compared with 
PLD alone in 566 patients with PRROC . The ORR for the combination was 13.3% (95% CI: 
8.8, 19.0%) compared with 4.2% (95% CI: 1.8, 8.1%) for PLD monotherapy; median PFS 
was 3.7 versus 3.5 months, respectively, and median OS was 15.7 versus 13.1 months, 
respectively. However, the retrospective PD-L1 subgroup analysis revealed that for the 
avelumab plus PLD arm, patients with PD-L1+ tumors had a higher ORR (18.5%; 95% CI: 
11.1, 27.9%) than those with PD-L1– tumors (3.4%; 95% CI: 0.4, 11.9%) [Pujade-Lauraine, 
E., et al 2019a].
Despite the inconclusive results of the JAVELIN Ovarian 200 study, other immunotherapy 
and chemotherapy combinations are being explored.
Studies have shown that pembrolizumab improves the efficacy of chemotherapy with or 
without bevacizumab in PRROC. The combination of pembrolizumab (200 mg Q3W) and 
PLD (40 mg/m2 Q4W) showed only modest improvement with an ORR of ~13% among 
23 evaluable patients [Matulonis, U. A., et al 2018a]. Grade 3 toxicities included 19% rash, 
8% ALT increase, 4% each of AST increase, anemia, diarrhea, fever, and mucositis; there 
was 8% Grade 2 pneumonitis. Substantial efficacy improvement was observed when 
pembrolizumab was added to paclitaxel as combination partner in patients with PRROC, 
with an ORR of 51.4% [Wenham, R. M., et al 2018] (see Section 2.2.4). 
In another investigator-initiated study, 30 patients with platinum-resistant disease and 
10 patients with platinum-sensitive disease who declined platinum-based therapy were 
treated with pembrolizumab (200 mg Q3W) added to oral cyclophosphamide (50 mg once 
daily), and bevacizumab (15 mg/kg Q3W) [Zsiros, E., et al 2020]. The ORR in patients with 
PRROC was 43.3% (3 CR and 10 PR) with median DOR of 5.5 months (range: 0 to 26 
months) and DCR (CR+PR+SD) of 93.3%. Median PFS in patients with PRROC was 7.6 
months (90% CI: 5.7, 10.3). Cyclophosphamide plus bevacizumab without pembrolizumab is 
associated with an ORR of approximately 24% [Garcia, A. A., et al 2008]. The combination 
was well tolerated; any grade of treatment-related AEs occurred in 33 (82.5%) patients, with 
≥Grade 3 AEs in 13 (32.5%). The most frequently reported AEs included fatigue (18 
[45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]) and the most common Grade 
3 to 4 treatment-related AEs were bevacizumab-induced hypertension (6 [15.0%]) and 
lymphopenia attributed to oral cyclophosphamide (3 [7.5%]). One Grade 4 AE was noted due 
to low white blood cell and platelet counts that resolved without clinical intervention. No 
treatment-related deaths occurred during the study and treatment-related AEs led to treatment 
discontinuation for 4 patients (10%) and dose interruption in 17 patients (42.5%).
Based on the published results and preliminary data, combination therapy of PD-1/PD-L1 
inhibitors and chemotherapy with or without an antiangiogenic therapy certainly has the 
potential to be superior to chemotherapy alone.
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2.2.4
Pembrolizumab and Paclitaxel in Platinum-resistant Recurrent Ovarian 
Cancer
Pembrolizumab 200 mg Q3W in combination with weekly paclitaxel (80 mg/m2 on Days 1, 
8, and 15 Q3W) has shown a signal of activity in a single arm Phase 2 study of 42 women 
with PRROC who had received up to 3 prior cytotoxic chemotherapeutic regimens 
[Wenham, R. M., et al 2018]. The ORR and disease control rate were 51.4% (all PR) and 
86.5%, respectively, in the 37 evaluable patients. This response rate is similar to the 53% 
response rate seen with the combination of bevacizumab and paclitaxel in AURELIA 
[Poveda, A. M., et al 2015]. The 6-month PFS was 64.5%, with median PFS of 7.6 (4.8, 
12.0) months and median OS of 13.4 (12.1, 27.0) months. Among the 42 treated patients, the 
most frequent AEs were anemia (77%), fatigue (65%), neutropenia (56%), and nausea (51%). 
The most frequent Grade 3 AEs were leukocytosis (18.6%), anemia (14%), neutropenia 
(11.6%), and lymphopenia (7.0%). There were 3 Grade 4 AEs (neutropenia, glucose 
intolerance, and hyponatremia) and no Grade 5 AEs [Wenham, R. M., et al 2018].
2.2.5
Safety Data on the Combination of Pembrolizumab and Chemotherapy in 
Other Malignancies
Safety data for pembrolizumab + chemotherapy in other tumor types show an acceptable 
tolerability profile of combination therapy. 
In KEYNOTE-407, participants with previously untreated metastatic squamous NSCLC were 
randomized 1:1 to chemotherapy (carboplatin plus paclitaxel/nab-paclitaxel for four 3-week 
cycles) plus either pembrolizumab (N=278) or placebo (N=281) Q3W for up to 35 cycles 
[Paz-Ares, L., et al 2020]. ≥Grade 3 AEs occurred in 74.1% of participants in the 
pembrolizumab plus chemotherapy group and in 69.6% of participants in the placebo plus 
chemotherapy group; discontinuation of any study drug due to AEs occurred in 27.3% and 
13.2%; immune-mediated AEs occurred in 35.3% and 8.9%, and AEs led to death in 11.2% 
and 6.8%. The most frequently occurring AEs in both treatment groups were anemia, 
alopecia, neutropenia, and nausea. Most immune-mediated AEs and infusion reactions were 
Grade 1/2.
The combination of pembrolizumab plus carboplatin and paclitaxel has also been 
investigated in participants with previously untreated Stage II or Stage III triple negative 
breast cancer in study KEYNOTE-522 [Schmid, P., et al 2020]. Participants received 
neoadjuvant pembrolizumab (N=784) or placebo (N=390) plus paclitaxel and carboplatin 
Q3W for 4 cycles, followed by an additional 4 cycles of pembrolizumab or placebo, and both 
groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After 
definitive surgery, the participants received adjuvant pembrolizumab or placebo Q3W for up 
to 9 cycles. Across all treatment phases, the incidence of ≥Grade 3 treatment-related AEs was 
76.8% in the pembrolizumab plus chemotherapy group and 72.2% in the placebo plus 
chemotherapy group; treatment-related AEs led to discontinuation of any study drug in 
23.3% and 12.3%, and deaths across both phases were reported in 0.4% and 0.3%. The only 
AEs of interest ≥Grade 3 occurring in ≥10 participants in the pembrolizumab plus 
chemotherapy group were severe skin reactions (3.8%), infusion reactions (2.6%), and 
adrenal insufficiency (1.3%).
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In KEYNOTE-826, participants with persistent, recurrent, or metastatic cervical cancer were 
randomized 1:1 to receive pembrolizumab 200 mg or placebo Q3W, each in combination 
with paclitaxel 175 mg/m2 and cisplatin 50 mg/m2 or carboplatin AUC 5 Q3W plus, per 
investigator discretion, bevacizumab 15 mg/kg Q3W [Colombo, N., et al 2021]. ≥Grade 3 
AEs occurred in 81.8% of 307 treated participants in the pembrolizumab plus chemotherapy 
group and in 75.1% of 309 treated participants in the placebo plus chemotherapy group; 
SAEs occurred in 49.8% and 42.4%; discontinuation of any study drug due to AEs occurred 
in 37.5% and 26.5%; immune-mediated AEs occurred in 33.9% and 15.2%; and AEs led to 
death in 4.6% and 4.5%. The most common ≥Grade 3 AEs were anemia (30.3% in the 
pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, 
respectively).
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Given the low response rates to subsequent chemotherapy without clear improvement in OS 
in women with PRROC, new treatment modalities and paradigms are needed to improve the 
prognosis of this patient group. Immunotherapy is emerging as a potential strategy to 
enhance traditional PRROC treatments. Pembrolizumab and chemotherapy may be more 
beneficial to the patient via enhancing immunostimulatory activity of pembrolizumab as a 
single agent. Investigator-initiated study data discussed in Sections 2.2.3 and 2.2.4 suggest 
that standard chemotherapy may be administered safely in combination with pembrolizumab 
in patients with OC. The addition of bevacizumab to single-agent chemotherapy has been 
shown to significantly improve PFS and ORR in patients with PRROC [Poveda, A. M., et al 
2015], and may therefore also be administered to eligible participants in this study. 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Throughout this protocol, the term Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 refers to the modification of RECIST 1.1 to include a maximum of 10 target lesions and a 
maximum of 5 target lesions per organ. Refer to Section 4.2.1.1 for additional details.
In female participants with platinum-resistant recurrent ovarian cancer who have received 
≤2 prior lines of therapy:
Primary Objective
Primary Endpoint
To compare pembrolizumab plus paclitaxel 
with or without bevacizumab to placebo 
plus paclitaxel with or without 
bevacizumab, with respect to progression-
free survival (PFS) per RECIST 1.1 as 
assessed by the investigator
Hypothesis (H1): pembrolizumab plus 
paclitaxel with or without bevacizumab is 
superior to placebo plus paclitaxel with or 
without bevacizumab, with respect to PFS 
per RECIST 1.1 as assessed by the 
investigator for participants with 
programmed cell death ligand 1 (PD-L1) 
positive tumors (Combined Positive Score 
[CPS] ≥1)
Hypothesis (H2): pembrolizumab plus 
paclitaxel with or without bevacizumab is 
superior to placebo plus paclitaxel with or 
without bevacizumab, with respect to PFS 
per RECIST 1.1 as assessed by the 
investigator for all participants
PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
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Secondary Objectives
Secondary Endpoints
To compare pembrolizumab plus paclitaxel 
with or without bevacizumab to placebo 
plus paclitaxel with or without 
bevacizumab, with respect to overall 
survival (OS)
Hypothesis (H3): Pembrolizumab plus 
paclitaxel with or without bevacizumab is 
superior to placebo plus paclitaxel with or 
without bevacizumab, with respect to OS 
for participants with PD-L1 positive tumors 
(CPS ≥1)
Hypothesis (H4): Pembrolizumab plus 
paclitaxel with or without bevacizumab is 
superior to placebo plus paclitaxel with or 
without bevacizumab, with respect to OS 
for all participants
OS: The time from randomization to death 
due to any cause
To compare pembrolizumab plus paclitaxel 
with or without bevacizumab to placebo 
plus paclitaxel with or without 
bevacizumab, with respect to PFS per 
RECIST 1.1 by blinded independent central 
review (BICR) for participants with PD-L1 
positive tumors (CPS ≥1) and all 
participants
PFS
To evaluate the safety and tolerability of 
pembrolizumab in combination with 
paclitaxel with or without bevacizumab
-Adverse events (AEs)
-Study treatment discontinuation due to AEs
To compare pembrolizumab plus paclitaxel 
with or without bevacizumab to placebo 
plus paclitaxel with or without 
bevacizumab, with respect to Global Health 
Status/Quality of Life (GHS/QoL) score 
using the European Organisation for 
Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire 
Core 30 (QLQ-C30) and abdominal and 
gastrointestinal (GI) symptoms using the 
EORTC Ovarian Cancer-Specific Quality of 
Life Questionnaire (QLQ-OV28) 
abdominal/GI symptom scale for 
participants with PD-L1 positive tumors 
(CPS ≥1) and all participants
Change from baseline and time to 
deterioration (TTD) of the QoL and 
symptom scores from the GHS/QoL scale 
(items 29 and 30) of the EORTC QLQ-C30 
and the abdominal/GI symptom scale (items 
31 to 36) of the EORTC QLQ-OV28
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
CCI
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CCI
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, placebo-controlled, parallel-group, multisite, double-blind 
study of pembrolizumab versus placebo in combination with paclitaxel with or without 
bevacizumab in participants with PRROC who have received ≤2 prior lines of therapy. 
Participants must have received at least 1 line of platinum-based chemotherapy for OC with 
radiographic evidence of disease progression within 6 months after the last dose 
(ie, platinum-resistant disease). Participants should have radiographic evidence of disease 
progression on the most recent line of therapy to be eligible. Participants with secondary 
platinum-refractory disease who were either platinum resistant or platinum sensitive in the 
first line are eligible. Secondary platinum-refractory disease is defined as disease that has 
progressed per radiographic imaging while receiving or within 28 days of the last dose of 
second-line platinum-based therapy.
Prior anti-PD-1 or anti-PD-L1, prior PARP inhibitor, and prior bevacizumab use is permitted.
Approximately 616 eligible participants are expected to be randomized in the global portion 
of the study. After enrollment of the global portion of the study is complete, the study may 
remain open to enrollment in China alone until the target number of China participants has 
been enrolled to meet local regulatory requirements. This extension portion of the study, if 
required, will be identical to the global study (eg, inclusion and exclusion criteria, study 
endpoints, primary and secondary objectives, study procedures, and statistical analyses).
Eligible participants will be stratified according to planned bevacizumab use in the current 
study (yes vs no), region (US vs EU vs ROW), and PD-L1 status (CPS <1 vs CPS 1 to <10 
vs CPS ≥10). The Sponsor, investigators, participants, and other study-site staff will be 
masked to participant PD-L1 status. Participants will be randomly assigned to 1 of the 
following 2 treatment arms in a 1:1 ratio:
Arm 1: 
Pembrolizumab 400 mg Q6W for 18 cycles
PLUS paclitaxel 80 mg/m2 on Days 1, 8, and 15 of each Q3W cycle
(with or without bevacizumab 10 mg/kg Q2W)
Arm 2: 
Placebo Q6W for 18 cycles
PLUS paclitaxel 80 mg/m2 on Days 1, 8, and 15 of each Q3W cycle
(with or without bevacizumab 10 mg/kg Q2W)
Crossover between treatment arms is not permitted.
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Pembrolizumab/placebo may be administered for a maximum of 18 Q6W cycles
(approximately 2 years). Paclitaxel and bevacizumab may continue until disease progression, 
prohibitive toxicity, other protocol-defined reasons for discontinuation, or the participant has 
received the maximum duration (if applicable) per the respective approved labels or local 
practice.
The use of bevacizumab is optional and may be administered to eligible participants at the 
investigator’s discretion. Bevacizumab use must be decided and selected in IRT before 
randomization as it is a stratification factor. Refer to Appendix 7 for country-specific 
requirements for bevacizumab.
Paclitaxel-related toxicities should be managed according to local practice and institutional 
guidelines with supportive care measures, dose interruptions and reductions before 
consideration of discontinuation, if clinically appropriate. Docetaxel (75 mg/m2 Q3W) may 
be considered after consultation with the Sponsor for participants who experience either a 
severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel 
only after consultation with the Sponsor. Refer to Appendix 7 for country-specific 
requirements.
On-study tumor scans will be performed Q9W (±7 days) from randomization through 
Week 54 and Q12W (±7 days) thereafter until disease progression is radiographically 
documented by the investigator per RECIST 1.1, initiating a new anticancer treatment, 
withdrawal of consent, becoming lost to follow-up, pregnancy, or death. Tumor scans are 
required at EOT if previous scans were obtained more than 4 weeks before the EOT visit, 
and must be performed before the start of new anticancer treatment. All scans obtained on 
study will be submitted to the iCRO for assessment of PFS per RECIST 1.1 by BICR. Refer 
to Section 8.2 for details about tumor scans and assessment.
AE monitoring will be ongoing throughout the study and graded according to the guidelines 
outlined in the NCI CTCAE version 5.0. All AEs will be reported through 30 days after the 
last dose of study intervention. All SAEs will be reported through 90 days after the last dose 
of study intervention, or 30 days after the last dose if participant initiates a new anticancer 
treatment, whichever is earlier.
Participants who have completed the first course may be eligible for retreatment with 
pembrolizumab. If eligible, these participants may receive 9 additional Q6W, 400 mg
administrations of pembrolizumab (Second Course retreatment) upon experiencing
investigator-determined progressive disease by RECIST 1.1 after initial treatment or first 
course has been completed or stopped for confirmed CR, as specified in Section 6.1.2. 
The primary efficacy endpoint is PFS per RECIST 1.1 as assessed by investigator, and the 
key secondary endpoint is OS. Comparisons between the 2 treatment arms will be conducted 
at 2 planned IAs (at approximately 27 and 38 months after the first participant is randomized) 
and the final analysis at approximately 64 months after the first participant is randomized. 
Results of the IAs will be reviewed by an eDMC. Details are provided in Section 9.7.
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Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This multisite, randomized, double-blind, Phase 3 study is designed to compare efficacy and 
safety of pembrolizumab added to SOC chemotherapy with or without bevacizumab in 
participants with PRROC. Randomization will be used in this study to avoid bias in the 
assignment of participants to treatment, to increase the likelihood that known and unknown 
participant attributes (eg, demographics and baseline characteristics) are balanced across 
treatment arms, and to ensure the validity of statistical comparisons across treatment arms. 
Intravenous placebo will be used to reduce bias as the primary study endpoint of PFS is per 
investigator. 
Randomization will be stratified according to planned bevacizumab use in the study, region, 
and PD-L1 status using CPS (Section 6.3.2). Planned bevacizumab use (yes vs no) is 
included as a stratification factor to ensure that bevacizumab use is equally balanced across 
treatment arms. PD-L1 status (CPS <1 vs CPS 1 to <10 vs CPS ≥10) is included as a 
stratification factor since KEYNOTE-100 showed a trend toward higher ORR with 
