Conditions: Cervical Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 617
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy and safety of pembrolizumab (MK-3475) plus one of four platinum-based chemotherapy regimens compared to the efficacy and safety of placebo plus one of four platinum-based chemotherapy regimens in the treatment of adult women with persistent, recurrent, or metastatic cervical cancer. Possible chemotherapy regimens include: paclitaxel plus cisplatin with or without bevacizumab and paclitaxel plus carboplatin with or without bevacizumab.

The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy is superior to placebo plus chemotherapy with respect to: 1) Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by the Investigator, or, 2) Overall Survival (OS).

Detailed description:

Arms:
arm 1: On Day 1 of each 21-day cycle, participants receive an intravenous (IV) infusion of pembrolizumab 200 mg for up to 35 cycles (up to approximately 2 years) PLUS Investigator choice of chemotherapy for up to 6 cycles (paclitaxel 175 mg/m\^2 PLUS cisplatin 50 mg/m\^2 WITH or WITHOUT bevacizumab 15 mg/kg per local label OR paclitaxel 175 mg/m\^2 PLUS carboplatin Area Under the Curve (AUC) 5 for up to 6 cycles, WITH or WITHOUT bevacizumab 15 mg/kg per local label). All treatments are administered until disease progression or toxicity. arm 2: On Day 1 of each 21-day cycle, participants receive an IV infusion of placebo (Normal Saline or Dextrose solution) for up to 35 cycles (up to approximately 2 years) PLUS Investigator choice of chemotherapy for up to 6 cycles (paclitaxel 175 mg/m\^2 PLUS cisplatin 50 mg/m\^2 WITH or WITHOUT bevacizumab 15 mg/kg per local label OR paclitaxel 175 mg/m\^2 PLUS carboplatin AUC 5 for up to 6 cycles, WITH or WITHOUT bevacizumab 15 mg/kg per local label). All treatments are administered until disease progression or toxicity.

Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel intervention 3: Cisplatin intervention 4: Carboplatin intervention 5: Bevacizumab intervention 6: Placebo to pembrolizumab
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: IV infusion intervention 5: IV infusion intervention 6: IV infusion

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Randomized, Double-Blind, Placebo-
Controlled Trial of Pembrolizumab (MK-3475) Plus 
Chemotherapy Versus Chemotherapy Plus Placebo for 
the First-Line Treatment of Persistent, Recurrent, or 
Metastatic Cervical Cancer (KEYNOTE-826)
NCT03635567
10 June 2022


PRODUCT: MK-3475
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Title Page
THIS PROTOCOL AMENDMENT 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, Placebo-Controlled Trial of 
Pembrolizumab (MK-3475) Plus Chemotherapy Versus Chemotherapy Plus Placebo for the 
First-Line Treatment of Persistent, Recurrent, or Metastatic Cervical Cancer (KEYNOTE-
826)
Protocol Number: 826-08
Compound Number: MK-3475
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
126191
EudraCT Number 
2018-001440-53
Approval Date: 10 June 2022
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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 8/
Global amendment
10-JUN-2022
Merck Sharp & Dohme Corp. underwent an entity name and address 
change to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name change and update to the 
address.
Amendment 7/
Global amendment
05-JAN-2022
To state that the preplanned second interim analysis (IA2) will not be 
performed since the success criteria for the study hypotheses of 
progression-free survival (PFS) and overall survival (OS) for all the 
3 groups (combined positive score [CPS] ≥1 group, all-comers, and 
CPS ≥10 group) were met at the first interim analysis (IA1).
Amendment 6/
Global amendment
29-JUN-2021
To update the dose modification and toxicity management guidelines for 
immune-related adverse events (irAEs).
Amendment 5/
Global amendment
30-OCT-2020
The objectives including primary efficacy endpoints were modified. The 
primary PFS endpoint per RECIST 1.1 will be assessed by the 
investigator.
Amendment 4/
Global amendment
02-APR-2020
Amendment 4 supersedes Amendment 3. The objectives and hypotheses 
were modified with an updated multiplicity strategy based on updated 
results from the KEYTRUDA program.
Amendment 3/
Global amendment
31-JAN-2020
The objectives and hypotheses were modified with an updated 
multiplicity strategy based on updated results from the KEYTRUDA 
program.
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Document
Date of Issue
Overall Rationale
Amendment 2/
Global amendment
25-JUN-2019
Clarification of stratification factors and treatment duration.
Amendment 1/
Germany-specific amendment
13-NOV-2018
Insertion of the requirements to perform HIV, hepatitis B and C testing 
at Screening, monthly pregnancy testing, and urinalysis at every cycle 
during which bevacizumab is administered
Original Protocol
13-JUN-2018
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 08
Overall Rationale for the Amendments:
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
10.1.1 Code of Conduct for 
Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities (SoA)................................................................................20
1.3.1
Schedule of Activities – Initial Treatment Phase.........................................20
1.3.2
Schedule of Activities – Second Course Retreatment Phase.......................27
2
INTRODUCTION..........................................................................................................30
2.1
Study Rationale....................................................................................................30
2.2
Background ..........................................................................................................31
2.2.1
Pharmaceutical and Therapeutic Background .............................................32
2.2.2
Preclinical and Clinical Studies ...................................................................32
2.2.3
Ongoing Clinical Studies.............................................................................33
2.2.4
Information on Other Study-related Therapy ..............................................33
2.3
Benefit/Risk Assessment......................................................................................34
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................34
4
STUDY DESIGN............................................................................................................38
4.1
Overall Design......................................................................................................38
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................41
Efficacy Endpoints.............................................................................41
Safety Endpoints................................................................................42
Patient-reported Outcomes.................................................................42
4.2.1.3.1
EQ-5D-5L ................................................................................42
4.2.1.3.2
EORTC QLQ-C30 ...................................................................42
4.2.1.3.3
EORTC QLQ-CX24 ................................................................43
Planned Exploratory Biomarker Research.........................................43
Future Biomedical Research..............................................................44
4.2.2
Rationale for the Use of Comparator/Placebo .............................................45
4.3
Justification for Dose...........................................................................................45
4.3.1
Pembrolizumab ............................................................................................46
Planned Dose for this Study...............................................................46
Maximum Dose/Exposure for this Study...........................................46
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Rationale for Dose Interval and Study Design ..................................47
4.3.2
Chemotherapy and Bevacizumab ................................................................47
Paclitaxel............................................................................................47
Cisplatin.............................................................................................47
Carboplatin.........................................................................................47
Bevacizumab......................................................................................48
4.4
Beginning and End of Study Definition .............................................................48
4.4.1
Clinical Criteria for Early Study Termination .............................................48
5
STUDY POPULATION ................................................................................................48
5.1
Inclusion Criteria.................................................................................................48
5.2
Exclusion Criteria................................................................................................51
5.3
Lifestyle Considerations......................................................................................54
5.3.1
Meals and Dietary Restrictions....................................................................54
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................54
5.3.3
Activity Restrictions ....................................................................................54
5.3.4
Contraception...............................................................................................54
5.3.5
Pregnancy.....................................................................................................55
5.3.6
Use in Nursing Women................................................................................55
5.4
Screen Failures.....................................................................................................55
5.5
Participant Replacement Strategy......................................................................55
6
STUDY INTERVENTION............................................................................................56
6.1
Study Intervention(s) Administered...................................................................56
6.2
Preparation/Handling/Storage/Accountability .................................................59
6.2.1
Dose Preparation..........................................................................................59
6.2.2
Handling, Storage, and Accountability........................................................59
6.3
Measures to Minimize Bias: Randomization and Blinding..............................60
6.3.1
Intervention Assignment..............................................................................60
6.3.2
Stratification.................................................................................................60
6.3.3
Blinding........................................................................................................60
6.4
Study Intervention Compliance..........................................................................60
6.5
Concomitant Therapy..........................................................................................61
6.5.1
Rescue Medications and Supportive Care ...................................................62
Hematopoietic Growth Factors..........................................................63
6.6
Dose Modification (Escalation/Titration/Other)...............................................63
6.6.1
Dose Modification (Escalation/Titration/Other)..........................................64
6.6.2
Second Course .............................................................................................69
6.7
Intervention After the End of the Study............................................................70
6.8
Clinical Supplies Disclosure................................................................................70
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6.9
Standard Policies..................................................................................................71
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................71
7.1
Discontinuation of Study Intervention...............................................................71
7.2
Participant Withdrawal From the Study...........................................................73
7.3
Lost to Follow-up .................................................................................................73
8
STUDY ASSESSMENTS AND PROCEDURES........................................................73
8.1
Administrative and General Procedures ...........................................................74
8.1.1
Informed Consent.........................................................................................74
General Informed Consent.................................................................74
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................75
8.1.2
Inclusion/Exclusion Criteria ........................................................................75
8.1.3
Participant Identification Card.....................................................................75
8.1.4
Medical History ...........................................................................................75
8.1.5
Prior and Concomitant Medications Review...............................................76
Prior Medications...............................................................................76
Concomitant Medications..................................................................76
8.1.6
Assignment of Screening Number...............................................................76
Treatment Eligibility Assessment (TEA and TEAA) Forms.............76
8.1.7
Assignment of Treatment/Randomization Number.....................................76
8.1.8
Study Intervention Administration ..............................................................76
Timing of Dose Administration.........................................................77
8.1.9
Discontinuation and Withdrawal .................................................................77
Withdrawal From Future Biomedical Research ................................78
8.1.10
Participant Blinding/Unblinding..................................................................78
8.1.11
Calibration of Equipment.............................................................................79
8.2
Efficacy Assessments ...........................................................................................79
8.2.1
Tumor Imaging and Assessment of Disease................................................79
8.2.2
Initial Tumor Imaging During Screening ....................................................79
8.2.3
Tumor Imaging During the Study................................................................80
End-of-Treatment and Follow-up Tumor Imaging............................81
Second Course (Retreatment) Tumor Imaging..................................81
RECIST 1.1 Assessment of Disease..................................................82
iRECIST Assessment of Disease.......................................................82
8.2.4
Patient-reported Outcomes...........................................................................85
8.3
Safety Assessments...............................................................................................86
8.3.1
Physical Examinations.................................................................................86
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Full Physical Examination.................................................................86
Directed Physical Examination..........................................................86
8.3.2
Vital Signs....................................................................................................86
8.3.3
Electrocardiograms ......................................................................................87
8.3.4
Clinical Safety Laboratory Assessments .....................................................87
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................87
Pregnancy Test...................................................................................87
8.3.5
Performance Assessments............................................................................88
Eastern Cooperative Oncology Group (ECOG) Performance 
Scale...................................................................................................88
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................88
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................88
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......90
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...91
8.4.4
Regulatory Reporting Requirements for SAE .............................................91
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................91
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................92
8.4.7
Events of Clinical Interest (ECIs)................................................................92
8.5
Treatment of Overdose........................................................................................92
8.6
Pharmacokinetics.................................................................................................92
8.7
Pharmacodynamics..............................................................................................93
8.8
Future Biomedical Research Sample Collection...............................................93
8.9
Planned Genetic Analysis Sample Collection....................................................93
8.10
Biomarkers ...........................................................................................................93
8.10.1
Tumor Tissue Collection for Biomarker Analyses ......................................93
8.11
Health Economics Medical Resource Utilization..............................................94
8.12
Visit Requirements...............................................................................................94
8.12.1
Screening......................................................................................................94
8.12.2
Treatment Period Visit.................................................................................95
8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................95
8.12.4
Post-treatment Visit .....................................................................................95
Safety Follow-up Visit.......................................................................95
Efficacy Follow-up Visits..................................................................95
Survival Follow-up Contacts .............................................................96
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8.12.5
Survival Status .............................................................................................96
9
STATISTICAL ANALYSIS PLAN .............................................................................96
9.1
Statistical Analysis Plan Summary.....................................................................96
9.2
Responsibility for Analyses/In-house Blinding .................................................98
9.3
Hypotheses/Estimation ........................................................................................99
9.4
Analysis Endpoints...............................................................................................99
9.5
Analysis Populations..........................................................................................100
9.5.1
Efficacy Analysis Populations...................................................................100
9.5.2
Safety Analysis Populations ......................................................................100
9.5.3
PRO Analysis Population ..........................................................................100
9.6
Statistical Methods.............................................................................................101
9.6.1
Statistical Methods for Efficacy Analyses.................................................101
Progression-free Survival.................................................................101
Overall Survival...............................................................................102
Objective Response Rate (ORR) .....................................................103
Duration of Response (DOR)...........................................................103
Progression-Free Survival Rate at 12 months..................................104
9.6.2
Statistical Methods for Safety Analyses ....................................................104
9.6.3
Statistical Methods for PRO Analyses:......................................................106
9.6.4
Summaries of Baseline Characteristics and Demographics.......................107
9.7
Interim Analyses ................................................................................................107
9.7.1
Safety Interim Analyses.............................................................................107
9.7.2
Efficacy Interim Analyses..........................................................................107
9.8
Multiplicity .........................................................................................................109
9.8.1
Efficacy Analyses ......................................................................................110
PFS...................................................................................................110
OS ....................................................................................................112
9.8.2
Safety Analyses..........................................................................................113
9.9
Sample Size and Power Calculations ...............................................................113
9.10
Subgroup Analyses.............................................................................................114
9.11
Compliance (Medication Adherence)...............................................................115
9.12
Extent of Exposure.............................................................................................115
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................116
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......116
10.1.1
Code of Conduct for Clinical Trials...........................................................116
10.1.2
Financial Disclosure...................................................................................118
10.1.3
Data Protection...........................................................................................119
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Confidentiality of Data ....................................................................119
Confidentiality of Participant Records.............................................119
Confidentiality of IRB/IEC Information..........................................119
10.1.4
Committees Structure.................................................................................120
Executive Oversight Committee......................................................120
External Data Monitoring Committee .............................................120
10.1.5
Publication Policy......................................................................................120
10.1.6
Compliance with Study Registration and Results Posting Requirements .120
10.1.7
Compliance with Law, Audit, and Debarmen ...........................................121
10.1.8
Data Quality Assurance .............................................................................121
10.1.9
Source Documents .....................................................................................122
10.1.10
Study and Site Closure...............................................................................123
10.2
Appendix 2: Clinical Laboratory Tests............................................................124
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................126
10.3.1
Definition of AE ........................................................................................126
10.3.2
Definition of SAE ......................................................................................127
10.3.3
Additional Events Reported in the Same Manner as SAE.........................128
10.3.4
Recording AE and SAE .............................................................................128
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................132
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................134
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................135
10.5.1
Definitions..................................................................................................135
10.5.2
Contraception Requirements......................................................................136
10.5.3
Pregnancy Testing......................................................................................136
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................137
10.7
Appendix 7: Country-specific Requirements..................................................142
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................144
10.9
Appendix 9: Eastern Cooperative Oncology Group (ECOG) Performance 
Status...................................................................................................................148
10.10 Appendix 10: Abbreviations .............................................................................149
11
REFERENCES.............................................................................................................153
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LIST OF TABLES
Table 1
Study Schedule of Activities – Initial Treatment Phase ..................................20
Table 2
Study Schedule of Activities – Second Course Retreatment Phase.................27
Table 3
Adequate Organ Function Laboratory Values .................................................51
Table 4
Study Interventions..........................................................................................57
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................65
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................68
Table 7
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.............................................................................................................83
Table 8
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................90
Table 9
Censoring Rules for Primary and Sensitivity Analyses of Progression-Free 
Survival..........................................................................................................102
Table 10
Efficacy Analysis Methods for Key Efficacy Endpoints...............................103
Table 11
Censoring Rules for DOR..............................................................................104
Table 12
Analysis Strategy for Safety Parameters........................................................106
Table 13
Summary of Interim and Final Analyses Strategy.........................................108
Table 14
Efficacy Boundaries and Properties for PFS Analyses..................................111
Table 15
Efficacy Boundaries and Properties for OS Analysis....................................112
Table 16
Protocol-required Safety Laboratory Assessments........................................124
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LIST OF FIGURES
Figure 1
Study Diagram .................................................................................................19
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator ......................................................................................................85
Figure 3
Multiplicity Graph for Type I Error Control of Study Hypotheses ...............110
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of 
Pembrolizumab (MK-3475) Plus Chemotherapy Versus Chemotherapy Plus Placebo for the 
First-Line Treatment of Persistent, Recurrent, or Metastatic Cervical Cancer (KEYNOTE-
826)
Short Title: Phase 3 Trial of 1L Pembrolizumab Plus Chemotherapy in Persistent, Recurrent, 
or Metastatic Cervical Cancer
Acronym: NA
Hypotheses, Objectives, and Endpoints:
In women with persistent, recurrent, or metastatic cervical cancer treated with 
pembrolizumab plus chemotherapy versus placebo plus chemotherapy:
The study will be considered positive if it is positive for either the PFS or OS hypothesis test 
for any of the 3 groups (CPS ≥1 group, all-comers, and CPS ≥10 group).  
Primary Objectives
Primary Endpoints
- Objective:  To compare progression-free 
survival (PFS) per Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1) as 
assessed by investigator 
Hypothesis (H1): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy with 
respect to PFS per RECIST 1.1 as assessed 
by investigator for the Combined Positive 
Score (CPS) ≥1 group. 
Hypothesis (H2): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy with 
respect to PFS per RECIST 1.1 as assessed 
by investigator for all-comers.
Hypothesis (H3): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy with 
respect to PFS per RECIST 1.1 as assessed 
by investigator for the CPS ≥10 group.
- PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
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- Objective:  To compare overall survival 
(OS)
Hypothesis (H4): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy with 
respect to OS for the CPS ≥1 group.
Hypothesis (H5): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy with 
respect to OS for all-comers.
Hypothesis (H6): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy with 
respect to OS for the CPS ≥10 group.
- OS:  The time from randomization to 
death due to any cause
Secondary Objectives
Secondary Endpoints
- Objective:  To evaluate the objective 
response rate (ORR), duration of response 
(DOR), and 12-month PFS rate per RECIST 
1.1 as assessed by investigator
- Objective Response (OR): Participants 
who have a best overall response of either 
confirmed complete response (CR) or 
partial response (PR)
- DOR:  The time from the first documented 
evidence of CR or PR until the first 
documented disease progression or death 
due to any cause, whichever occurs first
- PFS-12: The proportion of participants 
that are PFS event-free at 12 months 
- Objective:  To evaluate PFS per RECIST 
1.1 as assessed by BICR
- PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
- Objective:  To compare the safety and 
tolerability by the proportion of adverse 
events (AEs)
- Participants experiencing adverse events 
(AEs), serious AEs, and immune-related 
AEs
- Participants discontinuing study treatment 
due to AEs
- Objective:  To evaluate changes in Health-
Related Quality of Life (HRQoL) 
assessments using the global score of the 
European Organisation for the Research and 
Treatment of Cancer (EORTC) QLQ-C30
- The EORTC QLQ-C30 global score
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Cervical cancer
Population
Women at least 18 years of age with persistent, recurrent,
or metastatic cervical cancer who have not been treated 
with systemic chemotherapy.
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Participant
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 48 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.
Number of Participants:
Approximately 600 participants will be randomized in this study. 
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Intervention Groups and Duration:
Intervention 
Groups 
Arm 1: Pembrolizumab 200 mg intravenous (IV) infusion + 
Chemotherapy every 3 weeks (Q3W)
Arm 2: Placebo + Chemotherapy Q3W
Investigators may choose ANY 1 of 4 chemotherapy options prior to 
randomization:
1) Paclitaxel 175 mg/m2 IV infusion + cisplatin 50 mg/m2 IV infusion 
2) Paclitaxel 175 mg/m2 IV infusion + cisplatin 50 mg/m2 IV infusion 
+ bevacizumab 15 mg/kg IV infusion
3) Paclitaxel 175 mg/m2 IV infusion + carboplatin AUC 5 IV infusion  
4) Paclitaxel 175 mg/m2 IV infusion + carboplatin AUC 5 IV infusion 
+ bevacizumab 15 mg/kg IV infusion
The option to use bevacizumab is permitted according to local practice, 
local label, and at the choice of the investigator.
Total 
Number
2 treatment groups
Duration of 
Participation
Each participant will participate in the study for approximately 28 months 
from the time the participant provides documented informed consent
through the final contact. After the end of treatment, each participant will 
be followed for 90 days for serious AEs.
After a screening phase of a maximum of 28 days, each participant will be 
assigned to receive study intervention until any of the following occurs:

Disease progression per RECIST 1.1 is detected locally and ideally 
verified by BICR (waiting to discontinue participant from study 
treatment until verification of PD by BICR is encouraged if the 
participant is clinically stable)

Disease progression is confirmed per iRECIST based on 
investigator assessment

Unacceptable adverse event(s) (AEs)

Intercurrent illness that prevents further administration of 
treatment

Investigator’s decision to withdraw the participant

Administrative reasons requiring cessation of treatment
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
Until the participant has received a maximum number of cycles for 
each treatment component individually:
o
Until the participant has received 35 administrations of 
pembrolizumab/placebo (approximately 2 years) and 
o
Until the participant has received 6 cycles of paclitaxel-
platinum (cisplatin or carboplatin)
NOTE: Participants with on-going clinical benefit and who 
are tolerating combination chemotherapy may be allowed 
to continue chemotherapy beyond 6 cycles after Sponsor 
consultation.
o
Bevacizumab may continue until disease progression or 
unacceptable AEs, per the local label or local practice.