increasing PD-L1 CPS (see Section 2.1). Furthermore, in JAVELIN Ovarian 200, the 
prevalence of PD-L1+ patients was 58%, which is similar to CPS ≥1 in KEYNOTE-100. The 
PFS result of the combination of avelumab with PLD in PD-L1+ was longer than avelumab 
alone, indicating a potential role of PD-L1 status as predictor of clinical benefit [Pujade-
Lauraine, E., et al 2019a]. Region is included as a stratification factor as regional variability 
may be a prognostic factor.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use PFS based on RECIST 1.1 criteria as assessed by the investigator as the 
primary endpoint and OS as the key secondary endpoint as outlined in Section 3. 
PFS is an acceptable measure of clinical benefit for a late-stage study that shows superiority 
of a new antineoplastic therapy, especially if the magnitude of the effect is large, and the 
therapy has an acceptable risk/benefit profile. Additionally, assessment of PFS based on 
RECIST 1.1 will be performed by BICR as a secondary objective.
OS has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies.
RECIST 1.1 will be used by the investigator and BICR when assessing images for efficacy 
measures. Although original RECIST 1.1 publication recommends a maximum of 5 target 
lesions in total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 
to allow a maximum of 10 target lesions in total and 5 per organ, if a larger number of target 
lesions is needed to adequately represent the tumor burden. Refer to Section 8.2.1.5 for 
additional detail.
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4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version [5.0].
4.2.1.3
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. In this study, 
HRQoL and disease-related symptoms will be investigated via the following assessment 
tools: EORTC QLQ-C30 and EORTC QLQ-OV28 questionnaires. Health utilities will be 
evaluated using the EQ-5D-5L PRO instrument. These measures are not pure efficacy or 
safety endpoints because they are affected by both disease progression and treatment 
tolerability.
4.2.1.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for 
assessing HRQoL in oncology studies [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 
is the most widely used cancer-specific HRQoL instrument, which contains 30 items and 
measures 5 functional dimensions (physical, role, emotional, cognitive, and social), 3 
symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health 
and QoL scale [Aaronson, N. K., et al 1993]. For the global health status or QoL and function 
scales, a higher value indicates a better level of function; for symptom scales and items, a 
higher value indicates increased severity of symptoms. TTD and mean change from baseline 
in global health status or QoL scale of the EORTC QLQ-C30, will be evaluated as secondary
objectives.
4.2.1.3.2
EORTC QLQ-OV28
The EORTC QLQ-OV28 is an OC-specific module to supplement the EORTC QLQ-C30. It 
has been translated and validated in over 70 languages. The EORTC QLQ-OV28 comprises 
3 functional scales (body image, sexuality, and attitude to disease/treatment), 3 symptom 
scales (abdominal/gastrointestinal symptoms, peripheral neuropathy, and 
hormonal/menopausal symptoms), and 7 items for other chemotherapy side-effects [Greimel, 
E., et al 2003]. It is scored on a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very 
much).
The EORTC QLQ-OV28 is a psychometrically and clinically validated instrument 
appropriate for assessing QoL of participants with OC, supplementary to EORTC QLQ-C30 
[Greimel, E., et al 2003]. These instruments have been commonly used in Phase 3 studies of 
participants with OC [Stockler, M. R., et al 2014] [Brotto, L., et al 2016] [Stark, D., et al 
2013]. There are 7 items (items 31 to 37) in the QLQ-OV28 to measure abdominal/ GI 
symptoms, which are predominant and burdensome symptoms specific to OC. The item 37 
(heartburn/indigestion) was excluded from abdominal/GI symptoms because it was judged to 
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be a less specific symptom of OC and less correlated with abdominal/GI symptom scale than 
with items for other chemotherapy side-effects [Stockler, M. R., et al 2014] [Cull, A., et al 
2001]. A difference of 10 points on the 100-point scale either from baseline or between the 
cohorts is considered clinically relevant [Bjordal, K., et al 1994] [Bjordal, K., et al 2000].
4.2.1.3.3
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the following: 
Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). 
The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the 
participant rates his or her general state of health at the time of the assessment. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
4.2.1.4
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/pharmacodynamic biomarkers and generate information that may better guide 
single-agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, biospecimens (ie, blood components, tumor material) will be collected to support 
analyses of cellular components (eg, protein, DNA, RNA, metabolites) and other circulating 
molecules. Investigations may include, but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome to interpret tumor-specific DNA mutations. Finally, MSI may be evaluated as this is 
an important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes called a ‘hyper-mutated’ 
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state) may generate neoantigen presentation in the tumor microenvironment. To conduct this 
type of research, it is important to identify tumor-specific mutations that occur across all 
genes in the tumor genome. Thus, genome-wide approaches may be used for this effort. Note 
that to understand tumor-specific mutations, it is necessary to compare the tumor genome 
with the germline genome. Microsatellite instability may also be evaluated as this is an 
important biomarker for some cancers (ie, colorectal cancer). Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that correlate to clinical response 
to treatment with pembrolizumab or other immunotherapies. Pembrolizumab induces a 
response in tumors that likely reflects an inflamed/immune phenotype. Specific 
immune-related gene sets (ie, those capturing interferon-gamma transcriptional pathways) 
may be evaluated and new signatures may be identified. Individual genes related to the 
immune system may also be evaluated (eg, IL-10). MicroRNA profiling may also be pursued 
as well as exosomal profiling.
Proteomics and IHC using blood and/or tumor
Tumor and/or blood samples from this study may undergo proteomic analyses (eg, PD-L1 
IHC). PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate 
with response to pembrolizumab in patients with NSCLC, and an IVD device has been 
developed for use with pembrolizumab in NSCLC. Preliminary data indicates that this 
association may also be true in additional cancer types (ie, triple negative breast cancer, head 
and neck, and gastric). Additional tumor or blood-derived proteins may also correlate with 
response to pembrolizumab. Therefore, tumor tissue may be subjected to proteomic analyses 
using a variety of platforms that could include, but are not limited to, immunoassays and 
liquid chromatography/mass spectrometry. This approach could identify novel protein
biomarkers that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as ELISA measure such proteins in 
serum. Correlation of expression with response to pembrolizumab therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
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4.2.1.5
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in 
Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
The background regimen of single-agent chemotherapy (weekly paclitaxel) with or without 
bevacizumab (for clinically eligible participants) used in this study represents one of the 
current SOC options for PRROC. The use of a placebo for pembrolizumab will ensure the 
objectivity of investigator-assessed progression and safety, as well as any decisions to 
interrupt/discontinue therapy, and will control for knowledge of treatment effects on PRO 
data, while still providing all participants enrolled with the current SOC treatment.
4.3
Justification for Dose
4.3.1
Pembrolizumab
The planned dose of pembrolizumab for this study is 400 mg Q6W.
The current approved dosing regimens of pembrolizumab for IV administration are 200 mg 
Q3W and 400 mg Q6W for adults.
A 400 mg Q6W dosing regimen of pembrolizumab is expected to have a similar benefit-risk 
profile as 200 mg Q3W, in all treatment settings in which 200 mg Q3W pembrolizumab is 
currently appropriate [Lala, M., et al 2020]. Specifically, the dosing regimen of 400 mg Q6W 
for pembrolizumab is considered adequate based on M&S analyses, given the following 
rationale:
PK simulations demonstrating that in terms of pembrolizumab exposures:
•
Cavg (or AUC) at 400 mg Q6W is similar to the approved 200 mg Q3W dose, thus 
bridging efficacy between dosing regimens.
•
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients.
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•
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the highest 
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab.
•
E-R for pembrolizumab has been shown to be flat across indications, and OS predictions 
in melanoma and NSCLC show that efficacy at 400 mg Q6W is expected to be similar to 
200 mg or 2 mg/kg Q3W, given the similar exposures; thus, 400 mg Q6W is expected to 
be efficacious across indications.
4.3.2
Paclitaxel
The regimen and dose of paclitaxel was selected based on standard clinical practice for the 
treatment of participants with PRROC. Weekly paclitaxel at a dose of 80 mg/m2 is in 
accordance with NCCN guidelines for PRROC [National Comprehensive Cancer Network 
2020] supported by evidence from a Phase 2 study of single-agent weekly paclitaxel in 
women with both platinum and paclitaxel-resistant OC [Markman, M., et al 2006]. The same 
dose and regimen was used in combination with bevacizumab in the AURELIA study 
[Pujade-Lauraine, E., et al 2014], although the 4-weekly cycle length in AURELIA 
(paclitaxel on Days 1, 8, 15, and 22 of a 4-week cycle) is adapted to Days 1, 8, and 15 of a 3-
week cycle in this study to complement the Q6W pembrolizumab dosing schedule. 
Randomized studies in recurrent OC have used weekly paclitaxel in the control arm 
(eg, TRINOVA-1 [Monk, B. J., et al 2014], MITO-11 [Pignata, S., et al 2015], ESP2011-002 
[NCT01485848]).
The dose of docetaxel (75 mg/m2 Q3W), if approved by the Sponsor to be used in place of 
paclitaxel, reflects the recommended dose for OC as determined by the SGCTG group 
[Vasey, P. A., et al 2004].
All participants should receive premedication and other supportive care measures, to prevent 
severe hypersensitivity reactions and minimize toxicity, according to the local label and/or 
per local practice. Paclitaxel-related toxicities should be managed with dose interruptions 
and/or reductions prior to discontinuation, as clinically appropriate.
4.3.3
Bevacizumab
The use of bevacizumab is permitted for clinically eligible participants at the investigator’s 
discretion. The regimen and dose of 10 mg/kg Q2W of bevacizumab to be used in 
combination with weekly paclitaxel was selected based on the approved product label and 
evidence from the AURELIA study [Pujade-Lauraine, E., et al 2014]. Refer to Appendix 7 
for country-specific requirements for bevacizumab.
4.3.4
Maximum Dose/Exposure for This Study
The maximum dose/exposure of pembrolizumab allowed in the first course of this study is 
400 mg Q6W for 18 cycles. 
Paclitaxel (80 mg/m2 on Days 1, 8, and 15 of each Q3W cycle) and bevacizumab (10 mg/kg 
Q2W) may continue until disease progression, prohibitive toxicity, other protocol-defined 
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reasons for discontinuation, or the participant has received the maximum duration (if 
applicable) per the respective approved labels or local practice.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Has histologically confirmed epithelial (including high-grade serous or predominantly 
serous, low-grade serous, any-grade endometrioid, malignant mixed Müllerian tumors 
[carcinosarcoma], or clear cell) ovarian, fallopian tube, or primary peritoneal carcinoma.
Note: Enrollment of participants with low-grade serous OC is permitted but will be 
capped at 4% of the total population.
2. Has received 1 or 2 prior lines of systemic therapy for OC, including at least 1 prior 
platinum-based therapy.
-
Participants must have received at least 4 cycles but not more than 9 cycles of 
platinum-based therapy in first line.
Note: Participation in the study may be allowed in case of discontinuation of 
platinum-based therapy due to toxicity, following Sponsor consultation 
-
Adjuvant ± neoadjuvant therapy is considered 1 line
-
Participants may have received a prior PARPi; this will not be considered a separate 
line of therapy if received in maintenance
-
Participants may have received a prior anti-PD-1/anti-PD-L1 therapy or 
bevacizumab; these will not be considered a separate line of therapy
-
Any chemotherapy regimen change due to toxicity in the absence of disease 
progression will be considered part of the same line of therapy
-
Hormonal therapy for OC (eg, tamoxifen, aromatase inhibitors etc.) will not count as 
a separate line of prior therapy
3. Has radiographic evidence of disease progression within 6 months (180 days) after the 
last dose of platinum-based chemotherapy for OC (ie, platinum-resistant disease).
Note: Participants with secondary platinum-refractory disease who were either platinum 
resistant or platinum sensitive in the first line are eligible.
4. Is a candidate for paclitaxel chemotherapy (and bevacizumab, if using).
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Demographics
5. Is female, and at least 18 years of age, at the time of signing the informed consent.
6. Has an ECOG performance status of 0 to 1 assessed within 3 days before randomization.
Female Participants
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and:  
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), with low user dependency, or be abstinent from heterosexual intercourse as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as 
described in Appendix 5 during the intervention period and for at least the time 
needed to eliminate each study intervention after the last dose of study intervention 
and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use 
for the purpose of reproduction during this period. The length of time required to 
continue contraception for each study intervention is as follows:
-
Pembrolizumab: 120 days
-
Paclitaxel (or docetaxel, if applicable): 180 days
-
Bevacizumab (if administered): 180 days 
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study intervention. 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed. Refer to 
Appendix 7 for country-specific requirements.
-
Has a negative highly sensitive pregnancy test (urine or serum as required by local 
regulations) within 24 hours for urine or within 72 hours for serum before the first 
dose of study intervention. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive. 
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.5. 
-
Abstains from breastfeeding during the study intervention period and for at least 
120 days after the last dose of study intervention.
-
Has had her medical history, menstrual history, and recent sexual activity reviewed 
by the investigator to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
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Informed Consent
8. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR.
Additional Categories
9. Has radiographically evaluable disease, either measurable or nonmeasurable per 
RECIST 1.1, as assessed by the local site investigator/radiology.
10. Archival tumor tissue sample or newly obtained core or incisional/excisional biopsy of a 
tumor lesion not previously irradiated has been provided. Details pertaining to tumor 
tissue submission can be found in the Laboratory Manual. Prospective determination of 
PD-L1 status by a central laboratory is required for all participants. Refer to Appendix 7 
for country-specific requirements.
11. Have adequate organ function as defined in the following table (Table 3). Specimens 
must be collected within 7 days before randomization.
Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Measured or calculatedb creatinine clearance
≥60 mL/min
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
aCriteria must be met without erythropoietin dependency within the last 4 weeks and without packed red 
blood cell (pRBC) transfusion within last 2 weeks.
bEstimated creatinine clearance (CrCl) should be calculated per institutional standard using Cockcroft-Gault:
(140-age [years] × weight (kg) (×F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies.
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5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Has nonepithelial cancers (germ cell tumors and sex cord-stromal tumors), borderline 
tumors (low malignant potential), mucinous, seromucinous that is predominantly 
mucinous, malignant Brenner’s tumor and undifferentiated carcinoma.
2. Has primary platinum-refractory disease, defined as disease that has progressed per 
radiographic imaging while receiving or within 28 days of the last dose of first-line 
platinum-based therapy. 
3. Has prior disease progression on weekly paclitaxel alone.
Note: Sponsor consultation is required if the participant experienced disease progression 
after paclitaxel but while receiving bevacizumab maintenance therapy.
4. Has uncontrolled hypertension.
Note: This applies only to participants who will receive bevacizumab. Use of 
antihypertensive medications to control blood pressure is allowed.
5. Has current, clinically relevant bowel obstruction (including subocclusive disease) 
including related to underlying epithelial OC, abdominal fistula or gastrointestinal 
perforation, intra-abdominal abscess, or evidence of rectosigmoid involvement by pelvic 