Participants who stop study treatment after receiving 35 
administrations of pembrolizumab for reasons other than disease 
progression or intolerability, or participants who attain a CR after 
having been treated for at least 8 cycles and receiving 2 doses of 
pembrolizumab beyond the date when the initial CR was declared,
may be eligible for up to 17 additional administrations of 
pembrolizumab (approximately 1 year) upon experiencing disease 
progression (Section 6.6.2).
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy as described 
under Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1
and verified by BICR and only when clinically appropriate confirmed by 
the site per iRECIST (for participants treated with 
pembrolizumab/placebo), initiating a new anti-cancer treatment, 
withdrawing consent, becoming lost to follow-up, pregnancy, or death. All 
participants will be followed by telephone for overall survival until death, 
withdrawal of consent, or the end of the study.
Upon study completion, participants are discontinued and may be enrolled 
in a pembrolizumab extension study.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 10.
1.2
Schema
The study diagram is outlined in Figure 1.
Abbreviations:  AUC = area under concentration-time curve; CPS = combined positive score; ECOG = Eastern 
Cooperative Oncology Group; IV = intravenous; OS = overall survival; PD-L1 = programmed cell death ligand 
1; PFS = progression-free survival; PS = performance score
Figure 1
Study Diagram
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1.3
Schedule of Activities (SoA)
The SoAs for the Initial Treatment Phase and Second Course Retreatment Phase are outlined in Table 1 and Table 2, respectively.
1.3.1
Schedule of Activities – Initial Treatment Phase
Table 1
Study Schedule of Activities – Initial Treatment Phase
Study Period
Screening
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
Screening
C1
C2
C3
C4
C5
C6-
onward
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Scheduled Days
-28 to -1
±3
±3
±3
±3
±3
At time of 
discon-
tinuation
30 days from 
last dosea
(+7d)
Q9W or 
Q12Wb (±7d) Q12W (±7d)
Administrative Procedures
Informed Consent
X
Documented informed consent form 
may be obtained at any time prior to any 
protocol-specific screening procedures 
being performed.
Rescreened participants do not need to 
be reconsented if original consent was
obtained greater than 28 days prior to 
Cycle 1.
If the investigator plans to treat beyond 
initial investigator-assessed 
radiographic disease progression per 
RECIST 1.1, additional consent is 
required.
Informed Consent for Future 
Biomedical Research (FBR)
X
The participant may participate in the 
main study without participating in 
FBR.
Inclusion/Exclusion Criteria
X
Participant ID Card Issued
X
Add randomization number at C1
Demographics
X
Medical History
X
Cervical Cancer History
X
All prior historical information must be 
reviewed (eg, prior surgeries, radiation, 
and other oncologic therapies)
Prior/Concomitant Therapy
X
X
X
X
X
X
X
X
X
X
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Study Period
Screening
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
Screening
C1
C2
C3
C4
C5
C6-
onward
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Scheduled Days
-28 to -1
±3
±3
±3
±3
±3
At time of 
discon-
tinuation
30 days from 
last dosea
(+7d)
Q9W or 
Q12Wb (±7d) Q12W (±7d)
Randomize Participant
X
Participant may be randomized up to 
3 days prior to Cycle 1 Day 1
Review new anti-cancer 
therapy status
X
X
X
X
Survival Status
X
All participants may be contacted for 
survival status at any time during the 
course of the study.
Clinical Procedures or Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
Report all AEs through 30 days 
following cessation of study 
intervention. Report SAEs through 
90 days following cessation of study 
intervention or 30 days following 
cessation of study intervention if the 
participant initiates new anti-cancer
therapy, whichever is earlier.
Full Physical Exam
X
X
Directed Physical Exam
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
Assess within 14 days prior to 
randomization and prior to study 
intervention during treatment visits.
Investigator or designee is to confirm 
that ECOG performance status is 0 or 1 
prior to dosing at C1D1.
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Study Period
Screening
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
Screening
C1
C2
C3
C4
C5
C6-
onward
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Scheduled Days
-28 to -1
±3
±3
±3
±3
±3
At time of 
discon-
tinuation
30 days from 
last dosea
(+7d)
Q9W or 
Q12Wb (±7d) Q12W (±7d)
Laboratory Procedures and Assessments
Laboratory results must be reviewed 
before study drug administration.
Pregnancy Test 
(urine or β-HCG)
X
X
X
WOCBP require negative test within 
72 hours prior to randomization. In the 
event that more than 72 hours have 
elapsed between this pregnancy test and 
the first dose of study treatment, another 
pregnancy test must be performed and 
must be negative prior to receiving first 
dose of study treatment. 
A pregnancy test must be performed 
every month during study treatment.
More frequent pregnancy testing may
be performed if required by local
regulations or if clinically indicated.
Refer to Appendix 7 for country-
specific requirements.
HIV Testing
X
Not required unless mandated by local
health authority. Refer to Appendix 7 
for country-specific requirements. 
Hepatitis B and C Testing
X
Not required unless mandated by local
health authority. Refer to Appendix 7 
for country-specific requirements. 
PT/INR and aPTT/PTT
X
Perform eligibility labs within 14 days 
prior to randomization. 
Participants receiving coumarin-based 
anticoagulants should have more 
frequent INR monitoring as clinically 
indicated.
CBC with Differential
X
X
X
X
X
X
X
X
Perform eligibility labs within 14 days
prior to randomization. 
From Cycle 2 onwards, may perform up 
to 3 days prior to dosing. 
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Study Period
Screening
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
Screening
C1
C2
C3
C4
C5
C6-
onward
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Scheduled Days
-28 to -1
±3
±3
±3
±3
±3
At time of 
discon-
tinuation
30 days from 
last dosea
(+7d)
Q9W or 
Q12Wb (±7d) Q12W (±7d)
Chemistry Panel
X
X
X
X
X
X
X
X
Perform eligibility labs within 14 days
prior to randomization. 
From Cycle 2 onwards, may perform up 
to 3 days prior to dosing. 
T3/FT3, FT4, and TSH
X
X
X
X
X
X
At screening and every 2 cycles during 
treatment (C2, C4, C6,…). 
From Cycle 2 onwards, may perform up 
to 3 days prior to dosing.
May perform centrally if unable to 
perform locally.
Urinalysis
(for participants not receiving 
bevacizumab)
X
X
X
X
X
X
At screening, C2, C4, C6, and every 
4 cycles thereafter (C10, C14, C18,…). 
From Cycle 2 onwards, may perform up 
to 3 days prior to dosing.
Urinalysis
(for participants receiving 
bevacizumab)
X
X
X
X
X
X
X
X
At screening and at every cycle during 
which bevacizumab is administered 
from Cycle 2 onwards.
From Cycle 2 onwards, may perform up 
to 3 days prior to dosing.
Sample Collection for Biomarkers
Archival or Newly Obtained 
Tissue Collection
X
PD-L1 status must be determined prior
to randomization.
Blood for Genetic Analysis
X
Collect predose for randomized 
participants only
Blood for RNA Analyses
X
X
X
X
Collect predose on Day 1 of C1, C4, 
C7, C10, C13, C16 (Q9W through 
C16), Day 1 of C20, C24, C28, C32 
(Q12W up to C32), and at EOT.
Blood for Plasma Biomarker 
Analyses
X
X
X
X
Collect predose
Blood for Serum Biomarker 
Analyses
X
X
X
X
Collect predose
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Study Period
Screening
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
Screening
C1
C2
C3
C4
C5
C6-
onward
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Scheduled Days
-28 to -1
±3
±3
±3
±3
±3
At time of 
discon-
tinuation
30 days from 
last dosea
(+7d)
Q9W or 
Q12Wb (±7d) Q12W (±7d)
Blood for ctDNA
X
X
X
X
Collect predose on Day 1 of C1, C4, 
C7, C10, C13, C16 (Q9W through 
C16), Day 1 of C20, C24, C28, C32 
(Q12W after C16), and at EOT.
Efficacy Measurements
CT – chest
MRI – abdomen and pelvis
X
X
X
Xc
Perform within 28 days prior to 
randomization.
On treatment Q9W (±7 days) from 
randomization through Week 54, Q12W 
thereafter.
If imaging was obtained within 28 days
prior to EOT, scan at EOT is not 
mandatory. 
Schedule should be followed from date 
of randomization regardless of 
treatment delays.
Bone scan
X
Xc
Perform within 28 days prior to 
randomization ONLY for participants 
with a history of bone metastases or 
who are clinically symptomatic.
On study as clinically indicated.
Perform at CR for participants who 
were positive at baseline or at any point 
during the study.
Brain scan
X
Xc
Perform within 28 days prior to 
randomization ONLY for participants 
with brain metastases at baseline (to 
demonstrate stability) or who are 
clinically symptomatic.
On study as clinically indicated.
Perform at CR for participants who 
were positive at baseline or at any point 
during the study.
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Study Period
Screening
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
Screening
C1
C2
C3
C4
C5
C6-
onward
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Scheduled Days
-28 to -1
±3
±3
±3
±3
±3
At time of 
discon-
tinuation
30 days from 
last dosea
(+7d)
Q9W or 
Q12Wb (±7d) Q12W (±7d)
Health-Related Quality of Life (HRQoL)
ePROs (perform in this order)
1)
EQ-5D-5L
2)
EORTC QLQ-C30
3)
EORTC QLQ-CX24
X
X
X
X
X
X
X
X
Perform on Day 1 of Cycles 1 to 14, 
every other cycle thereafter up to 
Cycle 44, EOT, and Safety Follow-up.
If the participant does not complete the 
HRQoL survey(s), the MISS_MODE 
form must be completed to capture the 
reason the assessment(s) was not 
performed.
Study Drug Administration
Treatment eligibility 
assessment
X
Document rationale for participant 
eligibility for treatment with: 
1) bevacizumab and 2) the combination 
of cisplatin + paclitaxel + bevacizumab.
MK-3475 or placebo + 
Chemotherapy
X
X
X
X
X
X
Order of study intervention
administration: 1) pembrolizumab or 
placebo, 2) paclitaxel, 3) cisplatin or 
carboplatin, 4) bevacizumab.
Participants should receive up to 
6 cycles of paclitaxel-platinum 
(cisplatin or carboplatin) treatment. 
Participants with ongoing clinical 
benefit and who are tolerating 
combination chemotherapy may be 
allowed to continue chemotherapy 
beyond 6 cycles with Sponsor 
consultation. Subjects should continue 
biologic treatment 
(pembrolizumab/placebo and/or 
bevacizumab) until disease progression 
or prohibitive toxicity. Participants may 
receive a maximum of 
35 administrations of 
pembrolizumab/placebo.
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Study Period
Screening
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
Screening
C1
C2
C3
C4
C5
C6-
onward
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Scheduled Days
-28 to -1
±3
±3
±3
±3
±3
At time of 
discon-
tinuation
30 days from 
last dosea
(+7d)
Q9W or 
Q12Wb (±7d) Q12W (±7d)
AE = adverse event; aPTT = activated partial thromboplastin time; β-HCG = beta-human chorionic gonadotropin; BICR = blinded independent central review ; CBC = complete 
blood count; CR = complete response; CT = computed tomography; ctDNA = circulating tumor DNA; CX = Cycle X; ECOG = Eastern Cooperative Oncology Group; EORTC = 
European Organisation for the Research and Treatment of Cancer, EOT = End of treatment; ePRO = electronic patient-reported outcome; EQ-5D-5L = EuroQoL-5D-5L; FBR = 
Future biomedical research; FT3 = free triiodothyronine; FT4 = free thyroxine; HIV = human immunodeficiency virus; HRQoL = health-related Quality of Life; ID = identification; 
INR = international normalized ratio; iRECIST = modified RECIST 1.1 for immune-based therapeutics; MRI = magnetic resonance imaging; PD-L1 = programmed cell death 
ligand 1; PT = prothrombin time; PTT = partial prothrombin time; Q9W = every 9 weeks; Q12W = every 12 weeks; QLQ-C30 = Quality of Life Questionnaire Core 30; QLQ-
CX24 = Quality of Life Questionnaire Cervical Cancer Module; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; SAE=serious adverse event; 
T3 = triiodothyronine; TSH = thyroid-stimulating hormone; WOCBP = woman/women of child bearing potential.
a.
If the End of Treatment Visit occurs ≥30 days from last dose of study treatment, a Safety Follow-up Visit is not required. All procedures for both visits will be performed at 
the End of Treatment Visit.
b.
Efficacy Follow-Up visits to be scheduled to coincide with Follow-Up imaging.
c.
Participants who discontinue study treatment for reasons other than radiographic disease progression will have post-treatment efficacy follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1 by the investigator, and verified by BICR, and confirmed by the site per iRECIST when clinically 
appropriate (for participants treated with pembrolizumab/placebo), or upon initiating a new anti-cancer treatment, withdrawing consent, becoming lost to follow-up, pregnancy 
or death, whichever comes first.
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1.3.2
Schedule of Activities – Second Course Retreatment Phase
Table 2
Study Schedule of Activities – Second Course Retreatment Phase
Study Period
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6-
C17
EOT
Safety 
Follow-
up
Efficacy 
Follow-
up
Survival 
Follow-
up
Scheduled Days
±3
±3
±3
±3
±3
At time 
of 
discon-
tinuation
30 days 
from last 
dosea
(+7d)
Q12Wb
(±7d)
Q12W 
(±7d)
Administrative Procedures
Eligibility Criteria
X
Concomitant Therapy
X
X
X
X
X
X
X
X
X
Review new anti-cancer 
therapy status
X
X
X
X
Survival Status
X
All participants may be contacted for survival status 
at any time during the course of the study.
Clinical Procedures or Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
Report all AEs through 30 days following cessation 
of study intervention. Report SAEs through 90 days 
following cessation of study intervention or 30 days 
following cessation of study intervention if the 
participant initiates new anti-cancer therapy, 
whichever is earlier.
Full Physical Exam
X
X
Directed Physical Exam
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
X
ECOG Performance Status
X
X
X
X
X
X
X
Assess within 3 days prior to second course C1 and 
prior to treatment during treatment visits.
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Study Period
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6-
C17
EOT
Safety 
Follow-
up
Efficacy 
Follow-
up
Survival 
Follow-
up
Scheduled Days
±3
±3
±3
±3
±3
At time 
of 
discon-
tinuation
30 days 
from last 
dosea
(+7d)
Q12Wb
(±7d)
Q12W 
(±7d)
Laboratory Procedures and Assessments
Pregnancy Test 
(urine or β-HCG)
X
X
X
WOCBP require negative test within 72 hours prior 
to second course C1. 
A pregnancy test must be performed every month 
during study treatment. More frequent pregnancy 
testing may be performed if required by local
regulations or if clinically indicated. Refer to 
Appendix 7 for country-specific requirements.
PT/INR and aPTT/PTT 
X
Perform within 3 days prior to second course C1. 
Participants receiving coumarin-based 
anticoagulants should have more frequent INR 
monitoring as clinically indicated.
CBC with Differential
X
X
X
X
X
X
X
X
Perform within 3 days prior to second course C1. 
From C2 onwards, may perform up to 3 days prior 
to dosing. 
Chemistry Panel
X
X
X
X
X
X
X
X
Perform within 3 days prior to second course C1. 
From C2 onwards, may perform up to 3 days prior 
to dosing. 
T3/FT3, FT4, and TSH
X
X
X
X
X
X
Perform within 3 days prior to second course C1 and 
every 2 cycles during treatment (C3, C5, C7,…). 
May perform centrally if unable to perform locally.
Urinalysis
X
X
X
X
X
X
Perform within 3 days prior to second course C1. 
Perform at C3, C5 and every 4 cycles thereafter (C9, 
C13, C17). 
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Study Period
Treatment
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6-
C17
EOT
Safety 
Follow-
up
Efficacy 
Follow-
up
Survival 
Follow-
up
Scheduled Days
±3
±3
±3
±3
±3
At time 
of 
discon-
tinuation
30 days 
from last 
dosea
(+7d)
Q12Wb
(±7d)
Q12W 
(±7d)
Efficacy Measurements
CT – chest
MRI – abdomen and pelvis
Xc
Perform within 28 days prior to second course C1. 
On treatment Q12W or more frequently if clinically 
indicated.
Bone scan
Xc
Perform within 28 days prior to second course C1 
for those participants with a history of bone 
metastases or clinically symptomatic. On treatment
as clinically indicated.
Brain scan
Xc
Perform within 28 days prior to second course C1 
for those participants with a history of brain 
metastases or clinically symptomatic. On treatment
as clinically indicated.
Study Drug Administration
MK-3475
X
X
X
X
X
X
AE = adverse event; aPTT = activated partial thromboplastin time; β-HCG = beta-human chorionic gonadotropin; CBC = complete blood count; CT = computed tomography; 
CX = Cycle X; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FT3 = free triiodothyronine; FT4 = free thyroxine; INR = international normalized ratio; 
iRECIST = modified RECIST 1.1 for immune-based therapeutics; MRI = magnetic resonance imaging; PT = prothrombin time; PTT = partial prothrombin time; Q12W = every 
12 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid-stimulating hormone; WOCBP = 
woman/women of child bearing potential.
a.
If the second course End of Treatment Visit occurs ≥30 days from last dose of study treatment, a second Safety Follow-up Visit is not required. All procedures for both visits 
will be performed at the second End of Treatment Visit.
b.
Second course Efficacy Follow-Up visits to be scheduled to coincide with second course Follow-Up imaging.
c.
Participants who discontinue the second course for reasons other than radiographic disease progression will have post-treatment efficacy follow-up imaging for disease status 
until disease progression (or until progression is confirmed per iRECIST if the participant is clinically stable), initiating a nonstudy cancer treatment, withdrawing consent, 
or becoming lost to follow-up.
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2
INTRODUCTION
Globally, cervical cancer is the fourth most common cancer in women, with an estimated 
528,000 new cases in 2012, representing 12% of all female cancers [International Agency for 
Research on Cancer 2012]. Approximately 90% of the ~270,000 deaths from cervical cancer 
in 2015 occurred in low- and middle-income countries [International Agency for Research on 
Cancer 2012]. 
Cervical cancer occurs at much lower rates in the United States (US), ranking 21st among all 
new cancer cases, accounting for approximately 0.8% of the new cases [National Cancer 
Institute. 2014]. Due to current screening procedures used in Western countries for the early 
detection of cervical intraepithelial neoplasia (CIN) and cervical cancer, almost half of the 
newly diagnosed adult cervical cancer patients (46%) have Stage I (localized) cancer, with a 
5-year survival rate of 91.5% [National Cancer Institute. 2014]. It is estimated that in 2017, 
there will be 12,820 new cases of cervical cancer and an estimated 4,210 women will die of 
this disease [National Cancer Institute. 2014]. The median age at the diagnosis of cervical 
cancer is 49 years. Five-year survival rates decrease with stage at diagnosis, from 91.5% for 
localized disease to 17.3% for metastatic disease [National Cancer Institute. 2014]. Patients 
with distant metastases and/or recurrent disease have a poor prognosis, with a median OS 
between 6.4 and 9.4 months [National Comprehensive Cancer Network 2017].
Treatment options for cervical cancer in adults include surgery (conization and 
hysterectomy), radiation, and chemotherapy alone or in combination, depending on the stage 
of the disease [National Comprehensive Cancer Network 2017]. Patients with advanced 
(persistent, recurrent, or metastatic) cervical cancer have limited, mainly palliative, treatment
options. Standard first-line chemotherapy for advanced cervical cancer consists of paclitaxel 
combined with cisplatin or carboplatin [Moore, D. H., et al 2004] [Kitagawa, R., et al 2015] 
[Tewari, K. S. 2017]. However, the National Comprehensive Cancer Network (NCCN) 
guidelines recommend consideration of clinical trials as a treatment option even in the first-
line setting, highlighting the unmet medical need for adult women with advanced cervical 
cancer [National Comprehensive Cancer Network 2017].
2.1
Study Rationale
Women with persistent, recurrent, or metastatic cervical cancer face a grim prognosis with 
survival dependent on stage at diagnosis [Landy, R., et al 2016].  Once cervical cancer 
becomes advanced, surgery and radiation are no longer treatment options and systemic 
chemotherapy is provided for palliation.  Both the NCCN and European Society for Medical 
Oncology (ESMO) cervical cancer treatment guidelines offer limited options.  For example, 
ESMO recommends the following [Marth, C., et al 2017]:

Palliative chemotherapy with the aim of relieving symptoms and improving quality of 
life if the patient has a performance score (PS) <2 and no formal contraindications.

Cisplatin-based doublets with topotecan or paclitaxel have demonstrated superiority 
to cisplatin monotherapy in terms of response rate and PFS.
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
Paclitaxel and cisplatin combined with bevacizumab is considered the preferred 
first-line regimen in metastatic or recurrent cervical cancer based on a balance 
between the efficacy and toxicity profile.

The combination of paclitaxel and carboplatin could be considered an alternative for 
patients who are not candidates for cisplatin.
Similarly, the NCCN recommends various combinations of cisplatin, paclitaxel, 
bevacizumab, topotecan, and gemcitabine as first-line combination therapy. Cisplatin, 
carboplatin, and paclitaxel are possibilities as first-line monotherapy, and there are various 
regimens of similar chemotherapies for second-line treatment [National Comprehensive 
Cancer Network 2017].
Both NCCN and ESMO rely on the results from the Gynecologic Oncology Group (GOG) 
204 and 240 clinical trials.  The GOG 240 trial compared cisplatin (50 mg/m² on Day 1 or 2) 
plus paclitaxel (135 mg/m² or 175 mg/m² on Day 1) in 21-day cycles with and without IV
bevacizumab (15 mg/kg on Day 1) [Tewari, K. S., et al 2017].  The GOG 204 study, which 
investigated 4 cisplatin-containing doublet chemotherapy regimens for the treatment of 
patients with recurrent or metastatic cervical carcinoma, showed that the ORR was 29.1%, 
PFS was 5.8 months, and OS was 12.9 months for the cisplatin plus paclitaxel combination 
[Monk, B. J., et al 2009].
The current study will evaluate paclitaxel plus cisplatin or carboplatin with or without 
bevacizumab plus pembrolizumab or placebo.  KEYNOTE-158 served as the proof of 
concept to demonstrate efficacy of pembrolizumab monotherapy in second and later lines of 
treatment for participants with cervical cancer. The ORR for participants treated with 
pembrolizumab in the cervical cancer cohort of KEYNOTE-158 was 17.0% (95% CI: 8%, 
31%), with 3 confirmed and 5 unconfirmed responses [Schellens, J. H. M., et al 2017]. The 
observed ORR appeared to increase with longer follow-up, suggesting that immunotherapy 
may offer long-term responses in a heavily pretreated population with considerable unmet 
medical need.
2.2
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (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 intravenous (IV) immunotherapy for 
advanced malignancies. KEYTRUDA® (pembrolizumab) is indicated for the treatment of 
patients across a number of indications. For more details on specific indications refer to the 
Investigator’s Brochure.
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2.2.1
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 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon 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 Ig-variable–type (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. Following 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 CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (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 cervical cancer.
2.2.2
Preclinical and Clinical Studies
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
the PD-1/PD-L1 interaction enhances infiltration of tumors by CD8+ T-cells and leads
ultimately to tumor rejection. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have 
demonstrated anti-tumor responses as a monotherapy in murine models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma and colorectal cancer (CRC). Blockade of the 
PD-1 pathway effectively promoted CD8+ T-cell infiltration into the tumor and the presence 
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of IFN-, granzyme B and perforin, indicating that the mechanism of action involved local 
infiltration and activation of effector T-cell function in vivo [Nomi, T., et al 2007] [Cai, G., et 
al 2004] [Blank, C. and Mackensen, A. 2007] [Iwai, Y., et al 2002] [Tsushima, F., et al 2006] 
[Korman, A., et al 2007]. Experiments have confirmed the in vivo efficacy of PD-1 blockade 
as a monotherapy as well as in combination with chemotherapy in syngeneic mouse tumor 
models (refer to the IB).
Refer to the IB for preclinical and clinical study data for pembrolizumab.
2.2.3
Ongoing Clinical Studies
Refer to the IB for ongoing clinical study data for pembrolizumab.
2.2.4
Information on Other Study-related Therapy
Cisplatin is generally regarded as the most active agent and is recommended as a first-line 
single-agent chemotherapy option for recurrent or metastatic cervical cancer; reported 
response rates are approximately 20% to 30%, with an occasional complete response 
[National Comprehensive Cancer Network 2016]. Overall survival with cisplatin is 
approximately 6 to 9 months. Both carboplatin and paclitaxel have each been reported to be 
tolerable and efficacious and are possibilities as first-line single-agent chemotherapy. 
Therefore, palliation with single agents cisplatin, carboplatin, or paclitaxel is a reasonable 
approach in patients with recurrent disease not amenable to surgical or radio therapeutic 
approaches.  
Cisplatin-based combination chemotherapy regimens, such as
cisplatin/paclitaxel/bevacizumab (category 1), cisplatin/paclitaxel (category 1), and 
cisplatin/topotecan (category 2A), have been extensively investigated in clinical studies
[National Comprehensive Cancer Network 2016]. A randomized Phase 3 study (GOG 169) 
in 264 patients compared cisplatin/paclitaxel versus cisplatin alone for metastatic, recurrent, 
or persistent cervical cancer. Patients receiving the 2-drug combination had a higher response 
rate (36% vs. 19%) and improved PFS (4.8 months vs. 2.8 months; p>0.001) compared to 
single-agent cisplatin, although no improvement was seen in median survival. Patients who 
responded to cisplatin/paclitaxel had a significant improvement in quality of life.  
Recently published data from a Phase 3 randomized trial (JCOG0505) suggested that 
carboplatin/paclitaxel is noninferior to cisplatin/paclitaxel in 253 women with metastatic or 
recurrent cervical cancer [Kitagawa, R., et al 2015]. Many physicians use 
carboplatin/paclitaxel because of ease of administration and tolerability. Results from 
JCOG0505 showed that the carboplatin/paclitaxel (TC) regimen was noninferior to
cisplatin/paclitaxel (TP) in terms of median overall survival (18.3 months for TP vs. 17.5 
months for TC; HR=0.994 (90% CI, 0.79 to 1.25); p=0.032) and non-hospitalization periods 
were significantly longer for patients receiving TC. However, among patients who had not
received prior cisplatin, the OS for TC and TP was 13.0 and 23.2 months, respectively 
(HR=1.571; 95% CI, 1.06 to 2.32). Based on these data, the panel recommends 
carboplatin/paclitaxel as a category 1 option for patients who have received prior cisplatin 
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therapy. Carboplatin/paclitaxel is a category 2A recommendation for other indications (ie, for 
patients who have not received prior platinum-based therapy).
A recent systematic review of the data on cisplatin/paclitaxel and carboplatin/paclitaxel 
regimens also suggested that lower toxicity carboplatin-based regimens appear to be an 
equally effective alternative to cisplatin-based regimens for treating recurrent or metastatic 
cervical cancer [Skarlos, D. V., et al 1994]. Based on the collective findings from GOG 240 
and JGOG0505, the panel has opted to include carboplatin/paclitaxel/bevacizumab as an 
additional treatment option for recurrent or metastatic cervical cancer (category 2A). Based 
on the previous studies, cisplatin/paclitaxel and carboplatin/paclitaxel have become the most 
widely used systemic regimens for metastatic or recurrent cervical cancer.
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.
The analysis of data from 47 subjects in Group E from KEYNOTE-158 showed that 
pembrolizumab is an effective and generally well tolerated treatment for cervical cancer in 
subjects who received prior treatments. Treatment with pembrolizumab 200 mg Q3W 
provided a clinically meaningful ORR of 17.0%, with 3 confirmed and 5 unconfirmed 
responses [Schellens, J. H. M., et al 2017]. No new safety signals associated with 
pembrolizumab were identified. The nature, frequency, and severity of AEs were either 
generally consistent with the established safety profile of pembrolizumab or with the 
underlying disease or anticipated in patients who received prior treatments including pelvic 
irradiation. 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICF documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
In women with persistent, recurrent, or metastatic cervical cancer treated with 
pembrolizumab plus chemotherapy versus placebo plus chemotherapy:
The study will be considered positive if it is positive for either the PFS or OS hypothesis test 
for any of the 3 groups (CPS ≥1 group, all-comers, and CPS ≥10 group).  
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Objectives
Endpoints
Primary

Objective:  To compare progression-free 
survival (PFS) per Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1) 
as assessed by investigator
Hypothesis (H1): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy
with respect to PFS per RECIST 1.1 as 
assessed by investigator for the
Combined Positive Score (CPS) ≥1 
group. 
Hypothesis (H2): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy 
with respect to PFS per RECIST 1.1 as 
assessed by investigator for all-comers.
Hypothesis (H3): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy 
with respect to PFS per RECIST 1.1 as 
assessed by investigator for the CPS ≥10 
group.

PFS: The time from randomization to 
the first documented disease 
progression or death due to any cause, 
whichever occurs first

Objective:  To compare overall survival 
(OS)
Hypothesis (H4): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy
with respect to OS for the CPS ≥1 
group.
Hypothesis (H5): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy 
with respect to OS for all-comers.
Hypothesis (H6): The combination of 
pembrolizumab plus chemotherapy is 
superior to placebo plus chemotherapy 
with respect to OS for the CPS ≥10 
group.

OS:  The time from randomization to 
death due to any cause
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Objectives
Endpoints
Secondary

Objective:  To evaluate the objective 
response rate (ORR), duration of 
response (DOR), and 12-month PFS rate 
per RECIST 1.1 as assessed by 
investigator

Objective Response (OR): Participants 
who have a best overall response of 
either confirmed complete response 
(CR) or partial response (PR)

DOR:  The time from the first 
documented evidence of CR or PR until 
the first documented disease 
progression or death due to any cause, 
whichever occurs first

PFS-12: The proportion of participants 
that are PFS event-free at 12 months 

Objective:  To evaluate PFS per 
RECIST 1.1 as assessed by BICR

PFS: The time from randomization to 
the first documented disease 
progression or death due to any cause, 
whichever occurs first

Objective:  To compare the safety and 
tolerability by the proportion of adverse 
events (AEs)

Participants experiencing adverse events 
(AEs), serious AEs, and immune-related 
AEs

Participants discontinuing study 
treatment due to AEs

Objective:  To evaluate changes in 
Health-Related Quality of Life 
(HRQoL) assessments using the global 
score of the European Organisation for 
the Research and Treatment of Cancer 
(EORTC) QLQ-C30

The EORTC QLQ-C30 global score
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Objectives
Endpoints
Tertiary/Exploratory

Objective:  To evaluate the objective 
response rate (ORR), duration of 
response (DOR), and 12-month PFS rate 
per RECIST 1.1 as assessed by BICR

Objective Response (OR): Participants 
who have a best overall response of 
either confirmed complete response 
(CR) or partial response (PR)

DOR:  The time from the first 
documented evidence of CR or PR until 
the first documented disease 
progression or death due to any cause, 
whichever occurs first

PFS-12: The proportion of participants 
that are PFS event-free at 12 months 

Objective:  To evaluate PFS using 
modified RECIST 1.1 for immune-based 
therapeutics (iRECIST), as assessed by 
investigator

PFS per iRECIST is defined as time 
from the date of randomization to the 
date of the first documentation of 
confirmed immune-related progressive 
disease (iPD) or death (whichever 
occurs first)

Objective:  To identify molecular 
(genomic, metabolic, and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of pembrolizumab 
and other treatments

Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor 
and blood RNA variation, proteomics 
and IHC, and other biomarkers

To evaluate changes in HRQoL 
assessments using the EORTC QLQ-
C30, EORTC QLQ-CX24, and 
European Quality of Life EQ-5D-5L 
instruments

HRQoL will be assessed using the 
EORTC QLQ-C30 (scores other than 
global score), EORTC QLQ CX24, and 
EQ-5D-5L