exam.
Note: This applies only to participants who will receive bevacizumab.
6. Has a history of thrombotic disorders, hemorrhage, hemoptysis, or active gastrointestinal 
bleeding within 6 months before randomization.
Note: This applies only to participants who will receive bevacizumab.
Prior/Concomitant Therapy
7. Has received >2 prior lines of systemic therapy for OC.
8. Has received prior systemic anticancer therapy, including investigational agents or 
maintenance therapy (including bevacizumab maintenance therapy), within 4 weeks 
before randomization.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants 
with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may 
be eligible.
Note: Hormonal therapy is permitted up to the time of randomization. 
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9. Has received prior radiation therapy within 2 weeks of start of study intervention. 
Note: Participants must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted 
for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
10. Has not recovered adequately from surgery and/or any complications from the surgery.
Note: For participants who will receive bevacizumab, surgery must have been at least 
28 days before randomization.
11. Has received colony-stimulating factors (eg, G-CSF, GM-CSF or recombinant 
erythropoietin) within 4 weeks before randomization.
12. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study intervention. Administration of killed vaccines are allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
13. Has received an investigational agent or has used an investigational device within 
4 weeks prior to study intervention administration.
Diagnostic Assessments
14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days before the first dose of study medication.
15. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have 
undergone potentially curative therapy are not excluded.
16. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging (Note: 
The repeat imaging should be performed during study screening.), clinically stable and 
without requirement of steroid treatment for at least 14 days before the first dose of study 
intervention.
Note: Participants with known untreated, asymptomatic brain metastases (ie, no 
neurological symptoms, no requirement for corticosteroids, no or minimal surrounding 
edema, and no lesion >1.5 cm) may participate but will require regular imaging of the 
brain as a site of disease.
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17. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, paclitaxel, or bevacizumab (if 
using) and/or any of their excipients.
Note: participants with known sensitivity to Chinese Hamster Ovary (CHO) cell products 
or other recombinant human or humanized antibodies are prohibited from receiving 
bevacizumab during the study.
18. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
19. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
20. Has an active infection requiring systemic therapy.
21. Has a known history of HIV infection. 
Note: No HIV testing is required unless mandated by local health authority. Refer to 
Appendix 7 for country-specific requirements.
22. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority. Refer to Appendix 7 for country-specific requirements.
23. Has a history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that might confound the results of the study or interfere with the 
participant's participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
24. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
25. Participant, in the judgement of the investigator, is unlikely to comply with the study 
procedures, restrictions, and requirements of the study.
26. Has had an allogenic tissue/solid organ transplant.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be rescreened for eligibility after consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 4.
Country-specific differences are noted in Appendix 7.
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Table 4
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experimental Pembrolizumab 
(MK-3475)
Drug
Solution
25 mg/mL
400 mg
IV Infusion
Q6W for 18 cycles
Test 
Product
IMP
Central
Arm 1
Experimental Paclitaxel
Drug
Solution
Variable
80 mg/m2
IV Infusion
Days 1, 8, 15 of 
each Q3W cycle 
until disease 
progression or 
prohibitive toxicity
Background 
Treatment
NIMP/AxMP Local or 
central
Arm 1
Experimental Docetaxel (in 
place of 
paclitaxel, only 
after Sponsor 
consultation)
Drug
Solution
Variable
75 mg/m2
IV Infusion
Q3W until disease 
progression or 
prohibitive toxicity
Background 
Treatment
NIMP/AxMP Local or 
central
Arm 1
Experimental Bevacizumab 
(if using)
Drug
Solution
25 mg/mL
10 mg/kg
IV Infusion
Optional, Q2W 
until disease 
progression or 
prohibitive toxicity
Background 
Treatment
NIMP/AxMP Local or 
central
Arm 2
Placebo 
Comparator
Placebo
Drug
Solution
Normal 
Saline or 
Dextrose
0 mg/mL
IV Infusion
Q6W for 18 cycles
Placebo
IMP
Local
Arm 2
Placebo 
Comparator
Paclitaxel
Drug
Solution
Variable
80 mg/m2
IV Infusion
Days 1, 8, 15 of 
each Q3W cycle 
until disease 
progression or 
prohibitive toxicity
Background 
Treatment
NIMP/AxMP Local or 
central
Arm 2
Placebo 
Comparator
Docetaxel (in 
place of 
paclitaxel, only 
after Sponsor 
consultation)
Drug
Solution
Variable
75 mg/m2
IV Infusion
Q3W until disease 
progression or 
prohibitive toxicity
Background 
Treatment
NIMP/AxMP Local or 
central
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Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 2
Placebo 
Comparator
Bevacizumab 
(if using)
Drug
Solution
25 mg/mL
10 mg/kg
IV Infusion
Optional, Q2W 
until disease 
progression or 
prohibitive toxicity
Background 
Treatment
NIMP/AxMP Local or 
central
Abbreviations: AxMP=auxiliary medicinal product; EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP=noninvestigational 
medicinal product; QW=weekly; Q2/3/6W=every 2/3/6 weeks.
The unit dose strength for background treatment may vary depending on market availability.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
In this protocol, placebo for pembrolizumab is diluent alone (normal saline and/or dextrose); diluent is used for blinding purposes and does not contain active ingredients.
Paclitaxel and bevacizumab may continue until disease progression, prohibitive toxicity, other protocol-defined reasons for discontinuation, or the participant has received the 
maximum duration (if applicable) per the respective approved labels or local practice.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Treatment
The initial treatment or first course of pembrolizumab consists of 18 Q6W treatments. Note: 
The number of treatments is calculated starting with the first dose.
These participants may be eligible for Second Course described in Section 6.1.2.
6.1.2
Second Course
All participants who have completed the first course may be eligible for up to an additional
9 Q6W cycles of pembrolizumab if there is investigator-determined progressive disease by 
RECIST 1.1 after initial treatment or first course has been completed or stopped for 
confirmed CR. This retreatment is the Second Course of this study.
Participants may enter the Second Course if all of the following criteria are met:
1. The participant received pembrolizumab, determined on unblinding if applicable
2. No new anticancer treatment was administered after the last dose of study intervention
3. The participant meets all of the inclusion criteria and none of the exclusion criteria
4. The study is ongoing
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Paclitaxel, bevacizumab (if using), and docetaxel (if used in place of paclitaxel) will 
be prepared and administered as per the approved product label(s) and institutional 
guidelines.
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6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to Arm 1 
(pembrolizumab + paclitaxel with or without bevacizumab) and Arm 2 (placebo + paclitaxel 
with or without bevacizumab), respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Planned bevacizumab use in the study (yes vs no)
2. Region (US vs EU vs ROW)
3. PD-L1 status (CPS <1 vs CPS 1 to <10 vs CPS ≥10)
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A total of 18 strata will be used for this study.
6.3.3
Blinding
A double-blinding technique will be used. Pembrolizumab and pembrolizumab placebo will 
be prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified 
study-site personnel. The participant, the investigator, and Sponsor personnel or delegate(s) 
who are involved in the study intervention administration or clinical evaluation of the 
participants are unaware of the intervention assignments. Paclitaxel (or docetaxel) and 
bevacizumab (if applicable) will be administered open-label. 
The Sponsor, investigators, participants, and other study-site staff will be masked to 
participant PD-L1 status throughout the study.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for Dose Modification and Toxicity Management Guidelines for irAEs 
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study-site staff other than the person administering the study 
intervention.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator is to discuss prohibited medication/vaccination with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
The following medications and vaccinations are prohibited during the study:
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
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•
Hormonal therapy
•
Investigational agents other than pembrolizumab
•
Radiation therapy
Note: Palliative radiation therapy to symptomatic lesions may be allowed following 
Sponsor consultation after assessment of disease progression has been determined.
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study (see Appendix 7 for country-specific requirements for 
live vaccines). Note: Killed vaccines are allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, 
replication-incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will 
be treated just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected due to chemotherapy or to have an 
immunologic etiology
-
For the prevention of emesis or other chemotherapy-related side-effects
-
To premedicate for IV contrast allergies
-
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses 
>10 mg/day prednisone equivalent)
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
•
Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or COPD
•
Prophylactic cytokines (eg, G-CSF, GM-CSF, or recombinant erythropoietin) should not 
be administered within 4 weeks before randomization, but may be administered during 
the treatment period.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
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All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
For further information on the prohibited concomitant therapies for paclitaxel, docetaxel (if 
applicable), and bevacizumab (if applicable), please refer to their respective approved 
product label.
6.5.1
Cautions for Use of Paclitaxel
Caution should be exercised when paclitaxel is concomitantly administered with known 
substrates, inhibitors, or inducers of CYP2C8 and/or CYP3A4. 
Note: A current list of strong/moderate inducers/inhibitors of CYP2C8 and CYP3A4 can be 
found at the below website. The link from the FDA does not provide an all-inclusive list. 
Any CYP2C8 or CYP3A4 inducers or inhibitors not approved in the US will not appear in 
the list. The investigator must review locally-approved product labels and use best medical 
judgment.
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
6.5.2
Cautions for Use of Docetaxel
Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of 
docetaxel may be modified by the concomitant administration of compounds that induce, 
inhibit, or are metabolized by CYP3A4. Avoid using concomitant strong CYP3A4 inhibitors 
with docetaxel. Close monitoring for toxicity and a 50% docetaxel dose reduction should be 
considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided.
6.5.3
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic
etiology are outlined along with the dose modification guidelines in Section 6.6.
6.6
Dose Modification (Escalation/Titration/Other)
Dose modifications in response to treatment-related AEs are permitted to keep the participant 
on study intervention, when appropriate. Details on the modifications for each study 
intervention are provided in the sections below. In general:
•
If the participant experiences either a severe hypersensitivity reaction to paclitaxel or an 
AE requiring discontinuation of paclitaxel, then docetaxel may be substituted after 
consultation with the Sponsor.
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•
Pembrolizumab/placebo, paclitaxel (or docetaxel, if applicable), and bevacizumab (if 
using) may be interrupted together or separately at the investigator’s discretion to 
determine which treatment component is the source for a given toxicity.
•
Action may be taken independently for each component of study intervention (eg, 
chemotherapy should be discontinued for prohibitive toxicity that is 
chemotherapy-related, but pembrolizumab/placebo and bevacizumab, if using, may 
continue if well tolerated).
•
Chemotherapy may be interrupted, dose reduced or discontinued.
•
Pembrolizumab/placebo and bevacizumab may only be interrupted or discontinued.
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated With 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids, and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation.
Dose Modification and Toxicity Management Guidelines for irAEs Associated With 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations are provided in Table 5.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic antibiotics 
for opportunistic infections
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer antihyperglycemic 
in participants with 
hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of 
care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion of 
myocarditis (which 
was previously 
myocarditis Grade 1 
using CTCAE v4.0)
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event e
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating  
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may cause severe or life-
threatening infusion reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab monotherapy, coformulations, or IO 
combinations associated infusion reactions are provided in Table 6.
Table 6
Pembrolizumab Monotherapy, Coformulations or IO Combinations Infusion 
Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 h
Stop Infusion
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (eg, from 100 mL/h to 
50 mL/h). Otherwise, dosing will be 
held until symptoms resolve and the 
participant should be premedicated for 
the next scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate premedication 
should be permanently discontinued 
from further study intervention.
Participant may be premedicated 1.5 h 
(±30 min) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500 to 1000 mg po (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms after initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued 
from further study intervention.
No subsequent dosing
CTCAE=Common Terminology Criteria for Adverse Events; h=hour; IV=intravenous; NCI=National Cancer 
Institute; NSAIDs=nonsteroidal anti-inflammatory drugs.
Note: Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. However, study intervention is to 
be restarted within 6 weeks (42 days) of the originally scheduled dose and within 12 weeks 
(84 days) of the previously administered dose, unless otherwise discussed with the Sponsor. 
The reason for study intervention interruption is to be documented in the participant’s study 
record.
6.6.2
Dose Modification for Chemotherapy-related Toxicity
Management for participants (ie, dose reduction, interruption, or discontinuation) who 
experience paclitaxel-related toxicity will be in accordance with the paclitaxel prescribing 
information in each country/region or local institutional guidelines. For participants who 
have transitioned to docetaxel due to paclitaxel-related toxicity, management of 
docetaxel-related toxicity will be in accordance with the docetaxel prescribing information in 
each country/region or local institutional guidelines. Participants may not start paclitaxel with 
a reduced dose. Participants must initiate Cycle 1 Day 1 with the protocol-specified dose of 
80 mg/m2 QW for paclitaxel.
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Interruptions from paclitaxel (or docetaxel, if applicable) of greater than 6 consecutive weeks 
(42 days) from the originally scheduled dose require consultation between the investigator 
and the Sponsor. 
Supportive care measures (eg, G-CSF, erythropoietin, blood transfusion) should be used 
according to local standards to manage chemotherapy-induced myelosuppression, including 
to prevent severe infections linked to febrile neutropenia. To minimize dose reductions, 
interruptions, and discontinuations of chemotherapy, these supportive care measures should 
be used before implementing dose modifications, when appropriate.
6.6.3
Dose Modification for Bevacizumab-related Toxicity 
Management for participants (ie, interruption or discontinuation) who experience 
bevacizumab-related toxicity will be in accordance with the bevacizumab prescribing 
information in each country/region or local institutional guidelines.
Interruptions from bevacizumab of greater than 6 consecutive weeks (42 days) from the 
originally scheduled dose require consultation between the investigator and the Sponsor.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in this study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.3 unless the participant has 
withdrawn from the study as specified in Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Radiographic disease progression outlined in Section 8.2.1.5, documented by the 
investigator per RECIST 1.1 (after obtaining informed consent addendum and Sponsor 
communication, the investigator may elect to continue treatment beyond disease 
progression).
Note: Where treatment is continued beyond disease progression, Sponsor consultation 
should be sought after each subsequent imaging evaluation and where the investigator 
may continue treatment.
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•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
Note: If only local treatment is performed for an occurrence of another malignancy, the 
participant may continue on study intervention upon Sponsor consultation and approval.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
Note: Requirement for toxicity-related discontinuation applies to each treatment 
component individually (eg, paclitaxel should be discontinued for prohibitive toxicity 
that is paclitaxel-related, but pembrolizumab/placebo and bevacizumab [if using] may 
continue if well tolerated).
•
Completion of 18 administrations of pembrolizumab/placebo (calculated from first dose), 
or the participant has received the maximum duration of paclitaxel (or docetaxel, if 
applicable), and bevacizumab (if using) per the approved label or local practice.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
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•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study 
will not exceed the amount specified in the Laboratory Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place. Refer to Appendix 7 for country-specific 
requirements.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant meets eligibility requirements before randomization.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
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the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history. If the medical condition is due to any protocol-specified 
intervention (eg, screening procedure, screening laboratory tests), this will be recorded as an 
AE.
8.1.4.1
Ovarian Cancer History Details
Comprehensive details regarding the participant’s OC history will be recorded separately and 
not listed as medical history. These details include, but are not limited to, FIGO stage at 
diagnosis (Appendix 8), histopathology, location(s) of tumor burden, investigator-assessed 
tumor burden at baseline per RECIST 1.1, BRCA and/or HRD status (if local results are 
available), and all prior treatment (including prior radiation, prior chemotherapy, and prior 
surgery).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study and up to 30 days after the last dose of study intervention. In addition, new 
medications started during the Second Course and up to 30 days after the last dose of study 
intervention in Second Course should be recorded.
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All concomitant medications administered during SAEs and ECIs (as defined in Section 8.4) 
are to be recorded.
8.1.5.3
Subsequent Anticancer Treatment
Details of subsequent treatments for cancer (including surgical procedures and radiation) 
after discontinuation of study intervention will be collected. These details include, but are not 
limited to, treatment start and stop dates, reason for treatment, response to treatment, dates of 
progression after the completion of subsequent treatment, and reason for discontinuation 
from treatment. This information will be required for all subsequent anticancer treatments, 
including, but not limited to, other PD-1/PD-L1 inhibitors, PARP inhibitors, or 
investigational drugs.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any individual who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.6.1
Treatment Eligibility Assessment Form
Two TEA forms are included in this study to document the investigator’s choice of selecting 
or not selecting bevacizumab treatment and the rationale. 
TEA1 form will document the justification for adding bevacizumab to SOC paclitaxel (if 
applicable).
TEA2 form will document why bevacizumab was not selected (if applicable).
The investigator must complete these forms before randomization.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual.
Treatment sequencing:
Depending on which individual components of the regimen are being administered during 
any given cycle, administer in the following order:
1. Pembrolizumab or placebo
2. Paclitaxel (or docetaxel, if applicable)
3. Bevacizumab (if using)
Note: local practice for drug administration sequence can be followed if preferred. The date 
and dose of administration must be captured in the eCRF. 
Additional dosing details are provided in Section 8.1.8.1. 
Study intervention should begin within 3 days of randomization.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
Pembrolizumab/Placebo
Pembrolizumab will be administered as a dose of 400 mg Q6W for 18 cycles using a 
30-minute IV infusion. Sites should make every effort to target infusion timing to be as close 
to 30 minutes as possible. However, given the variability of infusion pumps from site to site, 
a window of -5 minutes and +10 minutes is permitted (ie, infusion time is 25 to 40 minutes).
The first dose of pembrolizumab/placebo must be administered within 3 days after 
randomization. Pembrolizumab/placebo should be administered every 42 days (±3 days). 
The Pharmacy Manual contains specific instructions for pembrolizumab/placebo preparation.
8.1.8.1.2
Paclitaxel (or Docetaxel)
Paclitaxel will be initiated on Cycle 1 Day 1 with the first administration of 
pembrolizumab/placebo, within 3 days after randomization. Paclitaxel may continue until 
disease progression, prohibitive toxicity, other protocol-defined reasons for discontinuation, 
or the participant has received the maximum duration (if applicable) per the respective 
approved label or local practice.
Paclitaxel will be administered by IV infusion as a dose of 80 mg/m2 on Days 1, 8, and 15 of 
each Q3W cycle according to prescribing information in each country/region or local 
institutional guidelines. The permitted window for paclitaxel dosing after Cycle 1 Day 1 is 
±1 day.
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Paclitaxel-related toxicities should be managed according to local practice and institutional 
guidelines with supportive care measures, dose interruptions and reductions before 
consideration of discontinuation, if clinically appropriate. Docetaxel (75 mg/m2 Q3W) may 
be considered for participants who experience either a severe hypersensitivity reaction to 
paclitaxel or an AE requiring discontinuation of paclitaxel, only after consultation with the 
Sponsor. Refer to Appendix 7 for country-specific requirements. If the participant is 
receiving a concomitant strong CYP3A4 inhibitor, close monitoring for toxicity and a 50% 
docetaxel dose reduction should be considered.
The preparation and administration of paclitaxel (or docetaxel, if applicable) should follow 
the local label and/or institutional guidelines. All participants should be premedicated with 
oral or IV steroid and antihistamines according to the approved product label and/or standard 
practice. Additional premedications should be administered as per standard practice.
8.1.8.1.3
Bevacizumab
The use of bevacizumab is optional and may be administered to eligible participants at the 
investigator’s discretion. Use of bevacizumab must be decided before randomization as it is a 
stratification factor.
Bevacizumab will be initiated on Cycle 1 Day 1 with the first administration of 
pembrolizumab/placebo. Bevacizumab may continue until disease progression, prohibitive 
toxicity, other protocol-defined reason for discontinuation, or the participant has received the 
maximum duration (if applicable) per the respective approved label or local practice.
Bevacizumab 10 mg/kg will be administered as an IV infusion Q2W, preferably following 
paclitaxel (or docetaxel, if applicable). The permitted window for bevacizumab dosing is 
±3 days. Refer to Appendix 7 for country-specific requirements.
The preparation and administration of bevacizumab should follow the local label and/or 
institutional guidelines. The bevacizumab biosimilar Zirabev™(bevacizumab-bvzr, Pfizer 
Inc.) may be allowed only after consultation with the Sponsor. Other biosimilars may be 
considered if approved in combination with paclitaxel in this indication in the US, EU, and 
other regions at the same time, only after consultation with the Sponsor.
Participants should remain on the same drug for the duration of the study. If a participant 
starts with Avastin, she should continue with Avastin until completion or discontinuation. If 
she starts on Zirabev, she should continue with Zirabev until completion or discontinuation. 
Similarly, participants receiving other biosimilars in accordance with the conditions above 
should remain on that biosimilar for the duration of the study.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
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Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the End-of-Treatment Visit at the time of withdrawal. Any AEs that 
are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the
toxicity grade of the AEs observed, the relation to study intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator and site personnel may be 
unblinded so that the appropriate follow-up medical care can be provided to the participant.
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Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
Note: In some instances (emergency and nonemergency), unblinding to study intervention 
may be needed for appropriate clinical management of complications, but may not 
necessitate discontinuation of study intervention. The Sponsor’s Clinical Director must be 
consulted to review individual requests, and the collaborative decision to unblind and allow a 
participant to remain on study intervention must be documented.
8.1.10.1
Nonemergency Unblinding
Nonemergency unblinding to study intervention (pembrolizumab/placebo) administration 
may occur on an individual participant basis and only after consultation with the Sponsor 
under the following circumstances:
•
Disease progression (as assessed by investigator) with discontinuation of study 
intervention and the participant is being considered for alternate treatment that 
necessitates knowledge of prior treatment on the study.
•
An AE necessitating discontinuation of study intervention and unblinding is required for 
appropriate clinical management of complications.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Tumor Tissue for Biomarker Status
During the screening period, a tumor sample for each participant is required and is to be:
•
A newly obtained core or incisional/excisional biopsy of a tumor lesion, which was not 
previously irradiated
Or
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•
An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the Laboratory Manual. Refer 
to Appendix 7 for country-specific requirements.
The central laboratory will use the tissue sample to ascertain PD-L1 status using the PD-L1 
IHC 22C3 pharmDx (Investigational Use Only) diagnostic kit. The diagnostic test is identical 
to the US FDA-approved PD-L1 IHC 22C3 pharmDx diagnostic kit except it is labeled IUO.  
The PD-L1 result will be masked to the site and Sponsor. PD-L1 status must be determined 
before randomization as it is a stratification factor.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from efficacy follow-up and 
goes into survival follow-up. The process and acceptable modality for scan collection and 
transmission to the iCRO can be found in the SIM. The same scan technique should be used 
in a participant throughout the study to optimize the reproducibility of the assessment of 
existing and new tumor burden and improve the accuracy of the response assessment based 
on scans. 
Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility.
If brain scans are performed, MRI is preferred; however, CT imaging will be acceptable, if 
MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain X-rays acquired for 
correlation, should also be submitted to the iCRO.
Other imaging modalities that may be collected, submitted to the iCRO, and included in the 
response assessment include PET and X-rays. Other types of medical imaging (such as 
ultrasound) should not be submitted to the iCRO and will not be included in response 
assessment.
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Participant eligibility and the primary PFS endpoint will be determined using local 
assessment (investigator assessment) based on RECIST 1.1. All scheduled scans for each 
participant will be submitted to the iCRO for assessment of the secondary PFS endpoint by 
BICR. In addition, unscheduled scans used to determine disease progression and scans 
obtained for other reasons, but which show radiologic progression, are to be submitted to the 
iCRO.
8.2.1.1
Initial Tumor Scans
The screening scans for randomized participants must be submitted to the iCRO.
Tumor scans performed as part of routine clinical management are acceptable for screening if 
they are of acceptable diagnostic quality and performed within 28 days of randomization and 
can be assessed by the iCRO.
If brain scans are required to document the stability of existing metastases, the brain scan 
should be acquired during screening. The specific methods permitted for this study are 
described in the SIM.
Bone scans are required at screening for participants with a history of bone metastases and/or 
for those participants with indicative clinical signs/symptoms such as bone pain or elevated 
alkaline phosphatase levels.
Bone scan refers to imaging methods used to assess bone metastasis. The specific methods 
permitted for this study are described in the SIM.
8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at 9 weeks (63 days 7 days) from the date of 
randomization. Subsequent tumor scans should be performed every 9 weeks (63 days 
7 days) or more frequently if clinically indicated. After 54 weeks (378 days 7 days), 
participants who remain on treatment will have scans performed every 12 weeks (84 days 
7 days). Scan timing should follow calendar days and should not be adjusted for delays in 
cycle starts. Scans are to be performed until disease progression is identified by the 
investigator, or until the start of new anticancer treatment, withdrawal of consent, pregnancy, 
death, or the end of the study, whichever occurs first.
Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular scan 
schedule, starting with the next scheduled time point. Participants who receive additional 
scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 
weeks later; scans may resume at the subsequent scheduled time point.
On-study brain or bone scans should be performed if clinically indicated or to confirm CR (if 
other lesions indicate CR and brain or bone lesions existed at baseline).
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8.2.1.3
End-of-treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization, refer to Section 8.2.1.2.
Scans are to be continued until one of the following conditions are met:
•
disease progression as defined by RECIST 1.1 as assessed by the investigator
•
the start of a new anticancer treatment
•
pregnancy
•
death
•
withdrawal of consent
•
the end of the study
Participants who are clinically stable may be treated beyond RECIST 1.1 radiographic 
progression after consultation with the Sponsor (see Section 8.2.1.5).
8.2.1.4
Second Course (Retreatment) Tumor Scans
Tumor scans must be performed within 28 days before restarting study intervention with 
pembrolizumab.
Response assessments and progressive disease are determined by investigator assessment.
The only Second Course scan to be provided to the iCRO is the baseline scan if it is the final 
scan for the Initial Treatment or First Course.
The first scan should be performed at 12 weeks (84 days 7 days) after restarting study 
intervention. Subsequent tumor scans are to be performed every 12 weeks (84 days 7 days) 
or more frequently, if clinically indicated.
Scans are to be performed until disease progression, the start of a new anticancer treatment, 
withdrawal of consent, death, completion of Second Course, or notification by the Sponsor, 
whichever occurs first.
If participants discontinue study intervention, tumor scans are to be performed at 
discontinuation (±4 week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
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If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans every 12 weeks 
(84 days 7 days) until the start of a new anticancer treatment, disease progression, 
withdrawal of consent, pregnancy, death, or the end of the study, whichever occurs first.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be assessed by the investigator as the primary measure for assessment of 
tumor response, date of disease progression, and as a basis for all protocol guidelines related 
to disease status (eg, discontinuation of study intervention). Although RECIST 1.1 references 
a maximum of 5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 
target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of 
tumor burden.
If disease progression is established by the investigator, the process continues as follows:
•
investigator judgement will determine action
•
if the participant is clinically stable and study intervention is to continue, communication 
with the sponsor is required and a reconsent addendum must be signed 
•
obtain scans per original protocol schedule
•
send scans to iCRO
For the purpose of this decision process, lack of clinical stability is defined as:
•
unacceptable toxicity
•
clinical signs or symptoms indicating clinically significant disease progression
•
decline in performance status
•
rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
As described above, treatment beyond documented disease progression may be permitted at 
the discretion of the investigator after consultation with the Sponsor and receiving 
appropriate documented informed consent. Sponsor consultation should be sought after each 
subsequent imaging evaluation and where the investigator may continue treatment.