To characterize utilities using the EQ-
5D-5L

Utilities will be assessed using the EQ-
5D-5L
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3 randomized, double-blind, placebo-controlled trial of pembrolizumab plus 
chemotherapy versus chemotherapy alone in women at least 18 years of age with a 
histologically confirmed diagnosis of persistent, recurrent, or metastatic cervical cancer who 
are not eligible for treatment with curative intent (such as with surgery and/or radiation) and 
who have not previously been treated with systemic chemotherapy, with the exception of 
chemotherapy used as a radiosensitizing agent.
Approximately 600 participants will be enrolled into the study. Participants must have 
measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology and 
must provide an adequate archival or newly obtained tumor tissue sample for determination 
of PD-L1 expression status in order to be eligible. A complete list of study 
inclusion/exclusion criteria is found in Section 5. The study includes dual-primary efficacy 
endpoints: 1) PFS per RECIST 1.1 as assessed by investigator and 2) OS.
After a screening period of a maximum of 28 days, eligible participants will first be stratified 
by metastatic (FIGO 2009 Stage IVB) at initial diagnosis (yes vs. no), investigator decision 
to use bevacizumab (yes vs. no), and PD-L1 status (CPS <1 vs. CPS 1 to <10 vs. CPS ≥10), 
then randomized centrally to one of the 2 treatment groups below. NOTE: The 2009 version 
of FIGO included para-aortic lymph node involvement as Stage IVB disease while the 2018 
version of FIGO does not include para-aortic lymph node involvement as Stage IVB disease. 
Para-aortic lymph node involvement will be considered evidence of metastatic disease for 
purposes of stratification of all participants at the time of randomization.
Arm 1: Pembrolizumab 200 mg by IV infusion plus chemotherapy Q3W
Arm 2: Placebo by IV infusion plus chemotherapy Q3W
In Arms 1 and 2, the investigator may select any one of the following four treatment 
regimens prior to randomization:
1) Paclitaxel 175 mg/m2 IV infusion + cisplatin 50 mg/m2 IV infusion 
2) Paclitaxel 175 mg/m2 IV infusion + cisplatin 50 mg/m2 IV infusion + bevacizumab 
15 mg/kg IV infusion
3) Paclitaxel 175 mg/m2 IV infusion + carboplatin AUC 5 IV infusion 
4) Paclitaxel 175 mg/m2 IV infusion + carboplatin AUC 5 IV infusion + bevacizumab 
15 mg/kg IV infusion
All study treatments should be administered on Day 1 of each 3-week treatment cycle. 
Cisplatin may be administered on Day 2 of each 3-week treatment cycle if per local practice.
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The option to use bevacizumab is permitted according to local practice and at the choice of 
the investigator; however, the decision to use or not use bevacizumab must be decided prior 
to randomization, as this is a stratification factor.
A participant may switch from cisplatin to carboplatin during the course of the study if 
required for clinical factors (eg, impairment of renal function). 
During the treatment period, participants will have routine clinic visits for administration of 
study treatment, monitoring safety and well-being, and assessing changes in disease status. 
Key safety assessments include physical examinations, vital signs, electrocardiography 
(ECG), hematology and chemistry laboratories, thyroid function testing and urinalysis. At 
each visit, AEs and SAEs will be evaluated and graded per the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. The doses 
of study treatment may be interrupted, reduced (only applicable for chemotherapy), or 
discontinued upon experiencing severe AEs in accordance with the dose modification 
guidelines for each study treatment (refer to Section 6.6 for details). 
Scheduled on-study imaging assessments for disease status include computed tomography 
(CT) of the chest and magnetic resonance imaging (MRI) of the abdomen and pelvis. The 
first on study imaging assessment will be performed at 9 weeks (63 days ±7 days) from the 
date of randomization. Subsequent tumor imaging should be performed every 9 weeks 
(Q9W) (63 days ±7 days) through Week 54 and every 12 weeks (Q12W) (84 days ±7 days)
thereafter. Bone scans and brain scans should be performed on study as clinically indicated 
and again at CR if the participant was positive for bone or brain metastases at baseline or at 
any point during the study. When a participant is first identified by the local site 
investigator/radiology as having radiographic disease progression (PD), the site will submit 
all imaging for PD to be verified by BICR. Participants who are clinically stable may 
continue study treatment while waiting for BICR verification of PD. Progressive disease may 
be further confirmed by subsequent imaging at the site. Refer to Section 8.2.1 for details 
about tumor imaging and assessments.
Participants may interrupt or discontinue pembrolizumab/placebo and continue other study 
treatment(s). Similarly, participants may interrupt or discontinue chemotherapy and/or 
bevacizumab and continue pembrolizumab/placebo. 
Participants will receive study treatments until disease progression per RECIST 1.1 is 
detected locally and ideally verified by BICR (waiting to discontinue participant from study 
treatment until verification of PD by BICR is encouraged if the participant is clinically 
stable), disease progression is confirmed per iRECIST based on investigator assessment,
unacceptable AEs, intercurrent illness that prevents further administration of treatment, 
investigator decision to withdraw the participant from treatment, or administrative reasons 
requiring cessation of treatment.
Participants may receive up to 6 cycles of paclitaxel-platinum (cisplatin or carboplatin).
Participants with ongoing clinical benefit and who are tolerating combination chemotherapy 
may be allowed to continue chemotherapy beyond 6 cycles after Sponsor consultation.
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Participants may receive a maximum of 35 administrations of pembrolizumab/placebo
(approximately 2 years). Note: Bevacizumab may continue after discontinuation of all other 
study drugs until disease progression or unacceptable AEs, per the local label or local 
practice.
In the event that a CR has been observed in a participant, study treatment may be 
discontinued at the discretion of the investigator after the CR has been confirmed by 
radiographic imaging and the participant has received at least 2 treatments with 
pembrolizumab/placebo beyond the date when the initial CR was declared and after 
completing a minimum of 8 total cycles of treatment (~24 weeks). Participants who 
discontinue study treatment after receiving 35 administrations of pembrolizumab for reasons 
other than disease progression or intolerability, or participants who attain a CR and stop 
study treatment may be eligible for up to 17 additional administrations of pembrolizumab 
(approximately 1 year) upon experiencing disease progression (refer to Section 6.6.2 for 
second course retreatment with pembrolizumab).
Participants who discontinue study treatment for reasons other than radiographic disease 
progression will have post-treatment efficacy follow-up imaging for disease status until 
disease progression is documented radiographically per RECIST 1.1 by the Investigator, and 
verified by BICR per RECIST 1.1, and when clinically appropriate, confirmed by the site per 
iRECIST, or upon initiating a new anti-cancer treatment, withdrawing consent, becoming lost 
to follow-up, pregnancy or death, whichever occurs first. 
After discontinuation of study treatment, participants may initiate subsequent anti-cancer 
treatment at the discretion of the treating physician and the participant per local standard of 
care. After verification of progression by BICR per RECIST 1.1 and/or initiation of a 
subsequent anti-cancer treatment, all participants will be followed for survival (by phone 
contact or clinic visit) until death, withdrawal of consent, loss to follow-up, or until the study 
is concluded or terminated early, whichever comes first.
This protocol does not allow participants to cross over to the pembrolizumab plus 
chemotherapy arm if they experience progression with placebo plus chemotherapy.
Two interim efficacy analyses (at approximately 22 months and 30 months from first 
participant randomized) and one final analysis (at approximately 40 months from first patient 
randomized) were planned, but IA2 will not be performed. Following Amendment 7, the 
preplanned IA2 is no longer required because the success criteria for the study hypotheses of 
PFS and OS were met at IA1. Study assumptions, sample size calculations, details and timing 
of the interim and final analyses for the CPS ≥1 group, all-comers, and CPS ≥10 group are 
described in detail in Section 9.7.2.
The study will have an external Data Monitoring Committee (eDMC) to monitor safety 
during the course of the study, to evaluate efficacy at the interim analyses, and to provide 
recommendations for the study in accordance with the eDMC charter and the sSAP (Section 
10.1.4).
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
Efficacy Endpoints
This is a pivotal Phase 3 randomized, double-blind study to evaluate the efficacy and safety 
of the combination of pembrolizumab plus chemotherapy compared with placebo plus 
chemotherapy. The study includes dual-primary efficacy endpoints: 1) PFS per RECIST 1.1 
as assessed by investigator and 2) OS.  
Progression-free survival has been used as an acceptable primary endpoint in randomized 
Phase 3 trials to support regulatory approval for new treatments in advanced solid tumors in 
both the first-line setting and in participants who have failed prior treatments. Therefore, PFS 
by investigator is included as a primary endpoint for the study. 
Overall survival is considered the gold standard endpoint to demonstrate superiority of 
anti-cancer therapy.  
RECIST 1.1 will be used by the investigator and BICR when assessing images for efficacy 
measures and by the investigator for determining eligibility (Section 8.2.3.3). Although 
traditional RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, 
this protocol has implemented a modification to RECIST 1.1 to allow a maximum of 10 
target lesions in total and 5 per organ.
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.3.3). Immunotherapeutic agents such 
as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and patients treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1, may not provide an 
accurate response assessment of immunotherapeutic agents such as pembrolizumab. Based 
on an analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had progressive disease (PD) by RECIST 1.1 but not by the immune-related 
response criteria [Wolchok, J. D., et al 2009] had longer overall survival than participants 
with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest that RECIST 
1.1 may underestimate the benefit of pembrolizumab in approximately 15% of participants. 
These findings support the need to apply a modification to RECIST 1.1 that takes into 
account the unique patterns of atypical responses in immunotherapy and enables treatment 
beyond initial radiographic progression, if the participant is clinically stable.
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Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of nontarget lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by investigators to assess tumor 
response and progression and make treatment decisions.
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 4.0.
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities. 
As part of the analyses for this study, participants will provide information regarding their 
HRQoL via the following questionnaires: EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-
CX24 (performed in this order). 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
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. 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].
4.2.1.3.2
EORTC QLQ-C30
The EORTC QLQ-C30 is the most widely used cancer-specific HRQoL instrument, which 
contains 30 items and measures five functioning dimensions (physical, role, cognitive, 
emotional, and social), three symptom items (fatigue, nausea/vomiting, pain), six single items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a 
global health and quality of life scale. This instrument has been translated and validated into 
81 languages and used in more than 3,000 studies worldwide.
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4.2.1.3.3
EORTC QLQ-CX24
The EORTC QLQ-CX24 is a disease-specific questionnaire developed and validated to
address measurements specific to cervical cancer. It is one of multiple disease-specific
modules developed by the EORTC QLG (Quality of Life Group) designed for use in clinical 
trials, to be administered in addition to the EORTC QLQ-C30 to assess disease-specific 
treatment measurements. 
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/PD 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 in order to interpret tumor-specific DNA mutations. Finally, microsatellite instability 
(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 referred to as a ‘hyper-
mutated’ state) may generate neo-antigen 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 in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
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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 blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and 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 immunohistochemistry (IHC) using blood or tumor
Tumor and 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 in vitro diagnostic (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 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 enzyme-linked immunoassay 
(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.
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma)
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and/or the measurement of other analytes, depending on which specimens are consented for
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere
in the protocol (as part of the main study) and will only be conducted on specimens from
appropriately consented participants. The objective of collecting/retaining specimens for
future biomedical research 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 future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
The use of placebo in combination with standard chemotherapy will ensure the objectivity of 
investigator-assessed progression as well as any decisions to interrupt/discontinue therapy. 
Cross over will not be allowed at time of documented disease progression. Chemotherapy is 
standard of care as recommended by the NCCN and ESMO guidelines.
4.3
Justification for Dose
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the KEYTRUDA development program, 200 mg Q3W is 
the appropriate dose of pembrolizumab for adults across all indications and regardless of 
tumor type. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically
based PK [PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and nonsmall cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 
2 mg/kg Q3W versus 10 mg/kg Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, 
KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B3, KN001 Cohort F2, and KN006). All of these studies demonstrated flat 
dose- and exposure-response relationships across the doses studied representing an 
approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200-mg fixed dose) Q3W 
provided similar responses to the highest doses studied. Subsequently, flat dose-exposure-
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response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer, and classical Hodgkin Lymphoma, confirming 200 mg 
Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune 
cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.1
Pembrolizumab
Planned Dose for this Study
The planned dose of pembrolizumab for this trial is 200 mg Q3W. The initial dose approved 
by the Food and Drug Administration (FDA) for treatment of melanoma subjects was 
2 mg/kg Q3W. Currently, clinical trials evaluating pembrolizumab are using a fixed dose of 
200 mg Q3W. The use of a fixed dose is based on PK findings summarized below.
Maximum Dose/Exposure for this Study
The PK profile of pembrolizumab is consistent with that of other humanized mAbs, which 
typically have a low clearance and a limited volume of distribution. A population PK model, 
which characterized the influence of body weight and other subject covariates on exposure 
using available data from 1139 subjects (from KN001 and KN002) has been performed. The 
majority of these subjects (1077; 94.6%) had advanced melanoma. The distribution of 
exposures from the 200 mg fixed dose were predicted to considerably overlap those obtained 
with the 2 mg/kg dose, and importantly, maintained individual subject exposures within the 
exposure range established in melanoma as associated with maximal clinical response. This 
comparison also demonstrated that the 200 mg Q3W regimen provided no substantive 
differences in PK variability (range of the distribution of individual exposures) as seen with 
weight-based dosing.
In translating to other solid tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as the 
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antitumor effect of pembrolizumab is driven through immune system activation rather than 
through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type. In addition, available PK results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in PK exposures obtained at tested doses 
among tumor types.
Rationale for Dose Interval and Study Design
A fixed-dose regimen is expected to simplify the dosing regimen (potentially reducing dosing 
errors), as well as be more convenient for physicians. A fixed-dosing scheme will also reduce 
complexity in the logistical chain at treatment facilities, as well as reducing waste.
4.3.2
Chemotherapy and Bevacizumab
Further monitoring/assessments should be performed in accordance with the local label 
and/or local practice for cisplatin, carboplatin, paclitaxel, and bevacizumab.
Paclitaxel
Paclitaxel 175 mg/m2 will be administered as an IV infusion on Day 1 of each 3-week 
treatment cycle according to the local label and/or per local practice.
All participants should receive premedication to prevent severe hypersensitivity reactions 
according to the local label and/or per local practice. It is highly recommended that the 
premedication be administered after pembrolizumab/placebo and before chemotherapy.
Cisplatin
Cisplatin 50 mg/m2 will be administered as an IV infusion on Day 1 of each 3-week 
treatment cycle immediately after paclitaxel according to the local label and/or per local 
practice.
Cisplatin may be administered on Day 2 of each 3-week treatment cycle if per local practice.
A participant may switch from cisplatin to carboplatin during the course of the study if 
required for clinical factors (eg, impairment of renal function).
Carboplatin
Carboplatin AUC 5 will be administered as an IV infusion on Day 1 of each 3-week 
treatment cycle immediately after paclitaxel according to the local label and/or per local 
practice.
A participant may switch from cisplatin to carboplatin during the course of the study if 
required for clinical factors (eg, impairment of renal function).
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Bevacizumab
Bevacizumab 15 mg/kg will be administered as an IV infusion on Day 1 of each 3-week 
treatment cycle immediately after cisplatin or carboplatin according to the local label and/or 
per local practice.
The option to use bevacizumab is permitted according to local practice and at the choice of 
the investigator.
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 (ie, the 
participant is unable to be contacted by the investigator).
On study completion, participants are discontinued and may be enrolled in a pembrolizumab 
extension study.
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, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Female participants who are at least 18 years of age on the day of providing informed 
consent.
2. Have persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous 
carcinoma, or adenocarcinoma of the cervix which has not been treated with systemic 
chemotherapy and is not amenable to curative treatment (such as with surgery and/or 
radiation).  
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NOTE: Prior chemotherapy utilized as a radiosensitizing agent and completed at least 
2 weeks prior to randomization with resolution of all treatment-related toxicities is 
allowed. AEs due to previous treatments should be resolved to ≤Grade 1 or baseline. 
Participants with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are eligible.
Female Participants
3. 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:
o
Pembrolizumab/placebo 120 days
o
Chemotherapy 210 days
o
Bevacizumab 210 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.
-
Has a negative highly sensitive pregnancy test (urine or serum as required by local 
regulations) within 72 hours 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 8.3.4.2.
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-
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.
Informed Consent
4. The participant (or legally acceptable representative if applicable) provides documented
informed consent for the study. The participant may also provide consent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
Additional Categories
5. Have measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are considered 
measurable only if progression has been demonstrated in such lesions.
6. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy 
of a tumor lesion not previously irradiated for prospective determination of PD-L1 status 
prior to randomization. 
Note: Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. 
Newly obtained biopsies are preferred to archived tissue. If submitting unstained cut 
slides, newly cut slides should be submitted to the testing laboratory within 14 days from 
the date slides are cut (details pertaining to tumor tissue submission can be found in the 
Laboratory Manual).
7. Have an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1 within 14 days prior 
to randomization.
8. Have adequate organ function as indicated by the following laboratory values (Table 3)
within 14 days prior to randomization:
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Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500/mcL
Platelets
≥100,000/mcL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine  OR
calculated or measured creatinine clearance 
(CrCl)b
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for participants with creatinine levels >1.5 X 
institutional ULN
Hepatic
Serum total bilirubin
≤1.5xULN OR
Direct bilirubin ≤ULN for participants with total bilirubin 
levels >1.5xULN
AST (SGOT) and ALT (SGPT)
≤2.5xULN  OR
≤5xULN for participants with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT) or Partial Thromboplastin Time 
(PTT)c
≤1.5 X ULN unless the participant is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range of 
intended use of anticoagulants
a.
Criterion must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
b.
Creatinine clearance (CrCl) should be calculated per institutional standard.
c.
PTT may be performed if the local laboratory is unable to perform aPTT.
5.2
Exclusion Criteria
Refer to Appendix 7 for country-specific requirements.
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to 
randomization (see Appendix 5). If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.
Note:  In the event that 72 hours have elapsed between the pregnancy test and the first 
dose of study treatment, another pregnancy test (urine or serum) must be performed and 
must be negative in order for participant to start receiving study medication. 
2. Has known active CNS metastases and/or carcinomatous meningitis.  Participants with 
known brain metastases may participate provided that the brain metastases have been 
previously treated (except with chemotherapy) and are radiographically stable.  To 
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demonstrate radiographic stability of previously treated brain metastases, a minimum of 
2 post-treatment brain imaging assessments are required: 1) The first brain imaging must 
be acquired after treatment of brain metastases has been completed 2) The second brain 
imaging must be obtained during screening (ie, within 28 days prior to randomization) 
and >4 weeks after the previous post-treatment brain imaging.
Note: Known brain metastases are considered active, if any of the following criteria are 
applicable:
a.
Brain imaging during screening demonstrates progression of existing metastases 
and/or appearance of new lesions compared to brain imaging performed at least 
4 weeks earlier. 
Radiographic stability of previously treated brain metastases is based on local 
radiology/investigator review, but dated reports of 2 imaging studies (the most 
recent performed during screening) documenting stability of brain 
metastasis(es) over ≥4 weeks must be available at the site for submission to 
the central imaging vendor, if later needed.
b. Neurological symptoms attributed to brain metastases have not returned to 
baseline.
c.
Steroids were used for management of symptoms related to brain metastases 
within 28 days prior to randomization.
3. 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, transitional cell carcinoma of urothelial cancer, or carcinoma in situ (eg, breast 
cancer) that have undergone potentially curative therapy are not excluded.
4. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
doses exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to randomization.
5. Has an active autoimmune disease that has required systemic treatment in 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.
6. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
7. Has an active infection requiring systemic therapy.
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8. Has a known history of human immunodeficiency virus (HIV) infection. 
Note: No testing for HIV is required unless mandated by local health authority.
9. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [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.
10. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
Prior/Concomitant Therapy
11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 
40, CD137).
12. Has received prior systemic chemotherapy for treatment of cervical cancer
(chemotherapy used as a radiosensitizing agent and completed at least 2 weeks prior to 
randomization is permitted).
13. Has not recovered adequately from toxicity and/or complications from major surgery 
prior to randomization.
14. Has received prior radiotherapy within 2 weeks prior to randomization. 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.
15. Has received a live vaccine within 30 days prior to randomization. Examples of live 
vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.
16. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
17. Has a contraindication or hypersensitivity to any component of cisplatin, carboplatin, 
paclitaxel, or bevacizumab. NOTE: Investigators must use the local label for 
contraindications, prohibited medications, and precautions for use.
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Prior/Concurrent Clinical Study Experience
18. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to randomization.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Other Exclusions 
19. Is pregnant or breastfeeding or expecting to conceive within the projected duration of the 
study, starting with the screening visit through 120 days following last dose of 
pembrolizumab/placebo and 210 days following last dose of chemotherapy or 
bevacizumab (if applicable).
20. Has had an allogeneic tissue/solid organ transplant.
21. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperating with the requirements of the study.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
5.3
Lifestyle Considerations
Not applicable.
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.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
None.
5.3.3
Activity Restrictions
None.
5.3.4
Contraception
Study intervention may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception.
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Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 5) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of pembrolizumab/placebo and 210 days after the last dose of 
chemotherapy/bevacizumab. If there is any question that a participant of childbearing 
potential will not reliably comply with the requirements for contraception, that participant 
should not be entered into the study.
5.3.5
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with study intervention, 
the participant will be immediately discontinued from study intervention. The site will 
contact the participant at least monthly and document the participant’s status until the 
pregnancy has been completed or terminated. The outcome of the pregnancy will be reported 
to the Sponsor without delay and within 24 hours if the outcome is a serious adverse 
experience (eg, death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study Investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor.
5.3.6
Use in Nursing Women
It is unknown whether study intervention is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment.
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 
Consolidated Standards of Reporting Trials (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.
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.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 4.
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Table 4
Study Interventions
Arm Name
Arm 
Type
Interven-
tion 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administra-
tion
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Pembro-
lizumab
Experi-
mental
Active
Drug
Vial
25 mg/mL 
(100 
mg/4 mL)
200 mg
IV Infusion
Day 1 of each 
3-week 
treatment 
cycle
Combination 
agent
IMP
Centrally by
Sponsor
Placebo
Placebo 
Com-
parator
Placebo
Drug
Solution 
for 
infusion
Normal 
Saline or 
Dextrose
0 mg
IV Infusion
Day 1 of each 
3-week 
treatment 
cycle
Placebo
IMP
Provided 
locally by the 
trial site, 
subsidiary, or 
designee 
Paclitaxel
Other
Chemo-
therapy
Drug
Vial
6 mg/mL 
(16.7 mL)a
175 
mg/m2
IV Infusion
Day 1 of each 
3-week 
treatment 
cycle
Combination 
agent
NIMP
Provided 
centrally by 
the Sponsor 
or locally by 
the trial site, 
subsidiary, or 
designee
Carboplatin
Other
Chemo-
therapy
Drug
Vial
10 mg/mL 
(60 mL)a
AUC 5
IV Infusion
Day 1 of each 
3-week 
treatment 
cycle
Combination 
agent
NIMP
Provided 
centrally by 
the Sponsor 
or locally by 
the trial site, 
subsidiary, or 
designee
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Arm Name
Arm 
Type
Interven-
tion 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administra-
tion
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Cisplatin
Other
Chemo-
therapy
Drug
Vial
1 mg/mL 
(50 mL)a
50 
mg/m2
IV Infusion
Day 1 of each 
3-week 
treatment 
cycleb
Combination 
agent
NIMP
Provided 
centrally by 
the Sponsor 
or locally by 
the trial site, 
subsidiary, or 
designee
Bevacizumab
Other
Chemo-
therapy
Drug
Vial
20 mg/mL 
(4 mL)a
15 
mg/kg
IV Infusion
Day 1 of each 
3-week 
treatment 
cycle
Combination 
agent
NIMP
Provided 
locally by the 
trial site, 
subsidiary, or 
designee
AUC = area under concentration-time curve; IMP = investigational medicinal product; IV = intravenous; NIMP = noninvestigational medicinal product.
a.
For locally sourced supplies, the unit dose strength may vary, depending on market availability.
b.
Cisplatin may be administered on Day 2 of each 3-week treatment cycle if per 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 with the exception of bevacizumab, which will be supplied locally and 
reimbursed by the Sponsor at sites that do not have other funding for bevacizumab purchase 
or reimbursement. Participants must continue with the same form of bevacizumab throughout 
the duration of the study. 
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.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Paclitaxel, cisplatin, carboplatin, and bevacizumab will be prepared and 
administered as per the approved product label(s).
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.
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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
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 2 treatment arms. Participants will be 
assigned randomly in a 1:1 ratio to pembrolizumab plus chemotherapy or placebo plus 
chemotherapy, respectively. The choice of chemotherapy will be determined prior to 
randomization and documented in the IVRS/IWRS.
6.3.2
Stratification
Treatment randomization will be stratified based on the following criteria:
1) Metastatic (FIGO [2009] Stage IVB) at initial diagnosis (yes vs. no)
2) Investigator decision to use bevacizumab (yes vs. no), and 
3) PD-L1 status (CPS <1, CPS 1 to <10, CPS ≥10).
A total of 12 strata will be utilized in this study.
NOTE: The 2009 version of FIGO included para-aortic lymph node involvement as 
Stage IVB disease while the 2018 version of FIGO does not include para-aortic lymph node 
involvement as Stage IVB disease. Para-aortic lymph node involvement will be considered 
evidence of metastatic disease for purposes of stratification of all participants at the time of 
randomization.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. Pembrolizumab and 
placebo will be prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or 
other qualified site personnel. The participant, the investigator, and Sponsor personnel or 
delegate(s) who are involved in the study treatment administration or clinical evaluation of 
the participants are unaware of treatment group assignments.
6.4
Study Intervention Compliance
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 
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administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification 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 ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should discuss any questions regarding this 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.
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phases of this study:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
Note: Palliative radiation therapy to a symptomatic, nontarget lesion may be allowed 
after consultation with the Sponsor. On-study nonpalliative radiation and radiation to 
a target lesion per RECIST 1.1  is not permitted.
Note: Palliative radiation during the screening phase (≤2 weeks of radiotherapy) to 
non-CNS disease is allowed.