8.2.2
Tumor Marker Assessment
Blood samples for tumor markers (ie, CA-125) will be obtained at time points indicated in 
Section 1.3. Additional assessments may be performed if clinically indicated (eg, suspected 
progression). CA-125 will be assessed by a local laboratory.
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8.2.3
Patient-reported Outcomes
The PRO questionnaire will be administered by trained site personnel and completed 
electronically by participants in the following order: EORTC QLQ-C30 first, then EORTC 
QLQ-OV28, and EQ-5D-5L. The questionnaires should be administered according to the 
schedule in the SoA (Section 1.3.1). It is acceptable for laboratory safety tests to be 
performed before administration of ePROs to accommodate institutional practice.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants before drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
Site staff must not read, administer, or complete the PRO questionnaires on behalf of the 
participant. If the participant is unable to read the questionnaire (eg, is blind or illiterate), that 
participant may still participate in the study, but is exempt from completing PRO 
questionnaires. Participants exempt in this regard should be documented appropriately by the 
site staff. Voice scripts may be used to complete the PRO questionnaires if available in the 
participant’s local language.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. 
The total amount of blood/tissue to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood/tissue volumes drawn/collected by 
visit and by sample type per participant, can be found in the Laboratory and/or Procedures 
Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete or symptom-directed physical examination will be conducted by an investigator 
or medically qualified designee (consistent with local requirements) per institutional 
standards.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical examinations are described in Section 1.3. After the 
first dose of study intervention, new clinically significant abnormal findings should be 
recorded as AEs.
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8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a symptom-directed physical examination as 
clinically indicated before study intervention administration. New clinically significant 
abnormal findings should be recorded as AEs.
8.3.2
Vital Signs
The investigator or qualified designee will assess vital signs at screening and as specified in 
the SoA (Section 1.3). Vital signs will include height (at screening only), weight, 
temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate. It is highly 
recommended that abnormal blood pressure measurements be confirmed.
For participants receiving bevacizumab, blood pressure should be measured before each 
bevacizumab administration (Q2W). 
8.3.3
Electrocardiograms
A standard 12-lead ECG will be obtained at screening and reviewed by an investigator or 
medically qualified designee (consistent with local requirements) as outlined in the SoA 
(Section 1.3). Additional ECGs may be performed during the study as clinically indicated.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the Laboratory Manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Laboratory 
and/or Procedures Manual. Refer to the SoA (Section 1.3) for the timing of laboratory 
assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.5
Pregnancy Testing
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted for the time required to eliminate systemic exposure after the last dose of 
each study intervention as noted in Section 5.1. The length of time required to 
continue pregnancy testing for each study intervention is as follows:
◦
Pembrolizumab: 120 days
◦
Paclitaxel (or docetaxel, if applicable): 180 days
◦
Bevacizumab (if administered): 180 days
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
-
Home pregnancy tests are acceptable when a scheduled visit does not occur within 
the month (per local regulation), but the site must make monthly telephone contact 
with the participant to determine the results of the pregnancy test. The results of the 
test must be recorded in the participant’s eCRF.
8.3.6
Performance Assessments
8.3.6.1
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc) with grades 0 to 5.
The investigator or qualified designee will assess ECOG performance status (see 
https://ecog-acrin.org/resources/ecog-performance-status) at screening (within 3 days before 
randomization) to determine eligibility, and at subsequent timepoints as specified in the SoA 
(Section 1.3).
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days after cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention randomization through 90 
days after cessation of study intervention or 30 days after cessation of study intervention 
if the participant initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
randomization through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.5, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
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•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 7.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Pregnancy/
Lactation Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout or run-in 
treatment 
including placebo 
run-in)
Exception: A 
positive 
pregnancy test at 
the time of initial 
screening is not a 
reportable event.
Report all
Previously reported –
Follow to completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- potential DILI
- require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
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make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
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Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
•
An overdose of Sponsor's product, as defined in Section 8.5.
•
An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample
collections for analysis of ADA/NAb and PK are currently planned as shown in Section 1.3.1
(SoA). These samples will only be collected for participants receiving bevacizumab enrolled 
after approval of Amendment 03. Data analysis, if performed, will be reported separately.
Ongoing PK and/or ADA sampling may be reduced or discontinued upon alignment with
requesting health authorities.
Sample collection, storage, and shipment instructions for PK and ADA samples will be
provided in the laboratory procedure manual.
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8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Blood for genetic analysis
•
Blood for ctDNA analyses
•
Tumor tissue
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be in the Laboratory Manual. Refer to Appendix 7 for country-specific 
requirements.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
Refer to Appendix 7 for country-specific requirements.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover from biomarker samples listed in Section 8.8.
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of tests or procedures performed before the participant provides 
documented informed consent may be used for screening or baseline purposes provided the 
tests or procedures met the protocol-specified criteria and were performed within the time 
frame defined in the SoA.
Screening procedures are to be completed within 28 days before the first dose of study 
intervention.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria 
(see Section 5.4). Results from assessments during the initial screening period are acceptable 
in lieu of a repeat screening test if performed within the specified time frame and the 
corresponding inclusion/exclusion criteria is met. Participants who are rescreened will retain 
their original screening number.
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Sections 8.1, 8.2, and 8.3.
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
When a participant discontinues study intervention during the treatment period, procedures 
for study intervention discontinuation will be performed.
The End-of-Treatment Visit should occur at the time study intervention is discontinued for 
any reason. If the End-of-Treatment Visit occurs 30 days from the last dose of study 
intervention, at the time of the mandatory Safety Follow-up Visit, the End-of-Treatment Visit 
procedures and any additional safety follow-up procedures should be performed. Visit 
requirements are outlined in Section 1.3. Additional details regarding participant withdrawal 
and discontinuation are in Section 7.
8.11.4
Posttreatment Visit
Posttreatment visit requirements are outlined in the SoA (Section 1.3).
8.11.4.1
End-of-Treatment Visit
The End-of-Treatment Visit should occur at the time study intervention is completed or 
discontinued for any reason. 
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Participants who discontinue study treatment for a reason other than disease progression will 
still be considered on-study and should continue with regularly scheduled assessments (see 
Section 8.11.3), including collecting participant information on the start of new anticancer 
treatment, disease progression, and death. If the End-of-Treatment Visit occurs 30 days from 
the last dose of study intervention, at the same time as the mandatory 30-Day Safety Follow 
up visit, the End-of-Treatment Visit procedures and any additional Safety Follow-up 
procedures can be combined into a single visit.
8.11.4.2
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first. AEs should continue to be recorded until 30 days after the last dose of study 
intervention, regardless of whether or not the participant has started new anticancer treatment 
(see Section 8.4.1).
Participants who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits: 1 after the Initial Treatment or First Course and 1 after the Second Course.
8.11.4.3
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin Efficacy 
Follow-up and should be assessed according to the on-treatment scan schedule (Q9W 
[63 days ±7 days] from randomization through Week 54 and Q12W [84 days ±7 days] 
thereafter) to monitor disease status. Every effort should be made to collect information 
regarding disease status until the start of new anticancer treatment, disease progression, 
withdrawal of consent, pregnancy, death, end of study, or if the participant begins 
retreatment with pembrolizumab as detailed in Section 6.1.2. Information regarding 
poststudy anticancer treatment will be collected if new treatment is initiated. Participants 
who completed all efficacy assessments and/or will not have further efficacy assessments 
must enter Survival Follow-up.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.1.2 will move from Efficacy Follow-up to Second Course when they 
experience disease progression. Details are provided in the Second Course SoA 
(Section 1.3.2) for retreatment with pembrolizumab.
8.11.4.4
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
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The first survival follow-up contact should be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the End-
of-Treatment Visit and/or Safety Follow-up Visit (whichever is last).
•
For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.11.5
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but before any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized, but before 
unblinding, will be documented in an sSAP and referenced in the CSR for the study. A 
separate biomarker analysis plan will be provided. Posthoc exploratory analyses will be 
clearly identified in the CSR. The PRO analysis plan will also be included in the sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below. The comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A Phase 3, Randomized, Double-Blind Study of Pembrolizumab versus Placebo 
in Combination With Paclitaxel With or Without Bevacizumab for the 
Treatment of Platinum-resistant Recurrent Ovarian Cancer (KEYNOTE-B96)
Treatment Assignment
643 participants were randomized (double-blind) in a 1:1 ratio between 2 
treatment arms: (1) pembrolizumab + paclitaxel ± bevacizumab and (2) placebo 
+ paclitaxel ± bevacizumab.  
Stratification factors are as follows:
1.
Planned bevacizumab use in the study (yes vs no)
2.
Region (US vs EU vs ROW)
3.
PD-L1 status (CPS <1 vs CPS 1 to <10 vs CPS ≥10)
Analysis Populations
Efficacy: ITT
Safety: APaT
PRO: PRO FAS
Primary Endpoints
1. PFS per RECIST 1.1 assessed by investigator in participants with PD-L1 
positive tumors (CPS ≥1).
2. PFS per RECIST 1.1 assessed by investigator in all participants.
Key Secondary 
Endpoints
1. OS in participants with PD-L1 positive tumors (CPS ≥1).
2. OS in all participants.
Statistical Methods for 
Key Efficacy Analyses
The hypothesis testing for the primary endpoint of PFS and key secondary 
endpoint of OS will be evaluated by comparing the experimental group to the 
control group using a stratified log-rank test. The HR will be estimated using a 
stratified Cox proportional hazard model. Event rates over time will be 
estimated within each treatment group using the Kaplan-Meier method. 
Statistical Methods for 
Key Safety Analyses
For analyses in which 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events, these analyses will be 
performed using the Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985].
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Interim Analyses
Efficacy
Two efficacy interim analyses will be performed in this study. Results will be 
reviewed by an external data monitoring committee. These interim analyses are 
summarized below. Details are provided in Section 9.7. 
•
Interim Analysis 1: 
◦
Timing: To be performed when ~ 9 months after last participant 
randomized, and ~ 331 PFS events have been observed in 
participants with CPS ≥1, and ~ 460 PFS events have been 
observed in all participants.
◦
Testing: First interim PFS analysis and first interim OS analysis. 
•
Interim Analysis 2: 
◦
Timing: To be performed when ~ 20 months after last participant 
randomized, and ~ 389 PFS events have been observed in 
participants with CPS ≥1, and ~ 541 PFS events have been 
observed in all participants.
◦
Testing: Final PFS analysis and second interim OS analysis.
•
Final Analysis:
◦
Timing: To be performed after ~ 369 OS events have been 
observed in participants with CPS ≥1, and ~ 512 OS events have 
been observed in all participants.
◦
Testing: Final OS analysis.
Safety
An interim safety analysis may be performed and reviewed by the eDMC 
~ 10 months after first participant is randomized. Afterwards, the eDMC will 
review safety data periodically in the study. Details will be specified in the 
DMC Charter.
Multiplicity
The overall type I error over the 2 primary hypotheses of PFS and the 
2 secondary hypotheses of OS is strongly controlled at 2.5% (1-sided), with 2% 
initially allocated to PFS in participants with CPS ≥1 [H1] and 0.5% to PFS in 
all participants [H2]. 
By using the graphical approach of Maurer and Bretz [Maurer, W. and Bretz, F. 
2013], if one null hypothesis is rejected, the alpha will be reallocated to other 
hypotheses.
The study will be considered positive if it is successful for either PFS in 
participants with CPS ≥1 [H1] or PFS in all participants [H2].
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Sample Size and Power 
The sample size is 643 participants.
•
For PFS in participants with PD-L1 positive tumors (CPS ≥1), with 
~ 389 estimated events at the final PFS analysis, the study has ~ 98% 
power to detect a HR of 0.66 at the initially allocated α=0.02 (1-sided). 
•
For PFS in all participants, with ~ 541 estimated events at the final PFS 
analysis, the study has ~ 94% power to detect a HR of 0.70 at the initially 
allocated α=0.005 (1-sided). 
•
For OS in participants with PD-L1 positive tumors (CPS ≥1), with 
~ 369 estimated events at the final OS analysis, the study has ~ 96% power 
to detect a HR of 0.68 at the α=0.025 (1-sided). 
•
For OS in all participants, with ~ 512 estimated events at the final OS 
analysis, the study has ~ 98% power to detect a HR of 0.70 at α=0.025 
(1-sided).
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data has been declared final and 
complete.
The Sponsor will generate the randomized allocation schedule for study treatment 
assignment for this protocol and the randomization will be implemented in IRT.
The investigator, site staff, participants, and study team at the Sponsor consisting of clinical, 
statistical, statistical programming and data management personnel, will be masked to 
participant-level PD-L1 biomarker results. An unblinded Sponsor clinical scientist, unblinded 
data management personnel, unblinded Sponsor statistician and unblinded Sponsor statistical 
programmer will have access to the participant-level PD-L1 results for the purpose of data 
review and will have no other responsibilities associated with the study. Summaries by 
PD-L1 status may be provided to the study team at the Sponsor by the unblinded Sponsor 
statistician or the IVRS vendor and will be limited and documented. In addition, efficacy 
assessments will be by investigator and by BICR without knowledge of treatment 
assignments or PD-L1 status.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
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9.4
Analysis Endpoints
Efficacy, safety, and PRO endpoints that will be evaluated for within- and/or between-
treatment differences are listed below. Other endpoints will be described in the sSAP.
Primary
PFS: The time from randomization to the first documented PD as assessed by the investigator 
according to RECIST 1.1, or death due to any cause, whichever occurs first.
Secondary
OS: The time from randomization to death due to any cause.
PFS: The time from randomization to the first documented PD as assessed by BICR 
according to RECIST 1.1, or death due to any cause, whichever occurs first.
PRO: Change from baseline and TTD of the QoL and symptom scores from the EORTC 
QLQ-C30 GHS/QoL (items 29 and 30), and the Abdominal/GI symptom subscale (items 31 
to 36) from EORTC QLQ-OV28. 
Exploratory
 
 
 
 
 
. 
 
 
 
 
 
 
. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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9.5
Analysis Populations
 
 
 
 
 
 
9.5.1
Efficacy Analysis Populations
The analyses of efficacy endpoints are based on the ITT population. All randomized 
participants will be included in this population. Participants will be analyzed in the treatment 
group to which they are randomized.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study treatment. Participants will be included in 
the treatment group corresponding to the study treatment they actually received for the 
analysis of safety data using the APaT population. This will be the treatment group to which 
they are randomized except for participants who take incorrect study treatment for the entire 
treatment period; such participants will be included in the treatment group corresponding to 
the study treatment actually received.
At least 1 laboratory or vital sign obtained subsequent to at least 1 dose of study treatment is 
required for inclusion in the analysis of the respective safety parameter. To assess change 
from baseline, a baseline measurement is also required.
9.5.3
PRO Analysis Populations
The PRO analyses are based on the PRO FAS population, defined as all randomized 
participants who have at least 1 PRO assessment available for the specific endpoint and have 
received at least 1 dose of the study intervention. Participants will be analyzed in the 
treatment group to which they are randomized.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values may be computed for 
other efficacy analyses, but should be interpreted with caution due to potential issues of 
multiplicity, sample size, etc.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary efficacy 
objectives. Methods related to exploratory objectives will be described in the sSAP.
The stratification factors used for randomization (see Section 6.3.2) will be applied to all 
stratified analyses, in particular, the stratified log-rank test, stratified Cox model, and 
stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. If there 
are small strata, for the purpose of analysis, strata may be combined to ensure sufficient data 
in each stratum. Details regarding the pooling strategy will be prespecified in the sSAP prior 
to the database lock for the first efficacy analysis when each applicable endpoint will be 
analyzed, and decisions regarding the pooling will be based on a blinded review of data by 
stratum.
The efficacy analyses for PFS and ORR will include responses and documented progression 
events that occur before Second Course treatment.
9.6.1.1
Progression-Free Survival 
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, HR) between the treatment arms. 
The HR and its 95% CI from the stratified Cox model with a single treatment covariate will 
be reported. The stratification factors used for randomization (See Section 6.3.2) will be 
applied to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 as 
assessed by investigator and the date of death. Death is considered a PD event. Participants 
who do not experience a PFS event will be censored at the last disease assessment.
For the primary analysis, any participant who experiences an event (PD or death) 
immediately after 2 or more missed disease assessments will be censored at the last disease 
assessment prior to the missed visits. In addition, any participant who initiates new 
anticancer treatment prior to documented progression will be censored at the last disease 
assessment prior to the initiation of new anticancer treatment. Participants who do not start 
new anticancer treatment and who do not experience an event will be censored at the last 
disease assessment. If a participant meets multiple criteria for censoring, the censoring 
criterion that occurs earliest will be applied. 
To evaluate the robustness of the PFS endpoint per RECIST 1.1 by investigator, 2 sensitivity 
analyses with different sets of censoring rules will be performed. The first sensitivity analysis 
follows the ITT principle. That is, PDs/deaths are counted as events regardless of missed 
study visits or initiation of new anticancer treatment. The second sensitivity analysis 
considers initiation of new anticancer treatment or discontinuation of treatment due to 
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reasons other than CR, whichever occurs later, to be a PD event for participants without 
documented PD or death. If a participant meets multiple criteria for censoring, the censoring 
criterion that occurs earliest will be applied. The censoring rules for the primary and 
sensitivity analyses are summarized in Table 8.
Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anticancer 
treatment, if any
Progressed at date of 
documented PD or death 
Progressed at date 
of documented PD 
or death
Progressed at date of 
documented PD or death
Death or progression 
immediately after ≥2 
consecutive missed 
disease assessments, or 
after new anticancer 
treatment
Censored at last disease 
assessment prior to 
the earlier date of ≥2 
consecutive missed 
disease assessment and 
new anticancer 
treatment, if any
Progressed at date 
of documented PD 
or death
Progressed at date of 
documented PD or death
No PD and no death; and 
new anticancer treatment 
is not initiated
Censored at last disease 
assessment 
Censored at last 
disease assessment 
Progressed at treatment 
discontinuation due to reasons 
other than complete response; 
otherwise censored at last 
disease assessment if still on 
study treatment or completed 
study treatment.
No PD and no death; 
new anticancer treatment 
is initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last 
disease assessment
Progressed at date of new 
anticancer treatment
Abbreviation: PD=progressive disease
Similar analyses will be performed for the secondary endpoint of PFS per RECIST 1.1 by 
BICR assessment. Only the primary censoring rule will be applied for the analysis of PFS by 
BICR assessment. 
An analysis of PFS2, defined as the time from randomization to subsequent disease 
progression after initiation of new anticancer treatment, or death from any cause, whichever 
occurs first, will be carried out. Participants alive and for whom a disease progression 
following initiation of new anticancer treatment has not been observed will be censored at the 
last time the participant was known to be alive and without disease progression. The same 
stratified Cox proportional hazard model will be used to estimate the HR and its 95% CI.
9.6.1.2
Overall Survival 
The nonparametric Kaplan-Meier method will be used to estimate the OS curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess the 
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magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from the stratified 
Cox model with a single treatment covariate will be reported. The stratification factors used 
for randomization (See Section 6.3.2) will be applied to both the stratified log-rank test and 
the stratified Cox model. Participants without documented death at the time of analysis will 
be censored at the date the participant was last known to be alive.
9.6.1.3
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 9.
Table 9
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
Primary Hypothesis 1
PFS per RECIST 1.1 
by investigator in 
participants with CPS 
≥1
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling method 
ITT