Live vaccines within 30 days prior to randomization and while participating in the 
study. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not 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, adenoviral 
vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy.
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Investigational vaccines (ie, those not licensed or approved for Emergency Use) are 
not allowed.

Systemic glucocorticoids except when used for the following purposes:
o
To modulate symptoms of an AE that is suspected to have an immunologic 
etiology
o
For the prevention of emesis
o
To premedicate for IV contrast allergies
o
To treat COPD exacerbations (only short-term oral or IV use in doses 
>10 mg/day prednisone equivalent)
o
For chronic systemic replacement not to exceed 10 mg/day prednisone 
equivalent

Other glucocorticoid use except when used for the following purposes:
o
For topical use or ocular use
o
Intra-articular joint use
o
For inhalation in the management of asthma or chronic obstructive pulmonary 
disease
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
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, over-the-counter (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.
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. 
Concomitant medications administered 30 days after the last dose of study intervention 
should be recorded for SAEs and events of clinical interest (ECIs) as defined in Section 
8.4.7.
6.5.1
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 
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Section 6.6, Table 5. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab/placebo.
Note: If after the evaluation of the event, it is determined not to be related to 
pembrolizumab/placebo, the investigator does not need to follow the treatment guidance. 
Refer to Table 5 in Section 6.6.1 for guidelines regarding dose modification and supportive 
care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Hematopoietic Growth Factors
Primary prophylactic use of granulocyte colony stimulating factors (G-CSF) may be used to 
treat treatment emergent neutropenia as indicated by the current American Society of Clinical 
Oncology guidelines [National Comprehensive Cancer Network 2010]. The use of 
hematopoietic growth factors is at the discretion of the treating physician in line with local 
guidelines. 
6.6
Dose Modification (Escalation/Titration/Other)
Pembrolizumab/placebo may be interrupted or discontinued. Cisplatin, carboplatin, 
paclitaxel, and bevacizumab may be reduced, interrupted or discontinued; dose modifications 
should be performed according to the local label and/or local practice.   
Any component of the combination therapy may be interrupted or discontinued 
independently. It is allowed for participants to interrupt or discontinue chemotherapy or 
bevacizumab and continue pembrolizumab/placebo. Similarly, it is allowed for participants 
to interrupt or discontinue pembrolizumab/placebo and continue chemotherapy or 
bevacizumab. 
The investigator may attribute toxicity to one or more components of the combination. 
Reduction, interruption or discontinuation of an individual component is appropriate if, in the 
opinion of the investigator, the toxicity is clearly related to that component of the 
combination. If, in the opinion of the investigator, the toxicity is related to the combination 
itself, all components should be reduced, interrupted or discontinued appropriately.
Pembrolizumab/placebo may be interrupted due to toxicity for a maximum of 12 weeks. 
Prior to restarting pembrolizumab/placebo after an interruption of more than 12 weeks, the 
investigator must discuss this with the Sponsor.
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Cisplatin, carboplatin, paclitaxel, and bevacizumab may be interrupted due to toxicity for a 
maximum of 6 weeks. Restarting these treatments after an interruption of more than 6 weeks
will require a signed Sponsor Consultation Form. To ensure that subjects receive adequate 
standard of care chemotherapy, supportive care measures (eg, erythrocyte infusion, 
thrombocyte infusion, G-CSF, and erythropoietin) should be utilized before dose 
modification unless other reasons to modify standard of care dosing for chemotherapy agents
occur. For example, when it is appropriate, supportive care measures should be initiated for 
resolution of Grade 2 or Grade 3 chemotherapy-related AEs of anemia or leukopenia instead 
of immediately proceeding with a dose reduction or dose interruption.
Any requests for nonemergency unblinding will be considered on an individual participant
basis and only after consultation with the Sponsor.
6.6.1
Dose Modification (Escalation/Titration/Other)
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. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.
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 
(CTCAEv4.0)
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 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 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 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased Bilirubin
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5-1 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 or 4 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer anti-
hyperglycemic 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 a
Hyperthyroidism 
Grade 2
Continue
Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis and renal 
dysfunction
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
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
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 b
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
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.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN 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
Pembrolizumab 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 associated 
infusion reaction are provided in Table 6.
Table 6
Pembrolizumab 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/hr to 50 mL/hr). 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 
drug treatment.
Participant may be 
premedicated 1.5 h 
(± 30 minutes) prior to 
infusion of 
pembrolizumab/placebo with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 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 following 
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 drug treatment.
No subsequent dosing
CTCAE = Common Terminology Criteria for Adverse Event; IV = intravenous; NCI = National Cancer Institute; 
NSAID = nonsteroidal anti-inflammatory drug; po = orally.
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 Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant’s study record.
6.6.2
Second Course
Participants who stop treatment with stable disease (SD) or better who then experience 
radiographic disease progression may be eligible for up to 17 additional administrations 
(second course) of pembrolizumab, if unblinding reveals that the participant had received 
pembrolizumab during the first course. Second course is available on an individual basis and 
only after consultation with the Sponsor. This retreatment is termed the Second Course Phase 
of this study and is only available if the study remains open and the participant meets the 
following conditions.
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Participant must meet the criteria under either 1 or 2 below:
1. Stopped initial treatment with study treatment after attaining an investigator-
determined confirmed CR based on RECIST 1.1, and

Was treated with at least 8 infusions of pembrolizumab before discontinuing 
treatment, and

Received at least 2 infusions of pembrolizumab beyond the date when the initial 
CR was declared
OR
2. Had SD, PR, or CR and stopped pembrolizumab after receiving 35 infusions
(approximately 2 years) of pembrolizumab for reasons other than disease progression 
or intolerability
After meeting criteria under 1 or 2 above, participant must also meet all of the 
following:

Experienced investigator-determined radiographic disease progression by 
RECIST 1.1 after stopping initial treatment, and

Upon unblinding was found to have received pembrolizumab, and

No new anti-cancer treatment was administered after the last dose of study
treatment, and

The participant meets all of the safety parameters listed in the inclusion criteria
and none of the safety parameters listed in the exclusion criteria, and

The study is ongoing.
An objective response or disease progression that occurs during the Second Course Phase for 
a participant will not be counted as an event in the primary efficacy analyses in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the 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). In the event that 
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 
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and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted. 
6.9
Standard Policies
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
participants who received placebo in the image of the competitor’s product to provide the 
following advice:
“You have participated in a study conducted by the Sponsor. This letter is to advise you that 
you were among those who received a look-alike drug. You did not receive the active drug as 
manufactured by MSD.”
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 prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.12.3.
Participants may discontinue study intervention at any time for any reason or be dropped 
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. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
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.

The participant’s treatment assignment has been unblinded. Participants unblinded 
due to AEs suspected to be related to blinded treatment should be discontinued from 
blinded treatment but may continue with chemotherapy. Note: this applies only to 
first-course treatment.  
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
The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, places the participant at unnecessary risk 
from continued administration of study intervention.

The participant has a confirmed positive serum pregnancy test.

Confirmed radiographic disease progression (iCPD) outlined in Section 8.2.3.4
(exception if the Sponsor approves treatment continuation).

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.

The study is terminated by the Sponsor.

The study is terminated by the local health authority, IRB, or IEC.

Any prolonged interruption of study intervention beyond the permitted periods, for 
irAE management or other allowed dose interruptions, as noted in Section 6.6 require 
Sponsor consultation prior to restarting treatment. If treatment will be discontinued, 
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 meets a pembrolizumab/placebo discontinuation criteria specified in 
the dose modification in Table 5 and Table 6.

The participant has received a maximum number of cycles for each treatment 
component individually: 
o
The participant has received 35 administrations of pembrolizumab/placebo 
(approximately 2 years) and
o
The participant has received 6 cycles of paclitaxel-platinum (cisplatin or 
carboplatin) 
NOTE: Participants with ongoing clinical benefit and who are tolerating combination 
chemotherapy may be allowed to continue chemotherapy beyond 6 cycles after 
Sponsor consultation.
NOTE: Bevacizumab may continue until disease progression or unacceptable AEs, 
per the local label or local practice.
NOTE: The number of treatments is calculated starting with the first dose. 
Participants who stop the combination or pembrolizumab after receiving 35 doses 
may be eligible for retreatment if they progress after stopping study intervention 
provided they meet the requirements detailed in Section 6.6.2. Participants may be 
retreated in the Second Course Phase (Retreatment) for up to an additional 17 cycles 
(approximately 1 year).
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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 treatment 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 future biomedical research, 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.
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.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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 or trained staff. Delegation of study site personnel responsibilities will be 
documented in the Investigator Study File Binder (or equivalent).
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
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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 signing of ICF may be utilized for screening or baseline purposes 
provided the procedure met 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.
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 future biomedical 
research. 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.
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 Institutional Review Board/Independent Ethics Committee’s 
(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.
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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.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the Future Biomedical Research 
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 Future Biomedical Research. 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 qualifies for the study.
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 
the participant provides documented informed consent. At the time of intervention 
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare 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 significant. 
Comprehensive details regarding the participant’s cervical cancer history will be recorded 
separately and not listed as medical history. These details include but are not limited to FIGO 
stage at diagnosis, histopathology, location(s) of tumor burden, and all prior treatment 
(including prior radiation, prior radiosensitizing chemotherapy, and prior surgery).
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8.1.5
Prior and Concomitant Medications Review
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 randomization. Treatment for the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as a prior medication.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. In addition, new medications started 
during the Second Course Phase through the Second Course Safety Follow-up Visit should 
be recorded.
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 prior to randomization.Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Treatment Eligibility Assessment (TEA and TEAA) Forms
A TEA form is included in this study to document the investigators’ choice of treatment 
among the options within the control arm and the rationale. These data may be required to 
support reimbursement efforts for pembrolizumab.
The investigator must document the rationale for participant eligibility for treatment with: 
1) bevacizumab [TEAA form] and 2) combination of cisplatin + paclitaxel + bevacizumab
[TEA form].
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
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. Study treatment should begin within 3 days 
of randomization.
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Further monitoring/assessments should be performed in accordance with the local label 
and/or local practice for cisplatin, carboplatin, paclitaxel, and bevacizumab.
Timing of Dose Administration
The order of treatment administration is recommended to be as follows: 
1) pembrolizumab/placebo, 2) paclitaxel, 3) cisplatin or carboplatin and then 
4) bevacizumab. It is highly recommended that the premedication be administered after 
pembrolizumab/placebo and before chemotherapy.
Pembrolizumab/placebo will be administered on Day 1 of each 21-day cycle (± 3 days) 
starting on C1D1. Pembrolizumab/placebo should be administered after all predose study 
procedures and assessments have been completed. Pembrolizumab/placebo should be 
administered as 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 min and +10 min is permitted (ie, infusion time is 
30 minutes:  -5 min/+10 min). The Pharmacy Manual contains specific instructions for the 
preparation and administration of pembrolizumab/placebo.
Paclitaxel 175 mg/m2 will be administered as an IV infusion on Day 1 of each 3-week 
treatment cycle after the administration of pembrolizumab/placebo according to the local 
label and/or per local practice. All participants should receive premedication to prevent 
severe hypersensitivity reactions according to the local label and/or per local practice.
Cisplatin 50 mg/m2 will be administered as an IV infusion on Day 1 of each 3-week 
treatment cycle immediately after paclitaxel according to the local label and/or per local 
practice. Cisplatin may be administered on Day 2 of each 3-week treatment cycle per local 
practice.
Alternately carboplatin AUC 5 will be administered as an IV infusion on Day 1 of each 
3-week treatment cycle immediately after paclitaxel according to the local label and/or per 
local practice.
Bevacizumab 15 mg/kg will be administered as an IV infusion, preferably following 
paclitaxel and cisplatin or carboplatin. It is best to have all medications given within a single 
study visit on the same day, if possible. Bevacizumab use should follow the local label and/or 
local practice.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (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.
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Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main 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 future biomedical research 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 prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main 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
This is a double-blind trial; therefore, the Sponsor, investigator and participant will not know 
the treatment administered.
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 THE PARTICIPANT.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug 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. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s treatment 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 chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that 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 principal investigator, site personnel, and
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
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Nonemergency unblinding will only be permitted after consultation and approval from the 
Sponsor. 
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 is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor is in the 
SIM. 
Submit all of the following to the central imaging vendor:

All screening and on-study scheduled imaging per the SoA

Supplemental imaging performed to support a positive or negative bone scan, such as 
plain X-rays that may be acquired for correlation

Images obtained at an unscheduled time point, even via other modalities, to determine 
disease progression

Imaging performed for other reasons but captures radiologic disease progression 
based on investigator assessment
Tumor imaging of the chest is to be acquired by CT. MRI is preferred for the abdomen and 
pelvis, unless MRI is contraindicated or local practice standards dictate otherwise. The SIM 
provides alternative options for tumor imaging if MRI or the use of contrast is medically 
contraindicated. MRI is the strongly preferred modality for imaging the brain.
Note: for the purposes of assessing tumor imaging, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an off-site facility.
8.2.2
Initial Tumor Imaging During Screening
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization. Scans performed as part of routine clinical management are acceptable for 
use as screening tumor imaging if they are of diagnostic quality, were performed within 
28 days prior to the date of randomization, and can be assessed by the central imaging 
vendor.  
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Participant eligibility, confirmation of measurable disease, will be determined using local 
(investigator/site radiologist) assessment based on RECIST 1.1.
Required imaging at screening includes:

CT of the chest

MRI of the abdomen and pelvis

A bone scan for participants with a history of bone metastases or who are clinically 
symptomatic

MRI of the brain for participants with brain metastases at baseline (to demonstrate 
stability prior to enrollment) or who are clinically symptomatic
8.2.3
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days)
from the date of randomization. Subsequent tumor imaging should be performed Q9W
(63 days ±7 days) through Week 54 or more frequently if clinically indicated. After 
Week 54, participants who remain on treatment will have imaging performed Q12W (84 days 
±7 days). Imaging timing should follow calendar days and should not be adjusted for delays 
in cycle starts. 
Participants who discontinue study treatment for reasons other than radiographic disease 
progression will have post-treatment efficacy follow-up imaging for disease status until 
disease progression is documented radiographically per RECIST 1.1 by the investigator, and 
verified by BICR per RECIST 1.1, and when clinically appropriate, confirmed by the site per 
iRECIST, or upon  initiating a new anti-cancer treatment, withdrawing consent, pregnancy, 
or death, whichever occurs first. All supplemental imaging must be submitted to the central 
imaging vendor.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with
the next scheduled imaging time point. Participants who receive additional imaging for
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.
Per iRECIST (Section 8.2.3.4), disease progression in participants treated with
pembrolizumab/placebo should be confirmed by the site 4 to 8 weeks after site-assessed first
radiologic evidence of PD in clinically stable participants. Participants who have
unconfirmed disease progression may continue on treatment at the discretion of the site
investigator until progression is confirmed by the site, provided they have met the conditions
detailed in Section 8.2.3.4. Participants who obtain a confirmation scan do not need to
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point if clinically stable. Participants who
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have confirmed disease progression, as assessed by the site, will discontinue study treatment.
Exceptions are detailed in Section 8.2.3.4.
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4-week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. In participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (every 9 weeks through Week 54 
or 12 weeks after Week 54) until disease progression per RECIST 1.1 is verified by BICR, 
the start of a new anti-cancer treatment,  pregnancy, death, withdrawal of consent, or the end 
of the study, whichever occurs first.
Second Course (Retreatment) Tumor Imaging
Tumor imaging must be performed within 28 days prior to restarting treatment with
pembrolizumab. Investigator-determined progression will be used to determine eligibility. A 
second course imaging should be submitted to the central imaging vendor for quality control, 
storage, and possible retrospective review.
The first on-study imaging assessment should be performed at 12 weeks ( 84 days ±7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed every 12 weeks 
(84 days ±7 days) or more frequently if clinically indicated.
Per iRECIST (Section 8.2.3.4), if tumor imaging shows initial PD, tumor assessment should 
be repeated 4 to 8 weeks later in order to confirm PD with the option of continuing treatment 
while awaiting radiologic confirmation of progression. Participants who obtain confirmatory 
imaging do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and 
may wait until the next scheduled imaging time point, if clinically stable.
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first. In clinically stable participants, disease progression may be confirmed by the 
investigator using iRECIST 4 to 8 weeks after the first tumor imaging indicating PD.
For participants who discontinue Second Course study intervention, tumor imaging should be 
performed at the time of treatment discontinuation (±4 week window). If previous imaging
was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
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For participants who discontinue Second Course study intervention without documented 
disease progression, every effort should be made to continue monitoring their disease status 
by radiologic imaging every 12 weeks ( 84 days ±7 days) until either the start of a new 
anticancer treatment, disease progression, death, withdrawal of consent, or the end of the 
study, whichever occurs first.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by investigator as the primary measure for assessment of tumor 
response, date of disease progression, and as a basis for protocol guidelines related to disease 
status. 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.
Initial tumor imaging showing site-assessed PD should be submitted immediately for BICR 
verification of PD. The site will be notified if the BICR verifies PD using RECIST 1.1. 
Figure 2 illustrates the imaging flow involving verification of PD for clinically stable 
participants.
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 8. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured
in the clinical database.
Clinical stability is defined as the following: 
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status 
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at
central verification of site-assessed first radiologic evidence of PD, and is not required to 
have repeat tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
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PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR. 
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 8, 
study treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 1.3 and 
submitted to the central imaging vendor.
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 7 and illustrated as a flowchart in Figure 2.
Table 7
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 per 
investigator 
assessment
Submit the 
imaging to BICR 
for verification 
of progression 
and repeat 
imaging at 4 to 
8 weeks to 
confirm PD per 
iRECIST.
Should continue 
study treatment at 
the investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST and BICR 
verification of 
progression.
Submit the 
imaging to BICR 
for verification 
of progression 
and repeat 
imaging at 4 to 
8 weeks to 
confirm PD per 
investigator’s 
discretion.
Discontinue treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
investigator 
assessment
No additional 
imaging required  
(continue 
imaging if 
Sponsor grants 
exception to 
continue 
treatment) 
Discontinue 
treatment (exception 
is possible upon 
consultation with 
Sponsor).
No additional 
imaging 
required.
Not applicable
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Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
Repeat tumor 
imaging shows 
iUPD by 
iRECIST per 
investigator 
assessment
Repeat imaging 
at 4 to 8 weeks to 
confirm PD. May 
occur at next 
regularly 
scheduled 
imaging visit.
Submit the 
imaging to BICR 
for verification 
of progression.
Continue study 
treatment at the 
investigator’s 
discretion.
Repeat imaging 
at 4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Submit the 
imaging to BICR 
for verification 
of progression.
Discontinue treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
treatment at the 
investigator’s 
discretion.
Continue 
regularly 
scheduled 
imaging 
assessments.
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next tumor 
imaging should occur 
according to the 
regular imaging 
schedule.
BICR=blinded independent central review; iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete 
response; iPR=iRECIST partial response; iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed progressive disease; 
PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1; VOP=verification of 
progression.
Note:  If progression has been centrally verified, further management is by the site, based on iRECIST. Any further 
imaging should still be submitted to the central imaging vendor, but no rapid review will occur. If RECIST 1.1 disease 
progression has not been centrally verified, ideally the site should continue treatment. Whether or not treatment 
continues, imaging should be collected and submitted to the central imaging vendor with VOP request until RECIST 1.1 
progression is verified by BICR.)
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Abbreviations: CRO=contract research organization; iCR=iRECIST complete response; iCRO=imaging 
contract research organization; iPR=iRECIST partial response; iRECIST=modified Response Evaluation 
Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST 
unconfirmed progressive disease; PD=progressive disease; RECIST=Response Evaluation Criteria in Solid 
Tumors; VOP=verification of progression.
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
8.2.4
Patient-reported Outcomes
The EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-CX24 questionnaires will be 
administered by trained site personnel and completed electronically by participants in the 
following order: EQ-5D-5L first, then EORTC QLQ-C30, and then EORTC QLQ-CX24.
The questionnaires should be administered prior to dosing on Day 1 of Cycles 1 to 14, every 
other cycle thereafter up to Cycle 44, EOT, and Safety Follow-up.
The translated version of the EORTC QLQ-CX24 may not be available at the time a site 
opens for enrollment. If the local language translation is not available at the time for a 
participant’s Cycle 1 Day 1 visit, then the EORTC QLQ-CX24 will not be required for this 
participant at any point during the study. All other PRO measures must be completed per the 
SoA. The translated EORTC QLQ-CX24 may become available after a site begins enrolling 
participants. Any participant who is enrolled after the local language translation becomes 
available must complete all PRO measures, including the EORTC QLQ- CX24 according to 
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the SoA from Cycle 1 Day 1 onwards. For some sites, the EORTC QLQ-CX24 translation 
might not be available for the entire duration of the study.
It is best practice and strongly recommended that electronic patient-reported outcomes 
(ePROs) are administered to randomized participants prior to 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.
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 Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete or directed physical examination will be conducted by an investigator or 
medically qualified designee (consistent with local requirements) as per institutional
standards. Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
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 exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
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 directed physical examination as clinically 
indicated prior to the administration of the study intervention. New clinically significant 
abnormal findings should be recorded as AEs.
8.3.2
Vital Signs
Blood pressure, temperature, pulse, respiratory rate, and weight will be assessed according to 
the SoA (Section 1.3). Height will be measured at screening only. It is highly recommended 
that abnormal blood pressure measurements be confirmed.
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8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA in Section 1.3. Clinically significant abnormal findings at 
screening should be recorded in the medical history. Additional ECGs may be performed as 
clinically necessary.
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 case report form (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 (Section 1.3).
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.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours prior to
randomization. In the event that more than 72 hours have elapsed between this pregnancy test 
and the first dose of study treatment, another pregnancy test must be performed and must be 
negative prior to receiving first dose of study treatment. If a urine test is positive or not 
evaluable, a serum test will be required. Participants must be excluded/discontinued from the 
study in the event of a positive test result.
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Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
monthly intervals during intervention. 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 participant’s participation in the 
study. Refer to Appendix 7 for country-specific requirements.
8.3.5
Performance Assessments
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 9) at screening
(within 14 days prior to randomization), prior to the administration of each dose of study 
intervention and during the efficacy follow-up period as specified in the SoA, Section 1.3.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), 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.
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 remain responsible for following up AE, 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 randomization, must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event causes 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.
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All AEs from the time of randomization through 30 days following cessation of study 
intervention must be reported by the investigator.
All AEs meeting serious criteria, from the time of randomization through 90 days following 
cessation of study intervention or 30 days following cessation of study intervention if the 
participant initiates new anti-cancer therapy, whichever is earlier, must be reported by the 
investigator.
All pregnancies and exposure during breastfeeding, from the time of randomization through 
120 days following last dose of pembrolizumab/placebo and 210 days following last dose of 
chemotherapy or bevacizumab (if applicable), or 30 days following cessation of study 
intervention if the participant initiates new anti-cancer therapy must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately to the Sponsor if the event is 
considered drug-related.
Investigators are not obligated to actively seek AE or SAE 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 he/she 
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 8.
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Table 8
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization
Reporting Time 
Period:
Randomization 
through Protocol-
Specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
Specified Follow-up 
Period
Timeframe to 
Report Event 
and Follow-up 
Information to 
SPONSOR
Nonserious 
Adverse Event 
(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
Serious Adverse 
Event (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
Pregnancy/
Lactation 
Exposure
Report if:
- Due to 
intervention
- Causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 
24 hours of 
learning of 
event
Event of Clinical 
Interest (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
Event of Clinical 
Interest (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
ECI = event of clinical interest; DILI = drug-induced liver injury; 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 AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
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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 AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECI), 
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 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 towards 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. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (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 SAE) 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 MSD. 
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 
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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
Progression of the cancer under study is not considered a reportable event. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint which upon review 
is not progression of the cancer under study will be forwarded to global safety as a SAE 
within 24 hours of determination that the event is not progression of the cancer under study. 
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs 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, that is not associated 
with clinical symptoms or abnormal laboratory results.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
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 (≥5 times the indicated dose).
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
There is no pharmacokinetic evaluation in this trial.
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8.7
Pharmacodynamics
There is no pharmacodynamic evaluation in this trial.
8.8
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
leftover specimens listed in Section 8.10 Biomarkers will be retained as part of future 
biomedical research.
8.9
Planned Genetic Analysis Sample Collection
Samples should be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/Independent Ethics Committee [IEC] does not approve) sample collection for these 
purposes, then such samples should not be collected at the corresponding sites. Leftover 
DNA extracted from planned genetic analysis samples will be stored for future biomedical 
research only if the participant provides documented informed consent for Future Biomedical 
Research.
8.10
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 in this study as specified in the SoA:

Blood for genetic analysis

Blood for RNA analysis

Blood for plasma biomarker analysis

Blood for serum biomarker analysis

Blood for ctDNA

New or archival tumor tissue
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Laboratory Manual.
8.10.1 Tumor Tissue Collection for Biomarker Analyses
Characterization of PD-L1 expression will be evaluated by a central laboratory for all 
participants as part of screening. Archival tumor tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion (not previously irradiated) must be provided to the central 
laboratory for testing, and be deemed adequate for evaluation, prior to randomization. Newly 
obtained biopsies are preferred to archived tissue. FFPE tissue blocks are preferred to slides.  
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If submitting unstained slides, the slides should be freshly cut and submitted to the testing 
laboratory within 14 days from the site slide section date. If the sample is determined to be 
nonevaluable prior to testing by the central laboratory, a new sample should be submitted if 
available. Individual subject PD-L1 status will not be disclosed to investigative sites or study 
participants. 
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Laboratory Manual.
8.11
Health Economics Medical Resource Utilization
Medical resource utilization and health economics data, associated with medical encounters, 
will be collected in the CRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include:

All-cause hospitalizations and emergency room visits, from the time of treatment 
allocation/randomization through 90 days following cessation of study treatment, or 
30 days following cessation of study treatment, if the participant initiates new 
anticancer therapy, whichever is earlier.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Documented informed consent must be provided prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant providing documented 
informed consent as part of routine clinical management are acceptable in lieu of a screening 
test if performed within the specified time frame. Screening procedures are to be completed 
within 28 days prior to the first dose of study intervention except for the following:

Eligibility laboratory tests are to be performed within 14 days prior to randomization.

Evaluation of ECOG is to be performed within 14 days prior to randomization.  

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to randomization. If pregnancy test is done more 
than 72 hours prior to first dose of study intervention, another negative pregnancy test 
is required prior to starting study medication. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required (performed by the 
local study site laboratory).
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Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
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.
8.12.2
Treatment Period Visit
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue from study treatment should continue to be monitored 
according to the requirements in the SoA (Section 1.3). 
8.12.4
Post-treatment Visit
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted 30 days (+7 days) after the last 
dose of study intervention or before the initiation of a new anti-cancer treatment, whichever 
comes first. Reasonable efforts should be made to have the participant return for the Safety 
Follow-up Visit and report any AEs that may occur prior to initiating new anti-cancer
therapy. If the participant has an End of Treatment visit ≥30 days after the last dose of study 
treatment, the Safety Follow-up Visit is not required; all procedures for both visits will be 
performed at the End of Treatment Visit.
Participants who are eligible for second course retreatment with pembrolizumab may have up 
to 2 safety follow-up visits, 1 after the Initial Treatment Period and 1 after the Second Course 
Retreatment Phase.
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 the 
Efficacy Follow-up Phase and should be assessed according to the on-treatment imaging 
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 anti-cancer therapy, BICR-verified 
disease progression, withdrawal of consent, pregnancy, death, and end of the study.
Information regarding poststudy anti-cancer treatment will be collected if new treatment is 
initiated. Participants who will not have further efficacy assessments must enter the Survival 
Follow-up Phase.
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Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.6.2 will move from the Efficacy Follow-up Phase to the Second Course 
Phase when they experience disease progression. Details are provided in the SoA
(Section 1.3.2) for retreatment with pembrolizumab.
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.
The first survival follow-up assessment should be scheduled as described below:

For participants who discontinue treatment intervention and who will not enter the 
Efficacy Follow-up Phase, the first survival follow-up contact will be scheduled 
12 weeks after the discontinuation visit and/or safety follow-up visit (whichever is 
last).

For participants who entered but are no longer being assessed during the Efficacy 
Follow-up Phase, the first survival follow-up contact will be scheduled 12 weeks after 
the last efficacy assessment follow-up visit has been performed.
8.12.5
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (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 time period will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section outlines the statistical analysis strategy and procedures for the study. If, after 
the study has begun, 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 prior to the conduct of any analysis, will be 
documented in a supplemental statistical analysis plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study. A biomarker analysis plan will be provided. Post hoc 
exploratory analyses will be clearly identified in the CSR. The PRO analysis plan will also 
be included in the sSAP.
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Key elements of the statistical analysis plan (SAP) are summarized below. The 
comprehensive plan is provided in Sections 9.2 through 9.12.
Study Design Overview
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of 
Pembrolizumab (MK-3475) Plus Chemotherapy Versus Chemotherapy Plus 
Placebo for the First-Line Treatment of Persistent, Recurrent, or Metastatic 
Cervical Cancer (KEYNOTE-826)
Treatment Assignment
Approximately 600 participants will be randomized in a 1:1 ratio between 2 
treatment arms: 

Arm 1:  Pembrolizumab plus paclitaxel and cisplatin or carboplatin 

Arm 2:  Placebo plus paclitaxel and cisplatin or carboplatin 
Stratification factors are as follows:

Metastatic (FIGO [2009] Stage IVB) at initial diagnosis (yes vs. no)

Bevacizumab use (yes vs. no)

PD-L1 status (CPS <1 vs. CPS 1 to <10 vs. CPS ≥ 10)
Analysis Populations

Efficacy: Intention-to-Treat (ITT)

Safety: All Participants as Treated (APaT)
Primary Endpoints

Progression-free survival (PFS) based on RECIST 1.1 as assessed by 
investigator 

Overall survival (OS)
Secondary Endpoints

Objective response rate (ORR) by investigator using RECIST 1.1

Duration of response (DOR) by investigator using RECIST1.1

PFS rate at 12 months by investigator using RECIST 1.1

PFS by BICR using RECIST 1.1

Patient-reported quality of life by EORTC QLQ-C30 global score

Safety and tolerability of the two treatment arms
Statistical Methods for
Key Efficacy Analyses
The primary hypotheses will be evaluated by comparing PFS and OS using a
stratified Log-rank test.  The hazard ratio will be estimated using a stratified
Cox regression model.  Event rates over time will be estimated within each 
treatment group using the Kaplan-Meier method. 
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach.  The tiers differ with 
respect to the analyses that will be performed. There are no events of interest 
that warrant elevation to Tier 1 events in this study.  Tier 2 parameters will be 
assessed via point estimates with 95% confidence intervals (CIs) provided for 
between-group comparisons; only point estimates by treatment group are 
provided for Tier 3 safety parameters.  The 95% CIs for the between-treatment 
differences in percentages will be provided using the Miettinen and Nurminen 
method.
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Interim Analyses
Two interim analyses (IAs) and 1 final analysis (FA) are planned in this study.
Comparisons between two treatment arms will be conducted at the IAs and final 
analysis. Results of the IAs will be reviewed by the eDMC. Details are 
provided in Section 9.7 – Interim Analyses.

IA1: PFS and OS analysis approximately 22 months after the first 
participant is randomized. The analysis will be triggered when
approximately 370 PFS events for CPS ≥1 group have been observed.

IA2: PFS and OS analysis approximately 30 months after the first 
participant is randomized. The analysis will be triggered when at least 
435 PFS events for CPS ≥1 group have been observed. 