Primary censoring rule

Sensitivity analysis 1

Sensitivity analysis 2
(More details are in Table 8)
Primary Hypothesis 2
PFS per RECIST 1.1 
by investigator in all 
participants
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling method 
ITT

Primary censoring rule

Sensitivity analysis 1

Sensitivity analysis 2
(More details are in Table 8)
Key Secondary Analyses
Key Secondary Hypothesis 1 (Hypothesis 3)
OS in participants 
with CPS ≥1
Testing: stratified log-rank test 
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored at the date 
participant last known to be 
alive
Key Secondary Hypothesis 2 (Hypothesis 4)
OS in all participants 
Testing: stratified log-rank test 
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored at the date 
participant last known to be 
alive
Other Secondary Analyses
PFS per RECIST 1.1 
by BICR in 
participants with CPS 
≥1 and in all 
participants
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Primary censoring rule 
(More details are in Table 8)
Abbreviations: BICR=blinded independent central review; CPS=combined positive score; ITT=intent-to-
treat; OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response Evaluation Criteria in 
Solid Tumors.
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach (Table 10). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) are either prespecified as “Tier 1” endpoints, or will be classified as belonging to 
“Tier 2” or “Tier 3” based on the observed proportions of participants with an event.
Tier 1 Events
AEs that are immune-mediated or potentially immune-mediated are well documented and 
will be evaluated separately; however, these events have been characterized consistently 
throughout the pembrolizumab clinical development program and determination of statistical 
significance is not expected to add value to the safety evaluation. Similarly, the combination 
of pembrolizumab and paclitaxel has not been associated with any new safety signals. 
Therefore, there are no Tier 1 events in this study.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic method.
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the AE; all other adverse experiences and predefined limits of change will belong to Tier 3. 
The threshold of at least 10% of participants was chosen for Tier 2 event because the 
population enrolled in this study are in critical conditions and usually experience various AEs 
of similar types regardless of treatment; events reported less frequently than 10% of 
participants would obscure the assessment of overall safety profile and add little to the 
interpretation of potentially meaningful treatment differences. In addition, Grade 3 to 5 AE 
(≥5% of participants in one of the treatment groups) and SAE (≥5% of participants in one of 
the treatment groups) will be considered Tier 2 endpoints. Because many 95% CIs may be 
provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in safety review, not a formal method for assessing the 
statistical significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, a drug-related AE, a 
serious AE, an AE which is both drug-related and serious, a Grade 3-5 AE, a drug-related 
Grade 3-5 AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only 
point estimates by treatment group will be provided for Tier 3 safety parameters.
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Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory and vital signs, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format.
Table 10
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Grade 3-5 AE (incidence ≥5% of participants in one of the 
treatment groups)
X
X
Serious AE (incidence ≥5% of participants in one of the 
treatment groups)
X
X
AEs (incidence ≥10% of participants in one of the treatment 
groups)
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence <10% of participants in all 
of the treatment groups)
X
Change from Baseline Results (laboratory toxicity shift, 
vital signs)
X
Abbreviations: AE=adverse event; CI=confidence interval; SOC=system organ class.
9.6.3
Statistical Methods for PRO Analyses
This section describes the planned analyses for the PRO endpoints. Details of PRO analyses 
including exploratory PRO analysis will be described in the sSAP.
Change From Baseline
The time point for the change from baseline will be determined based on blinded data review 
before the database lock for any PRO analysis and the criteria will be documented in the 
sSAP. 
To assess the treatment effects on the PRO score change from baseline in the QoL and 
symptom scores from the GHS/QoL scale of the EORTC QLQ-C30 and the abdominal/GI 
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symptom scores of the EORTC QLQ-OV28, a cLDA model proposed by Liang and Zeger 
[Liang, K.-Y. and Zeger, S. L. 2000] will be applied, with the PRO score as the response 
variable, and treatment, time, the treatment by time interaction, and stratification factors used 
for randomization (see Section 6.3.2) as covariates. The treatment difference in terms of least 
square (LS) mean change from baseline will be estimated from this model together with 95% 
CI. Model-based LS mean with 95% CI will be provided by treatment group for PRO scores 
at baseline and postbaseline time point.
Time to Deterioration
The Kaplan-Meier method will be used to estimate the TTD curve for each treatment group. 
The estimate of median TTD and its 95% confidence interval will be obtained from the 
Kaplan-Meier estimates. The treatment difference in TTD will be assessed by the stratified 
log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie handling 
and with a single treatment covariate will be used to assess the magnitude of the treatment 
difference (ie, HR). The HR and its 95% CI will be reported. The same stratification factors 
used for randomization (see Section 6.3.2) will be used as the stratification factors in both the 
stratified log-rank test and the stratified Cox model.
9.6.4
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by tables and/or graphs. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants screened and 
randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables, baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
9.7
Interim Analyses
An eDMC will serve as the primary reviewer of the results of the interim analyses of the 
study and will make recommendations for discontinuation of the study or protocol 
modifications to an executive committee of the Sponsor. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
committee (and potentially other limited Sponsor personnel) may be unblinded to results at 
the treatment level to act on these recommendations. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented. Additional 
logistical details will be provided in the eDMC Charter. Key aspects of the interim analyses 
are described in this section.
Treatment-level results from the interim analyses will be provided to the eDMC by the 
unblinded statistician. Before final study unblinding, the unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
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9.7.1
Efficacy Interim Analysis
Two efficacy interim analyses are planned in addition to the final analysis for this study. For 
the interim and final analyses, all randomized participants will be included. Results of the 
interim analyses will be reviewed by the eDMC. Details of the boundaries for establishing 
statistical significance with regard to efficacy are discussed further in Section 9.8.
The analyses planned, endpoints evaluated, and drivers of timing are summarized in 
Table 11.
Table 11
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9.7.2
Safety Interim Analysis 
The eDMC will be responsible for periodic interim safety reviews as specified in the DMC 
charter. An interim safety analysis may be performed after ~ 10 months have elapsed after 
the first participant is randomized. Afterwards, the eDMC will review safety data 
periodically in the study. Interim safety analyses will also be performed at the time of interim 
efficacy analyses. Details will be specified in the DMC charter.
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
provide strong multiplicity control for multiple hypotheses as well as interim analyses. 
According to this approach, study hypotheses may be tested more than once, and when a 
particular null hypothesis is rejected, the α allocated to that hypothesis can be reallocated to 
other hypothesis tests. Figure 2 shows the initial 1-sided α allocation for each hypothesis in 
the ellipse representing the hypothesis. The weights for reallocation from each hypothesis to 
the others are shown in the boxes on the lines connecting hypotheses.
The family-wise Type I error rate for this study is strongly controlled at 0.025 (one-sided) 
across the 2 primary hypotheses on PFS and the 2 secondary hypotheses on OS. The initial α 
assigned to PFS endpoints will be 0.02 to PFS in participants with CPS ≥1 and 0.005 
assigned to PFS in all participants, respectively. No initial α will be assigned to OS 
endpoints. The study will be considered a success if PFS in participants with CPS ≥1 or PFS 
in all participants is shown to be statistically significant under multiplicity control. If the null 
hypothesis of PFS in participants with CPS ≥1 (H1) is rejected, the corresponding alpha can 
be reallocated to PFS in all participants (H2). If the null hypothesis of PFS in all participants 
(H2) is rejected, the corresponding alpha can be reallocated to PFS in participants with CPS 
≥1 (H1). If both H1 and H2 are rejected, the corresponding alpha can be reallocated to OS in 
participants with CPS ≥1 (H3). If the null hypothesis of OS in participants with CPS ≥1 is 
rejected (H3), the corresponding alpha can be reallocated to OS in all participants (H4). A 
detailed graphical illustration of multiplicity will be provided in the sSAP.
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Figure 2
Multiplicity Diagram for Type I Error Control
Abbreviations: CPS=combined positive score; H=hypothesis; OS=overall survival; PFS=progression-free 
survival. 
9.8.1
Progression-free Survival
The study will test PFS hypothesis at IA1 and IA2 only, with IA2 being the final analysis of 
PFS endpoint. 
 
 Note that the final 
row for PFS endpoint at IA2 indicates the total power to reject the corresponding null 
hypothesis. If the null hypothesis of PFS in participants with CPS ≥1 is rejected, the 
corresponding alpha can be reallocated to PFS in all participants. If the null hypothesis of 
PFS is rejected in all participants, 99.9% of the alpha can be reallocated to PFS in 
participants with CPS ≥1. Thus, PFS hypothesis in all participants may be tested at α=0.005 
(initial α), or α=0.025 (if the null hypothesis for the PFS in participants with CPS ≥1 is 
rejected). PFS hypothesis in participants with CPS ≥1 may be tested at α=0.02 (initial α), or 
α= ~ 0.025 (if the null hypothesis for the PFS in all participants is rejected).
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Table 12
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9.8.2
Overall Survival
The study will test OS at IA1, IA2 and FA. 
 
 
 If the null hypothesis for PFS is rejected, the alpha 
initially allocated to the PFS hypothesis will be reallocated to the OS hypothesis. Technically 
the hypotheses for OS in both populations may be tested at α=0.000005 (0.005*0.001) if the 
null hypothesis for PFS is rejected in all participants, but not in participants with CPS ≥1. 
However, this extremely small amount is negligible. Thus, in practice the hypothesis for OS 
in participants with CPS ≥1 may only be tested at α=0.025 if the null hypotheses for both the 
PFS in all participants and in participants with CPS ≥1 are rejected. The hypothesis for OS in 
all participants may only be tested at α=0.025 if the null hypotheses for the OS in participants 
with CPS ≥1 is rejected.  
Table 13
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9.8.3
Safety Analyses
The eDMC has responsibility for assessment of overall risk/benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. eDMC review of 
efficacy data to assess the overall risk/benefit to study participants will not require a 
multiplicity adjustment typically associated with a planned efficacy interim analysis. 
However, to account for any multiplicity concerns raised by the DMC review of unplanned 
efficacy data prompted by safety concerns, a sensitivity analysis for PFS and OS adopting a 
conservative multiplicity adjustment will be specified in the sSAP if DMC explicitly requests 
a review of efficacy comparison beyond the standard safety eDMC package.
9.9
Sample Size and Power Calculations
The study randomized 643 participants in a 1:1 ratio into the pembrolizumab plus paclitaxel 
with or without bevacizumab and placebo plus paclitaxel with or without bevacizumab arms. 
Based on blinded review of study data, the observed prevalence of PD-L1 CPS ≥1 in this 
study was approximately 72%.
PFS is the primary endpoint and OS is the key secondary endpoint for the study.
 
 
 
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analysis timing and spending have been designed to ensure the final alpha available is 
maximized to make testing most sensitive when follow-up is available across both early and 
late parts of the survival and PFS distributions.
. 
.
 