FA: Final OS analysis approximately 40 months after the first 
participant is randomized. The analysis will be triggered when at least 
378 OS events for CPS ≥1 group have been observed.
Multiplicity
The overall Type I error rate over the multiple endpoints will be controlled at 
2.5% (one-sided).  A total of 0.5% Type I error rate is initially allocated to test 
PFS superiority between two arms for CPS ≥10 group, CPS ≥1 group and 
all-comers; a total of 2% Type I error rate is initially allocated to test OS 
superiority between two arms for CPS≥10 group, CPS ≥1 group and all-comers. 
The graphical approach of Maurer and Bretz [Maurer, W. 2013]  will be applied
to reallocate alpha among the hypotheses of PFS and OS.  Lan-DeMets 
O’Brien-Fleming group sequential methods will be used to allocate alpha 
among the interim and final analyses for the PFS and OS endpoints. The study 
will be considered positive if it is positive for either PFS or OS hypothesis test 
for any of the three groups (CPS ≥10 group, CPS ≥1 group, and all-comers).
Sample Size and Power
The planned sample size is approximately 600 participants ( 510 participants for 
CPS ≥1 group; 300 participants for CPS ≥10 group) with 300 participants in each 
arm. The study is event-driven and completes after accumulation of sufficient 
events to determine efficacy for PFS and for OS. For all-comers (N=600), with
approximately 432 and 508 events between 2 arms at the planned PFS analyses, 
the study will have 91% power to detect a hazard ratio of 0.70 at the 0.004
significance level.  With 289, 378, and 445 events between 2 arms at the planned 
OS interim and final analyses, the study will have 90% power to detect a hazard 
ratio of 0.72 at the 0.016 significance level. Details are provided in section 9.9 –
Sample Size and Power Calculations.
Following Amendment 7, the preplanned second interim analysis (IA2) is no longer required
for formal hypothesis testing and will not be performed. This is because the success criteria 
for the study hypotheses of PFS and OS for all 3 groups (CPS ≥1 group, all-comers, and CPS 
≥10 group) were met at the first interim analysis (IA1). The prespecified final analysis will 
be performed without multiplicity adjustment when approximately 378 OS events for CPS ≥1 
group have been observed. Updated analyses may be performed during the study at any time 
point to provide additional estimates with longer follow-up.
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.
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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 have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.
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.
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 disease progression per RECIST 
1.1 as assessed by investigator or death due to any cause, whichever occurs first.
OS: The time from randomization to death due to any cause. 
Secondary
ORR: The proportion of participants who have a best overall response of either confirmed 
CR or PR per RECIST 1.1 as assessed by investigator.
DOR: For participants who demonstrate CR or PR, the time from the first documented 
evidence of CR or PR until the first documented disease progression assessed per RECIST 
1.1 by investigator or death due to any cause, whichever occurs first.
PFS-12: PFS rate as assessed at 12 months: The proportion of participants that are PFS 
event-free at 12 months per RECIST 1.1 as assessed by investigator.
PFS: The time from randomization to the first documented disease progression per RECIST 
1.1 as assessed by BICR or death due to any cause, whichever occurs first.
PRO:  PRO endpoints will be assessed by EORTC QLQ-C30 global score. Details will be 
provided in the sSAP.
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Exploratory
Objective response rate (ORR), duration of response (DOR), and 12-month PFS rate are 
assessed by BICR per RECIST 1.1. PFS per iRECIST is defined as specified for the 
respective endpoints using RECIST 1.1 above, with the exception that: 1) a confirmation 
assessment of PD (at least 4 weeks after the initial PD assessment) is required for participants 
who remain on study treatment following a documented PD per RECIST 1.1, and 
2) responses of iSD, iPR, and iCR are permitted as a best overall response after iUPD.  
Participants who discontinue study treatment following a documented PD assessment per 
RECIST 1.1 will be counted as having disease progression on the date of the documented PD 
assessment.  Responses will be based on investigator assessment. PRO endpoints will be 
assessed by EQ-5D-5L, EORTC QLQ-C30  (scores other than global score), and EORTC 
QLQ-CX24.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for the primary efficacy 
analyses.  All randomized participants will be included in this population.  Participants will 
be analyzed in the treatment arm to which they are randomized. 
9.5.2
Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study.  The APaT population 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 most participants, this will 
be the treatment group to which they are randomized.  Participants who take incorrect study 
treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received.  Any participant who receives the 
incorrect study treatment for 1 cycle, but receives the correct treatment for all other cycles, 
will be analyzed according to the correct treatment group and a narrative will be provided for 
any events that occur during the cycle for which the participant is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling safety analyses are provided in Section 9.6.
9.5.3
PRO Analysis Population
The PRO analyses are based on the PRO full analysis set (FAS) population, defined as 
participants who have at least 1 PRO assessment available and have received at least 1 dose 
of study medication.
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9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
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 will be computed for 
other efficacy analyses but should be interpreted with caution due to potential issues of 
multiplicity.
Progression-free Survival
The non-parametric 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, the HR) between the treatment 
arms.  The HR and its 95% CI from the stratified Cox model with Efron's method of tie 
handling and with a single treatment covariate will be reported.  The stratification factors 
used for randomization (Section 6.3.2) will be applied to both the stratified log-rank test and 
the stratified Cox model. Median PFS and its 95% CIs will be updated post the second 
interim analysis; however, no formal statistical test will be performed.
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 date of the 
first assessment at which PD is objectively documented per RECIST 1.1 (based on 
investigator assessment).  Death is always considered as a confirmed PD event. Participants 
who do not experience a PFS event will be censored at the last disease assessment. Similar
analyses will be performed for comparison of PFS per RECIST 1.1 based on BICR
assessment. 
In order to evaluate the robustness of the PFS endpoint, one primary and two sensitivity 
analyses with a different set of censoring rules will be performed. For the primary analysis, if 
the events (PD or death) are immediately after more than one missed disease assessment, the 
data are censored at the last disease assessment prior to missing visits. Also, data after new 
anti-cancer therapy are censored at the last disease assessment prior to the initiation of new 
anti-cancer therapy. The first sensitivity analysis follows the complete follow-up intention-
to-treat principle. That is, PDs/deaths are counted as events regardless of missed study visits 
or initiation of new anti-cancer therapy. The second sensitivity analysis considers 
discontinuation of treatment or initiation of an anti-cancer treatment subsequent to 
discontinuation of study-specified treatments, 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 
primary and sensitivity analyses are summarized in Table 9.
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Table 9
Censoring Rules for Primary and Sensitivity Analyses of Progression-Free 
Survival
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death 
documented after 
≤1 missed disease 
assessment and before 
new anti-cancer 
therapy, 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 
after ≥ 2 consecutive 
missed disease 
assessments without 
further valid non-PD 
disease assessments, or 
after new anti-cancer 
therapy
Censored at last disease 
assessment prior to 
the earlier date of 
≥2 consecutive missed 
disease assessment and 
new anti-cancer 
therapy, 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 anti-cancer
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 
or completed study 
treatment
No PD and no death; 
new anti-cancer
treatment is initiated
Censored at last disease 
assessment before new 
anti-cancer treatment 
Censored at last disease 
assessment
Progressed at date of new 
anti-cancer treatment 
PD=progressive disease
Median PFS and CIs will be updated at final OS analysis; however, there will be no formal 
statistical testing for the PFS endpoint. 
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves.  The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factors defined in Section 6.3.2).  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, 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 
(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 of last known contact.  Restricted Mean Survival Time (RMST) method may be 
conducted for OS to account for the possible non-proportional hazards effect.
A summary of the primary analysis strategy for the key efficacy endpoints is provided in
Table 10.
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Table 10
Efficacy Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses:
PFS (RECIST 1.1)
by investigator 
Testing: Stratified Log-rank test
Estimation: Stratified Cox 
model with Efron's tie handling 
method 
ITT
Censored according to rules in 
Table 9
OS
Testing: Stratified Log-rank test
Estimation: Stratified Cox 
model with Efron's tie handling 
method
ITT
Censored at last known alive date
Secondary Analyses:
ORR (RECIST 1.1) 
by investigator
Estimation: Stratified Miettinen 
and Nurminen method
ITT
Participants with missing data are 
considered non-responders
DOR (RECIST 1.1) 
by investigator
Summary statistics using 
Kaplan-Meier method
All 
responders 
in ITT 
Non-responders are excluded from 
the analysis
PFS rate at 12 
months (RECIST 
1.1) by investigator
Kaplan-Meier estimation with 
CI
ITT
Censored according to rules in 
Table 9
PFS (RECIST 1.1)
by BICR
Estimation: Stratified Cox model 
with Efron's tie handling method
ITT
Censored according to rules in 
Table 9
BICR = blinded independent central review; CI = confidence interval; DOR = duration of response; ITT = Intention-to-
Treat; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response 
Evaluation Criteria in Solid Tumors 1.1.
Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method will be used for comparison of the ORR 
between two treatment groups. The difference in ORR and its 95% confidence interval from 
the stratified Miettinen and Nurminen’s method with strata weighting by sample size will be 
reported. The stratification factors used for randomization (See Section 6.3.2) will be applied 
to the analysis.
Duration of Response (DOR)
For participants who demonstrate CR or PR, DOR is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first.  Censoring rules for DOR are summarized in Table 11. DOR will be 
assessed using RECIST 1.1 by investigator and BICR, respectively. For each DOR analysis, 
a corresponding summary of the censoring reasons for responding participant will also be 
provided. Responding participants who are alive, have not progressed, have not initiated new 
anti-cancer treatment, have not been determined to be lost to follow-up, and have had a 
disease assessment within ~5 months of the data cutoff date are considered ongoing 
responders at the time of analysis.  If a participant meets multiple criteria for censoring, the 
censoring criterion that occurs earliest will be applied.
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Table 11
Censoring Rules for DOR
Situation
Date of Progression or 
Censoring
Outcome
No progression nor death, no 
new anti-cancer therapy initiated
Last adequate disease 
assessment
Censor
(non-event)
No progression nor death, new 
anti-cancer therapy initiated
Last adequate disease 
assessment before new anti-
cancer therapy initiated
Censor
(non-event)
Death or progression after 
≥2 consecutive missed disease 
assessments
Last adequate disease 
assessment prior to the 
≥2 missed adequate disease 
assessments
Censor
(non-event)
Death or progression after 
≤1 missed adequate disease 
assessments
PD or death
End of response
(Event)
PD = progressive disease
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Progression-Free Survival Rate at 12 months
Kaplan-Meier estimates of the survival function for PFS at 12 months will be provided by 
treatment group.  Confidence intervals for the difference between the treatment groups will 
be constructed using standard methods.
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, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 12). The tiers differ with 
respect to the analyses that will be performed.  Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change (PDLCs) in 
laboratory values, vital signs, and ECG parameters 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
Safety parameters or AEOSIs that are identified a prior constitute “Tier 1” safety endpoints 
that will be subject to inferential testing for statistical significance. AEOSIs 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 
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significance is not expected to add value to the safety evaluation. Further, the addition of 
pembrolizumab to chemotherapy treatments included in this study has not been found to 
impact safety. Additionally, there are no known AEs associated with participants for which 
determination of a p-value is expected to impact the safety assessment. Therefore, there are 
no Tier 1 events in this study.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for differences in the proportion of participants with events (also via the Miettinen 
and Nurminen method [1985]).
Membership in Tier 2 requires that at least 10% of participants in any treatment group 
exhibit the event; all other AEs and predefined limits of change will belong to Tier 3. The 
threshold of at least 10% of participants was chosen for Tier 2 events because the population 
enrolled in this study is in critical condition and usually experiences various AEs of similar 
types regardless of treatment; events reported less frequently than 10% of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in 1 of the treatment groups) and SAEs (≥5% of participants in 1 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 as 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 are provided for Tier 3 safety parameters.
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
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Table 12
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-Value
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 (lab toxicity shift, 
vital signs)
X
Abbreviations: AE = adverse event; CI = confidence interval; SOC = system organ class.
9.6.3
Statistical Methods for PRO Analyses: 
To evaluate the treatment effect on the health-related QoL outcomes at prespecified time 
points, a constrained longitudinal data analysis (cLDA) model will be applied with the PRO 
score as the response variable and the treatment by time interaction and stratification factors 
as covariates. Least square mean (ls mean) change from baseline will be summarized.  
Groupwise comparisons will be performed and model-based ls mean score will be provided 
by treatment group and study visit.
A 10-point change in PRO score is perceived to be clinically meaningful to participants 
according to previous research. Correspondingly, a participant’s post-baseline PRO score 
will be classified as “improvement”, “stable”, or “deterioration” according to a 10 point or 
greater change for EORTC QLQ-C30 global score. The number and proportion of 
participants with “improved”, “stable”, or “deteriorated” symptoms/scales will be
summarized by treatment arm. 
Time-to-deterioration is defined as the time from the first PRO assessment to deterioration or 
death, whichever occurs first [Yang, J. C., et al 2013].  The Kaplan-Meier method will be 
used to estimate times to deterioration survival curve for each treatment arm, and the Cox 
proportional hazards regression model will be used to estimate the magnitude of treatment 
difference.  
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Details of PRO analyses will be described in the sSAP.
9.6.4
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of participants randomized and the primary 
reason for discontinuation will be displayed. Demographic variables (such as age) and 
baseline characteristics will be summarized by treatment either by descriptive statistics or 
categorical tables. The reasons for exclusion from the ITT population (if any) will be 
summarized.
9.7
Interim Analyses
An external Data Monitoring Committee (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 Oversight Committee 
(EOC) 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 in order to 
act on these recommendations.  The extent to which individuals are unblinded with respect to 
results of interim analyses will be documented by the unblinded statistician.  Additional 
logistical details will be provided in the eDMC Charter.  Key aspects of the interim analyses 
are described in Section 9.7.
Treatment-level results from the interim analysis will be provided to the eDMC by the 
unblinded statistician. Prior to 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.
9.7.1
Safety Interim Analyses
A safety assessment by the eDMC will take place after 20 participants in the experimental 
arm have completed 2 cycles of treatment.  Adverse events and dose modifications will be 
compared between arms.  If a substantial majority of the enrolled participants (ie, more than 
80%) in the experimental arm require a dose modification by the end of the Cycle 2, and 
taking into consideration the background rate of AEs and dose modifications for control-arm 
participants, the Sponsor may consider amending the protocol to reduce chemotherapy 
dose(s) for the remainder of the trial.
The eDMC will conduct regular safety interim analyses. The timing of these safety interim 
analyses will be specified in the eDMC charter.
9.7.2
Efficacy Interim Analyses
Two interim analyses are planned in addition to the final analysis for this study. Results of 
the interim analyses will be reviewed by the eDMC. There is no expectation to stop the trial 
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before superiority hypotheses for OS have been adequately evaluated.  However, earlier 
positive findings may form the basis for earlier regulatory submission based on the
recommendation of eDMC. 
The first interim analysis (interim analysis for PFS and OS) will be conducted when 
approximately 370 PFS events have been observed for CPS ≥1 group. The second interim 
analysis (final PFS analysis and interim OS analysis) may be conducted when at least 
435 PFS events for CPS ≥1 group have been observed. It is estimated that approximately
508 PFS events for all-comers and approximately 247 PFS events for CPS ≥10 group will be 
observed by then. The final analysis (final OS analysis) may be conducted when at least 
378 OS events for CPS ≥1 group have been observed. It is estimated that approximately
445 OS events for all-comers and approximately 196 OS events for CPS ≥10 group will be 
observed by then. The Sponsor will closely monitor the PFS and OS events for each 
hypothesis test. If the number of PFS or OS events for CPS ≥10 group or all-comers is
significantly lower than the required events for final analysis, then the timing of the final 
analysis for that hypothesis test may be re-evaluated.
The analyses planned, endpoints evaluated, and drivers of the timing are summarized in
Table 13.
Table 13
Summary of Interim and Final Analyses Strategy 
Analyses
Key 
Endpoints
Events Required for the 
Analysis
Estimated 
Time After 
First 
Participant 
Randomized
Primary Purpose of 
Analysis
IA1
(interim 
analysis for 
PFS and 
OS)
PFS
Timing of analysis will be 
triggered when ~ 370 PFS 
events for CPS ≥1 group has 
been observed.
It is estimated that ~210 PFS 
events for CPS ≥10 group 
and ~432 PFS events for 
all-comers will be observed 
at the same time.
~22 months
Demonstrate PFS 
superiority at interim 
analysis for CPS ≥1 group, 
CPS ≥10 group, and all-
comers 
OS
OS interim analysis will be 
performed at the same time. 
It is estimated ~246 OS 
events for CPS ≥1 group, 
~127 OS events for CPS ≥10 
group and ~289 OS events 
for all-comers will be 
observed.
Demonstrate OS 
superiority at interim 
analysis for CPS ≥1 group, 
CPS ≥10 group, and all-
comers
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Analyses
Key 
Endpoints
Events Required for the 
Analysis
Estimated 
Time After 
First 
Participant 
Randomized
Primary Purpose of 
Analysis
IA2 (final 
analysis for 
PFS/interim 
analysis for 
OS)
PFS
Timing of analysis will be 
triggered when at least 
435 PFS events for CPS ≥1 
group have been observed. It 
is estimated that ~247 PFS 
events for CPS ≥10 group 
and ~508 PFS events for 
all-comers will be observed 
by then.
~30 months
Demonstrate PFS 
superiority for CPS ≥1 
group, CPS ≥10 group and 
all-comers
OS
OS interim analysis will be 
performed at the same time. 
It is estimated ~321 OS 
events for CPS ≥1 group, 
~167 OS events for CPS ≥10 
group and ~378 OS events 
for all-comers will be 
observed.
Demonstrate OS 
superiority at interim 
analysis for CPS ≥1 group, 
CPS ≥10 group and all-
comers
Final 
analysis 
OS 
Timing of analysis will be 
triggered when at least 
378 OS events for CPS ≥1 
group has been observed. It 
is estimated that ~196 OS 
events for CPS ≥10 group 
and 445 OS events for all-
comers will be observed by 
then. 
~40 months
Demonstrate OS
superiority for CPS ≥1 
group, CPS ≥10 group and 
all-comers
CPS = combined positive score; IAX= interim analysis X; OS = overall survival; PFS = progression-free 
survival.
Following Amendment 7, the preplanned IA2 is no longer required and will not be 
performed, as described in Section 9.1.
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W. 2013] to provide 
strong multiplicity control across the 2 primary efficacy hypotheses regarding PFS and OS
for CPS ≥1 group, all-comers, and CPS ≥10 group.
Figure 3 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 
represented in the boxes on the lines connecting hypotheses. This is further explained below. 
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CPS = combined positive score; PFS= progression-free survival; OS = overall survival.
Figure 3
Multiplicity Graph for Type I Error Control of Study Hypotheses
9.8.1
Efficacy Analyses
PFS
The study initially allocates one-sided α=0.005 to test PFS between two treatment groups for 
CPS ≥1 group, all-comers, and CPS ≥10 group. If the null hypothesis of PFS for CPS ≥1 
group is rejected, as shown in Figure 3, its α=0.004 will be  reallocated to the PFS analysis 
for all-comers, and if the null hypothesis of PFS for all-comers is rejected, its α=0.004 will be 
reallocated to the PFS analysis for CPS ≥10 group. Table 14 below shows the bounds and 
boundary properties for PFS testing which were derived using a Lan-DeMets O'Brien-
Fleming α-spending function.  If the actual number of events at the PFS analyses differ from 
those specified in the table, the bounds will be adjusted using the Lan-DeMets O'Brien-
Fleming spending function accordingly.
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Table 14
Efficacy Boundaries and Properties for PFS Analyses
Population
Analysisa
Value
α=0.004
CPS ≥1
IA1: 85% 
Z 
2.911
N: 510
p (1-sided) 
0.002
Events:370 
~HR at bound 
0.739
Month: 22 
P(Cross) if HR=1 
0.002
P(Cross) if HR=0.68 
0.788
IA2: 100% 
Z 
2.700
N: 510 
p (1-sided) 
0.003
Events: 435 
~HR at bound 
0.772
Month: 30
P(Cross) if HR=1 
0.004
P(Cross) if HR=0.68 
0.911
Population
Analysisa
Value
α=0.004
All-comers
IA1: 85% 
Z 
2.911
N: 600
p (1-sided) 
0.002
Events: 432 
~HR at bound 
0.756
Month: 22
P(Cross) if HR=1 
0.002
P(Cross) if HR=0.70 
0.787
IA2: 100% 
Z 
2.700
N: 600
p (1-sided) 
0.003
Events: 508
~HR at bound 
0.787
Month: 30
P(Cross) if HR=1 
0.004
P(Cross) if HR=0.70 
0.910
Population
Analysisa
Value
α=0.005
α=0.001
CPS ≥10
IA1: 85% 
Z 
2.829
3.383
N: 300
p (1-sided) 
0.002
0.0004
Events: 210 
~HR at bound 
0.677
0.627
Month: 22
P(Cross) if HR=1 
0.002
0.0004
P(Cross) if HR=0.60
0.808
0.625
IA2: 100% 
Z 
2.627
3.125
N: 300
p (1-sided) 
0.004
0.001
Events: 247
~HR at bound 
0.716
0.672
Month: 30
P(Cross) if HR=1 
0.005
0.001
P(Cross) if HR=0.60 
0.921
0.817
CPS = combined positive score; HR = hazard ratio; IAX = interim analysis X; PFS = progression-free survival.
a.
This column displays the number (Events) and percentage (%) of needed PFS events, the expected sample size (N) 
and the estimated months (Month) after first participant is randomized for each analysis.
p (1-sided): the nominal α for testing.  
~HR at bound: the approximate hazard ratio required to reach an efficacy bound.
P (Cross if HR=1): the probability of crossing a bound at or before each analysis under the null hypothesis 
P (Cross if HR=0.68 or 0.70 or 0.60): the probability of crossing a bound at or before each analysis under the alternative 
hypothesis.
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OS
The study initially allocates one-sided α=0.020 to test OS between two treatment groups for 
CPS ≥1 group, all-comers, and CPS ≥10 group. The OS hypothesis for CPS ≥1 group may be 
tested at one-sided α=0.016 (initially allocated) or higher if one or more null hypothesis for 
PFS test are rejected. If the null hypothesis of OS for CPS ≥1 group is rejected, as shown in
Figure 3, its α will be allocated to the OS analysis for all-comers, and if the null hypothesis 
of OS for all-comers is rejected, its α will be reallocated to the OS analysis for CPS ≥10 
group. Table 15 below shows the bounds and boundary properties for OS testing which were 
derived using a Lan-DeMets O'Brien-Fleming α-spending function.  If the actual number of 
events at the OS analyses differ from those specified in the table, the bounds will be adjusted 
using the Lan-DeMets O'Brien-Fleming spending function accordingly.
Table 15
Efficacy Boundaries and Properties for OS Analysis
Population
Analysisa
Parameter
α=0.016
CPS ≥1
IA1: 65% 
Z 
2.767
N: 510
p (1-sided) 
0.003
Events: 246
~HR at bound 
0.703
Month: 22
P(Cross) if HR=1 
0.003
P(Cross) if HR=0.70 
0.512
IA2: 85% 
Z 
2.405
N: 510
p (1-sided) 
0.008
Events: 321
~HR at bound 
0.765
Month: 30
P(Cross) if HR=1 
0.009
P(Cross) if HR=0.70 
0.791
Final: 100% 
Z 
2.221
N: 510 
p (1-sided) 
0.013
Events: 378 
~HR at bound 
0.796
Month: 40
P(Cross) if HR=1 
0.016
P(Cross) if HR=0.70 
0.901
Population
Analysisa
Parameter
α=0.016
All-comers
IA1: 65% 
Z 
2.771
N: 600
p (1-sided) 
0.003
Events: 289
~HR at bound 
0.722
Month: 22 
P(Cross) if HR=1 
0.003
P(Cross) if HR=0.72 
0.509
IA2: 85% 
Z 
2.404
N: 600
p (1-sided) 
0.008
Events: 378
~HR at bound 
0.781
Month: 30 
P(Cross) if HR=1 
0.009
P(Cross) if HR=0.72 
0.790
Final: 100% 
Z 
2.221
N: 600 
p (1-sided) 
0.013
Events: 445 
~HR at bound 
0.810
Month: 40
P(Cross) if HR=1 
0.016
P(Cross) if HR=0.72 
0.901
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Population
Analysisa
Parameter
α=0.020
α=0.004
CPS ≥10
IA1: 65% 
Z 
2.665
3.339
N: 300
p (1-sided) 
0.004
0.0004
Events: 127 
~HR at bound 
0.623
0.548
Month: 22
P(Cross) if HR=1 
0.004
0.0004
P(Cross) if HR=0.60 
0.585
0.304
IA2: 85% 
Z 
2.306
2.928
N: 300
p (1-sided) 
0.011
0.002
Events: 167
~HR at bound 
0.700
0.636
Month: 30
P(Cross) if HR=1 
0.012
0.002
P(Cross) if HR=0.60 
0.845
0.648
Final : 100% 
Z 
2.137
2.704
N: 300 
p (1-sided) 
0.016
0.003
Events: 196 
~HR at bound 
0.737
0.680
Month: 40
P(Cross) if HR=1 
0.020
0.004
P(Cross) if HR=0.60 
0.931
0.815
CPS = combined positive score; HR = hazard ratio; IAX = interim analysis X; OS = overall survival.
a.
This column displays the number (Events) and percentage (%) of needed PFS events, the expected sample size (N) 
and the estimated months (Month) after first participant is randomized for each analysis.
p (1-sided): the nominal α for testing.  
~HR at bound: the approximate hazard ratio required to reach an efficacy bound.
P(Cross if HR=1): the probability of crossing a bound at or before each analysis under the null hypothesis 
P(Cross if HR=0.70 or 0.72 or 0.60): the probability of crossing a bound at or before each analysis under the alternative 
hypothesis.
Following Amendment 7, the preplanned IA2 is no longer required and will not be 
performed, as described in Section 9.1.
9.8.2
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 IA. However, to account 
for any multiplicity concerns raised by the eDMC review of unplanned efficacy data when 
prompted by safety concerns, a sensitivity analysis for OS adopting a conservative 
multiplicity adjustment will be prespecified in the sSAP.
9.9
Sample Size and Power Calculations
This study is well-powered for both primary endpoints.
Enrollment of 600 participants (all-comers) is assumed to occur over 16 months.
Approximately 510 participants are expected to be CPS ≥1 and 300 participants are expected 
to be CPS ≥10. 
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The duration of PFS in the control arm is assumed to follow an exponential distribution with 
a median of 7.1 months based on historical data. The PFS hypothesis testing was designed as 
below: 
H1: CPS ≥1 group (N=510): At one-sided α = 0.004 and power of 91% to detect a hazard 
ratio of 0.68 with approximately 370 and 435 events between 2 arms at the planned PFS 
analyses. 
H2: All-comers (N=600): At one-sided α = 0.004 and power of 91% to detect a hazard 
ratio of 0.70 with approximately 432 and 508 events between 2 arms at the planned PFS 
analyses (when H1 is rejected). 
H3: CPS ≥10 group (N=300): At one-sided α = 0.005 and power of 92% to detect a 
hazard ratio of 0.60 with approximately 210 and 247 events between 2 arms at the 
planned PFS analyses (when H1 and H2 are rejected). 
The duration of OS in the control arm is assumed to follow an exponential distribution with a 
median of 15.1 months based on historical data. The OS hypothesis testing was designed as 
follows:
H4: CPS ≥1 group (N=510): At one-sided α = 0.016 and power of 90% to detect a hazard 
ratio of 0.70 with approximately 246, 321, and 378 events between 2 arms at the planned
OS analyses. 
H5: All-comers (N=600): At one-sided α = 0.016 and power of 90% to detect a hazard 
ratio of 0.72 with approximately 289, 378, and 445 events between 2 arms at the planned 
OS analyses (when H4 is rejected). 
H6: CPS ≥10 group (N=300): At one-sided α = 0.020 and power of 93% to detect a 
hazard ratio of 0.60 with approximately 127, 167, and 196 events between 2 arms at the 
planned OS analyses (when H4 and H5 are rejected).
Power and interim analysis calculations were performed using EAST 6.4.
Following Amendment 7, the preplanned IA2 is no longer required and will not be 
performed, as described in Section 9.1.
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 classification variables:
Stratification factors
o
Metastatic (FIGO [2009] Stage IVB) at diagnosis (Yes vs. No)
o
Bevacizumab use (Yes vs. No)
o
PD-L1 status (CPS <1 vs. CPS 1 to <10 vs. CPS ≥10)
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Age group (<65 years vs. ≥65 years) 