The sample size and power calculations were performed using R (“gsDesign” package).  
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for PFS and OS (with a nominal 95% CI) will be estimated 
and plotted by treatment group within each category of the following subgroup variables. The 
subgroup analyses will be performed in participants with CPS ≥1 and in all participants, with 
the exception of the analysis by tumor PD-L1 expression level, which will only be performed 
in all participants.
•
Stratification factors:
◦
Planned bevacizumab use in the study (yes vs no)
◦
Region (US vs EU vs ROW)
◦
PD-L1 status (CPS <1 vs CPS 1 to <10 vs CPS ≥10)
•
Race (white vs non-white)
•
ECOG performance status (0 vs 1)
•
Prior PARPi use (yes vs no)
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•
Platinum free interval (<3 months vs 3-6 months from last platinum therapy to 
subsequent progression)
•
Planned bevacizumab use (10 mg/kg Q2W vs 15 mg/kg Q3W vs no bevacizumab)
Note: Bevacizumab dosing (if used) in this study is 10 mg/kg Q2W except per 
country-specific requirements in Appendix 7.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of Exposure for a participant is defined as the number of administrations and number 
of days in which the participant receives the study medication. Summary statistics will be 
provided on the Extent of Exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the 
safety and effectiveness of our products. As such, we are committed to designing, 
implementing, conducting, analyzing, and reporting these trials in compliance with 
the highest ethical and scientific standards. Protection of participants in clinical trials 
is the overriding concern in the design and conduct of clinical trials. In all cases, 
MSD clinical trials will be conducted in compliance with local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 
in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
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protection rights of all participants, trial site staff and, where applicable, third 
parties. All trial protocols are and will be assessed for the need and capability to 
enroll underrepresented groups. Participants must meet protocol entry criteria to 
be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
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authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations. Changes to the protocol that are required urgently to eliminate 
an immediate hazard and to protect participant safety may be enacted in anticipation 
of ethics committee approval. MSD will inform regulatory authorities of such new 
measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review and medical evaluation to identify 
potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc.) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial 
protocol, and in signing the protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the eDMC OR SAC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.3
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
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Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
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contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 14 will be performed by the local laboratory. 
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. Refer to Appendix 7 for 
country-specific requirements.
Table 14
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN or ureaa
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
above the ULN)
Albumin
Carbon dioxide (CO2 
or bicarbonate)b
Chloride
Phosphorous
Creatininec
Sodium
ALT/SGPT
Total Protein
Glucose (either 
fasting or 
nonfasting)
Calcium
Alkaline 
phosphatase
Magnesium
Thyroid-stimulating
hormone (TSH)d
Triiodothyronine
(T3) or free T3 thyroid 
hormone (FT3)d
Free thyroxine
(FT4)d
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterasee
by dipstick

Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing

Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP per local 
regulations)
Other 
Screening 
Tests

Coagulation: PT/INR and aPTT/PTT

FSH (as needed in WONCBP only)

Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) per local 
requirements

CA-125 (perform within 7 days before randomization and within ±14 days of each 
scheduled tumor scan).
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Laboratory 
Assessments
Parameters
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; BUN=blood urea nitrogen; CA-125=cancer antigen 125; FSH=follicle-stimulating 
hormone; FT3=free T3 thyroid hormone; FT4=free thyroxine; GFR=glomerular filtration rate; 
HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; INR=international normalized 
ratio; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; PT=prothrombin time; 
PTT=partial thromboplastin time; RBC=red blood cell; SGOT=serum glutamic oxaloacetic transaminase; 
SGPT=serum glutamic pyruvic transaminase; ULN=upper limit of normal; WOCBP=women of childbearing 
potential; WONCBP=women of nonchildbearing potential
a.
Blood urea nitrogen is preferred; if not available, urea may be tested.
b.
Performed only if considered local standard of care.
c.
GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
d.
Free T3 is acceptable where T3 cannot be determined. There may be instances when sites are unable to 
obtain the thyroid function testing results before scheduled dosing. Review of thyroid function test results 
after dosing is acceptable.
e.
Leukocyte testing can be performed when leukocyte esterase is not possible.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
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worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study).
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
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•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life-threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
Refer to Appendix 7 for country-specific requirements.
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantb,c

IUSc,d

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
Male condoms must be used in addition to female participant hormonal contraception.
d
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
China
4.1 Overall Design 
After enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in China alone until the target number of participants in China has been enrolled 
to meet local regulatory requirements. 
5.1 Inclusion Criteria
10.  Archival tumor tissue sample or newly obtained core or incisional/excisional biopsy of a 
tumor lesion not previously irradiated has been provided. Details pertaining to tumor tissue 
submission can be found in the Laboratory Manual. Prospective determination of PD-L1 
status by a central laboratory is required for all participants.
For study sites in China, tissue sample collected at screening for PD-L1 central analysis is 
required, to support a potential requirement from health authority.
8.1.12 Tumor Tissue for Biomarker Status
In China, the below samples, including tumor tissue or slides, will be collected for the 
participants who enrolled after HGRAC approval of the biomarker testing:
•
Tumor tissue 
8.8 Biomarkers
Biomarker sample collection for participants enrolled in China will be dependent on approval 
by the HGRAC. FBR will not be conducted in China.
10.7.2
Germany
Section 5.2 Exclusion Criteria
Exclusion Criterion: Participant has a known history of HIV infection. HIV testing is 
required for participants.
Exclusion Criterion: hepatitis B and C testing is required for participants.
Legally Acceptable Representative protocol sections
For a participant to be eligible to participate in Germany, they must be capable of providing 
documented informed consent; therefore, all references to a participant’s “legally acceptable 
representative” in the protocol are not applicable for participants in Germany.
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10.7.3
Ireland
Section 1.3 Schedule of Activities
HBV, HCV, HIV, and tuberculosis testing at screening is mandatory.
Section 5.2 Exclusion Criteria
Exclusion Criterion: Has a known history of HIV infection. Testing for HIV at screening is 
mandatory.
Exclusion Criterion: Has a known history of Hepatitis B (defined as HBsAg reactive) or 
known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 
Testing for HBV and HCV at screening is mandatory.
10.7.4
Italy
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing is required at screening.
Section 5.2 Exclusion Criteria
•
Exclusion Criterion: Has a known history of HIV infection. Testing for HIV is required at 
screening.
•
Exclusion Criterion: Has a known history of Hepatitis B (defined as HBsAg reactive) or 
known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 
Testing for HBV and HCV is required at screening.
10.7.5
Japan
Section 6.1 Study Intervention(s) Administered
The classification of Investigational Medicinal Product (IMP) and Non-Investigational 
Medicinal Product (NIMP) in Section 6.1 is based upon guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). As country 
differences with respect to the definition/classification of IMP/NIMP may exist, local 
legislation is followed. Local legislation in Japan requires that the agent paclitaxel for this 
study is considered as IMP. Diluent placebo (normal saline and/or dextrose) for this study is 
not considered as IMP in Japan.
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Synopsis: Intervention Groups and Duration; Section 1.2 Schema; Section 1.3.1 
Schedule of Activities – First Course Treatment; Section 4.1 Overall Design; Section 
4.3.2 Paclitaxel; Section 6.1 Study Intervention(s) Administered; Section 8.1.8.1.2 
Paclitaxel (or Docetaxel)
The starting dose of docetaxel, if approved by the Sponsor to be used in place of paclitaxel, 
will be 70 mg/m2 Q3W for participants in Japan.
Synopsis: Intervention Groups and Duration; Section 1.2 Schema; Section 1.3.1 
Schedule of Activities – First Course Treatment; Section 4.1 Overall Design; Section 
4.3.3 Bevacizumab; Section 6.1 Study Intervention(s) Administered; Section 8.1.8.1.3 
Bevacizumab
Sites in Japan have the option to use the 10-mg/kg Q2W or the 15-mg/kg Q3W bevacizumab 
dosing regimen in accordance with the approved local product label. Participants in Japan are 
allowed to switch dosing regimens (ie, from 15 mg/kg Q3W to 10 mg/kg Q2W or vice versa)
only once and only with prior approval of the Sponsor using an SCF.
10.7.6
United Kingdom
Section 5.2 Exclusion Criteria
Exclusion Criterion: HIV testing is required for participants.
Exclusion Criterion: hepatitis B and C testing is required for participants.
Section 6.5 Concomitant Therapy 
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
•
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
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10.8
Appendix 8: 2014 Federation of Gynecology and Obstetrics (FIGO) Ovarian, 
Fallopian Tube, and Peritoneal Cancer Staging System
Stage
Description
TNM
I
Tumor confined to ovaries or fallopian tube(s)
T1
IA
Tumor limited to one ovary (capsule intact) or fallopian tube, No tumor on 
ovarian or fallopian tube surface No malignant cells in the ascites or 
peritoneal washings
T1a
IB
Tumor limited to both ovaries (capsules intact) or fallopian tubes
No tumor on ovarian or fallopian tube surface
No malignant cells in the ascites or peritoneal washings
T1b
IC
Tumor limited to one or both ovaries or fallopian tubes, with any of the 
following:
IC1 Surgical spill intraoperatively
IC2 Capsule ruptured before surgery or tumor on ovarian or fallopian tube 
surface
IC3 Malignant cells present in the ascites or peritoneal washings
T1c
II
Tumor involves one or both ovaries or fallopian tubes with pelvic extension 
(below pelvic brim) or peritoneal cancer (Tp)
T2
IIA
Extension and/or implants on the uterus and/or fallopian tubes/and/or ovaries
T2a
IIB
Extension to other pelvic intraperitoneal tissues
T2b
III
Tumor involves one or both ovaries, or fallopian tubes, or primary peritoneal 
cancer, with cytologically or histologically confirmed spread to the
peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph 
nodes
T3
IIIA
Metastasis to the retroperitoneal lymph nodes with or without microscopic 
peritoneal involvement beyond the pelvis
T1,T2,T3aN1
  IIIA1
Positive retroperitoneal lymph nodes only (cytologically or histologically 
proven)
    IIIA1(i)
Metastasis ≤10 mm in greatest dimension (note this is tumor dimension and 
not lymph node dimension)
T3a/T3aN1
    IIIA1(ii)
Metastasis >10 mm in greatest dimension
  IIIA2
Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with 
or without positive retroperitoneal lymph nodes
T3a/T3aN1
IIIB
Macroscopic peritoneal metastases beyond the pelvic brim ≤2 cm in greatest 
dimension, with or without metastasis to the retroperitoneal lymph nodes
T3b/T3bN1
IIIC
Macroscopic peritoneal metastases beyond the pelvic brim >2 cm in greatest 
dimension, with or without metastases to the retroperitoneal nodes (Note 1)
T3c/T3cN1
IV
Distant metastasis excluding peritoneal metastases
IVA
Pleural effusion with positive cytology
Any T, Any 
N
IVB
Metastases to extra-abdominal organs (including inguinal lymph nodes and 
lymph nodes outside abdominal cavity) (Note 2)
M1
Note 1
Includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ.
Note 2
Parenchymal metastases are Stage IV B.
Adapted from the Federation of Gynecology and Obstetrics Guidelines 2014 [Prat, J. and FIGO Committee on 
Gynecologic Oncology 2014].
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
activities of daily living  
AE
adverse event 
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AST
aspartate aminotransferase
AUC
area under the curve
AxMP
auxiliary medicinal product
BICR
blinded independent central review
BRCA
breast cancer gene
CA-125
cancer antigen 125
CD
cluster of differentiation 
Cavg
average plasma concentration
CD3ζ
CD3 zeta
CI
confidence interval
cLDA
constrained longitudinal data analysis
Cmax
maximum plasma concentration
Cmin
trough plasma concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CPS
combined positive score
CR
complete response
CrCl
creatinine clearance
CRF
Case Report Form 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trials Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
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Abbreviation
Expanded Term
CYP
P450 cytochrome
DCR
disease control rate
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EEA
European Economic Area
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire
EORTC QLQ-OV28
European Organisation for Research and Treatment of Cancer Ovarian Cancer-
Specific Quality of Life Questionnaire
EOT
end of treatment
ePROs
electronic patient-reported outcomes
EQ-5D-5L
European Quality of Life Five-dimension Five-level Scale Questionnaire
E-R
exposure-response
EU
European Union
EU CTR
European Union Clinical Trials Regulation
EuroQoL
European Quality of Life
FA
final analysis
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
FIGO
International Federation of Gynecology and Obstetrics
FSH
follicle-stimulating hormone 
FSR
first site ready
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Abbreviation
Expanded Term
GCP
Good Clinical Practice 
G-CSF
Granulocyte Colony-Stimulating Factor
GFR
glomerular filtration rate
GHS
Global Health Status
GI
gastrointestinal
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
H
hypothesis
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HGRAC
Human Genetic Resources Administration of China
HIV
human immunodeficiency virus
HR
hazard ratio
HRD
homologous recombination deficiency
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
ID
identification
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IL-10
interleukin 10
IMP
investigational medicinal product
IO
immuno-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
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Abbreviation
Expanded Term
iRECIST
Modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRT
interactive response technology
ISO
International Standards Organization
ITT
intention-to-treat
IUD
intrauterine device
IUO
investigational use only
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
LAM
lactational amenorrhea method
LS
least square
M&S
modelling and simulation
mAb
monoclonal antibody
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
NAb
neutralizing antibodies
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIMP
noninvestigational medicinal product
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non–small cell lung cancer
OC
ovarian cancer
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PARP(i)
poly(adenosine-ribose) polymerase (inhibitor)
PCL
Protocol Clarification Letter
PD
progressive disease
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography
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Abbreviation
Expanded Term
PFS
progression-free survival
PFS2
progression-free survival after next-line treatment
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PLD
pegylated liposomal doxorubicin
PO
by mouth (per os)
PR
partial response
PRO
patient-reported outcome
PRROC
platinum-resistant recurrent ovarian cancer
QW
every week
Q2/3/6/9/12W
every 2/3/6/9/12 weeks
QoL
quality of life
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
ROW
Rest of World
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SCF
Sponsor Consultation Form
SGCTG
Scottish Gynaecological Cancer Trials Group
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SHP-1, SHP-2
Src homology region 2 domain-containing phosphatase-1/2
SIM
Site Imaging Manual
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TDT
time to discontinuation of study treatment
TEA
Treatment Eligibility Assessment (form)
TFST
time to first subsequent anticancer treatment
TSST
time to second subsequent anticancer treatment
TTD
time to deterioration
090B49

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Abbreviation
Expanded Term
TWiST
time without symptoms of disease progression or toxicity of treatment
ULN
upper limit of normal
US
United States
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
ZAP70
zeta-chain-associated protein kinase
090B49

PRODUCT: MK-3475
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11
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31-JAN-2024
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[U.S. Prescribing Information 
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