Race (white, non-white)

ECOG performance status (0, 1)
A Forest plot will be produced, which provides the estimated point estimates and confidence 
intervals for the treatment effect across the categories of subgroups listed above. The 
consistency of the treatment effect will be assessed descriptively via summary statistics by 
category for the classification variables listed above.
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
The extent of exposure will be summarized as duration of treatment in cycles.  Summary 
statistics will be provided on 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 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.
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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, 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.
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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.
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, commonly 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
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.
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.
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 report form 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 prior to 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.
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 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the 
DMC regarding the study.
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 Interim 
Analysis) 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.
10.1.5
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.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (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
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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 trial 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 Debarmen
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, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of good clinical practice); 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 Studies.
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 
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 
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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 signed ICF, 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. 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 may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
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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 will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 16 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 16
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Carbon dioxide 
(CO2 or 
Bicarbonate)c
Chloride
Phosphorous
Creatinined
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline 
phosphatase
Triiodothyronine
(T3/FT3)e
Free Thyroxine
(FT4)e
Thyroid-
stimulating 
hormone (TSH)e
Ureab
Uric acid
Routine 
Urinalysisf
Specific gravity
pH, glucose, protein, blood, ketones, by dipstick
Microscopic examination (if blood or protein is abnormal)
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Laboratory 
Assessments
Parameters
Other Screening 
Tests

PT/INR and aPTTg
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for 
WOCBP)h
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody) if mandated by local health authority
Abbreviations: aPTT = activated partial thromboplastin time; HIV = human immunodeficiency virus;
INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular 
volume; PT = Prothrombin Time; RBC = red blood cell; WBC = white blood cell; 
WOCBP = woman/women of child bearing potential.
NOTES:
a-
Reporting results as absolute values is preferable.
b-
Blood urea nitrogen is preferred; if not available, urea may be tested.
c-
Performed only if considered local standard of care.
d-
Creatinine clearance should be calculated per institutional standard. GFR (measured or calculated) or 
creatinine clearance can be used in place of creatinine.
e-
Free T4, T3, and TSH levels will be performed at screening and every 2 cycles during treatment (C2, 
C4, C6,…), at the time of discontinuation (End of Treatment), and at the Safety-Follow- up visit. May 
perform centrally if unable to perform locally. Free T3 is acceptable where T3 cannot be determined. 
There may be instances when sites are unable to obtain the thyroid function testing results prior to 
scheduled dosing. After Cycle 1, review of thyroid function test results after dosing is acceptable.
f-
Performed at every cycle during which bevacizumab is administered.
g-
Performed as part of the screening assessment and as clinically indicated.
h-
Perform on women of childbearing potential only.  Urine pregnancy test is preferred.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.  For women of 
childbearing potential, pregnancy testing should be conducted every month during study intervention, 
or more frequently if required by local regulations or if clinically indicated.
Investigators 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
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 (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, diagnostic 
agent, or protocol specified procedure whether investigational (including placebo or active 
comparator product) or marketed, 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 pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
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.”
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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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
Refer to Section 8.4.7 for protocol-specific exceptions.
10.3.2
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 pre-existing condition that has not 
worsened is not an SAE. A pre-existing 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.
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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.
10.3.3
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 timeframe 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
10.3.4
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.
The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets at 
each examination.
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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
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.

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 Common Terminology for Adverse Events 
(CTCAE), version 4.0. Any adverse event which changes CTCAE grade over the course 
of a given episode will have each change of grade recorded on the adverse event case 
report forms/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 activities of daily living (ADL).
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation or 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 Sponsor's product cause the adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event 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 
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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 adverse event based upon the available information.
●
The following components are to be used to assess the relationship between the 
Sponsor's product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor's 
product caused the adverse event:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product 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 Sponsor's product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to trials with investigational medicinal 
product)?
●
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 Sponsor's product 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 
Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
trial?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
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(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or 
permanent disability, or (2) the trial is a single-dose drug trial); or (3) Sponsor's 
product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS 
SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR’S 
PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR’S PRODUCT 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 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product 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 his/her best clinical judgment, 
including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the 
AE onset relative to the administration of the Sponsor's product is reasonable.  The 
AE is more likely explained by the Sponsor's product than by another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the AE 
is more likely explained by another cause than the Sponsor’s product.  (Also entered 
for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
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 his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
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●
The causality assessment is one 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 adverse event 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 adverse event 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.
10.3.5
Reporting of AE, SAE, 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 electronic data collection 
(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).
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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 e-mail 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 Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
N/A
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
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).
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
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 follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with 2 FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal 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).
10.5.3
Pregnancy Testing
WOCBP may only be randomized after a negative highly sensitive urine or serum pregnancy 
test within 72 hours prior to randomization. In the event that more than 72 hours have 
elapsed between this pregnancy test and the first dose of study treatment, another pregnancy 
test must be performed and must be negative prior to receiving the first dose of study 
treatment.  
Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
monthly intervals during intervention. 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 participant’s participation in the 
study. Refer to Appendix 7 for country-specific requirements. 
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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. 
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 Research
The specimens consented and/or collected in this study as outlined in Section 8.10 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 drugs/vaccines may interact with

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 Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research
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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.
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 Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' 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 gender, age, medical history, and treatment outcomes are 
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 which 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.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing 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 Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, 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 prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main 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 Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main 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 utilized 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 
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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 Security
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 Participants
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.
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 Population
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 Research
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.
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13. References
1.
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.
International Conference on Harmonization [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
Germany-specific Information
1. Section 1.3.1 Schedule of Activities – Initial Treatment Phase

Monthly urine or serum pregnancy testing is required until 120 days after the last 
dose of pembrolizumab/placebo and 210 days after the last dose of 
chemotherapy/bevacizumab.

Testing for HIV is required at Screening.

Testing for Hepatitis B and Hepatitis C is required at Screening.
2. Section 1.3.2 Schedule of Activities – Second Course Treatment Phase

Monthly urine or serum pregnancy testing is required until 120 days after the last 
dose of pembrolizumab.
3. Section 5.2 Exclusion Criteria

Exclusion Criterion 8: Testing for HIV is required at Screening.

Exclusion Criterion 9: Testing for Hepatitis B and Hepatitis C is required at 
Screening.
4. Section 8.3.4.2 Pregnancy Test

Monthly urine or serum pregnancy testing is required until 120 days after the last 
dose of pembrolizumab/placebo and 210 days after the last dose of 
chemotherapy/bevacizumab.
5. Section 10.2 Appendix 2: Clinical Laboratory Tests

Monthly urine or serum pregnancy testing is required until 120 days after the last 
dose of pembrolizumab/placebo and 210 days after the last dose of 
chemotherapy/bevacizumab.

Testing for HIV is required at Screening.

Testing for Hepatitis B and Hepatitis C is required at Screening.
6. Section 10.5 Appendix 5: Contraceptive Guidance and Pregnancy Testing

Monthly urine or serum pregnancy testing is required until 120 days after the last 
dose of pembrolizumab/placebo and 210 days after the last dose of 
chemotherapy/bevacizumab.
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France-specific Information
1. Section 5.2 Exclusion Criteria

Exclusion Criterion 9: Hepatitis B and Hepatitis C testing must be performed during 
the screening period and prior to enrollment.
2. Section 1.3.1 Schedule of Activities – Initial Treatment Phase

Monthly urine or serum pregnancy testing is required for all participants through 
6 months following the last dose of study intervention.
3. Section 1.3.2 Schedule of Activities – Second Course Treatment Phase

Monthly urine or serum pregnancy testing is required for all participants through 
6 months following the last dose of study intervention.
4. Section 8.3.4.2 Pregnancy Test

Monthly urine or serum pregnancy testing is required for all participants through 
6 months following the last dose of study intervention.
5. Section 10.2 Appendix 2: Clinical Laboratory Tests

Monthly urine or serum pregnancy testing is required for all participants through 
6 months following the last dose of study intervention.
6. Section 10.5 Appendix 5: Contraceptive Guidance and Pregnancy Testing

Monthly urine or serum pregnancy testing is required for all participants through 
6 months following the last dose of study intervention.
7. Section 6.6.1 Dose Modification, Table 5 Pembrolizumab/Placebo Dose Modification 
and Toxicity Management Guidelines for Immune-related AEs

Discontinuation is required for confirmed cases of Stevens-Johnson (SJS) and toxic 
epidermal necrolysis (TEN).
Argentina-specific Information
1. Section 1.3 Schedule of Activities - Screening and Treatment Phase

Pregnancy testing must be performed at each cycle during treatment as well as at the 
end of study intervention.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging is obtained (using iRECIST for participant management)
(see Table 7 and Figure 2). This decision by the investigator should be based on the 
participant’s overall clinical condition.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at  
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but 
“sum of diameters” will be used in this protocol, consistent with the original RECIST 
1.1 terminology.

Unequivocal progression of nontarget lesion(s) identified at baseline

Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional new lesions
Any new factor appears that would have triggered PD by RECIST 1.1
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
None of the progression-confirming factors identified above occurs AND
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
intervention may be considered following consultation with the Sponsor. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3 and submitted to the central imaging vendor.
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Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire study, either before or 
after an instance of pseudo-progression.
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
nontarget lesions, taken as a whole.
New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified nontarget lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: Eastern Cooperative Oncology Group (ECOG) Performance Status
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair
5
Dead
As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
1L
first line
AE
adverse event 
AEOSI
adverse events of special interest
ALT
alanine transaminase
APaT
All Participants as Treated
aPTT
activated partial thromboplastin time
AST
aspartate transaminase
AUC
area under concentration-time curve
BCG
Bacillus Calmette–Guérin 
β-HCG
beta-human chorionic gonadotropin
BICR
blinded independent central review 
CBC
complete blood count
CD28
cluster of differentiation 28
CI
confidence interval
CIN
cervical intraepithelial neoplasia
cLDA
constrained longitudinal data analysis
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials 
COVID-19
coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CPS
combined positive score
CR
complete response 
CRF
Case Report Form 
CSR
Clinical Study Report 
CT
computed tomography 
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CX
Cycle X
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EMA
European Medicines Agency
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQoL-5D-5L
EOC
Executive Oversight Committee
EORTC
European Organisation for the Research and Treatment of Cancer
EOT
end of treatment
ESMO
European Society for Medical Oncology
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration 
FDAAA
Food and Drug Administration Amendments Act
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PRODUCT: MK-3475 
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Abbreviation
Expanded Term
FFPE
Formalin-fixed, paraffin embedded 
FIGO
International Federation of Gynecology and Obstetrics (Fédération Internationale de 
Gynécologie et d’Obstétrique)
FSH
Follicle stimulating hormone 
FT3
Free triiodothyronine
FT4
Free thyroxine
GCP
Good Clinical Practice 
G-CSF
granulocyte colony stimulating factors
GFR
glomerular filtration rate
GI
gastrointestinal
GOG
Gynecologic Oncology Group 
HIV
human immunodeficiency virus 
HR
hazard ratio
HRQoL
health-related quality of life 
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IA
interim analysis
ICF
Informed Consent Form 
ICH
International Council on Harmonisation
iCPD
Confirmed radiographic disease progression
iCR
iRECIST complete response
iCRO
imaging contract research organization
IEC
Independent Ethics Committee
Ig
immunoglobulin 
IgG4
immunoglobulin G4 
IHC
immunohistochemistry
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
INR
international normalized ratio
iPD
immune-related progressive disease
iPR
immune-related partial response
irAE
immune-related AE
IRB
Institutional Review Board 
iRECIST
modified RECIST 1.1 for immune-based therapeutics
IRT
intervention randomization system 
iSD
iRECIST stable disease
ITT
Intention-to-Treat 
IUD
intrauterine device
iUPD
iRECIST unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
IVRS/IWRS
interactive voice response system / integrated web response system 
mAb
monoclonal antibody 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NDA
New Drug Application 
NIMP
Non-Investigational Medicinal Product
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
nonsmall cell lung cancer
NYHA
New York Heart Association
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Abbreviation
Expanded Term
OR
objective response
ORR
objective response rate 
OS
overall survival
OTC
over-the-counter
PBPK
physiologically based PK
PD
progressive disease 
PD 1
programmed cell death 1
PD-L1
programmed cell death ligand 1 
PD-L2
programmed cell death ligand 2
PDLC
predefined limit of change
PFS
progression-free survival
PK
pharmacokinetic
PKCθ
protein kinase C-theta 
po
orally
PR
partial responses 
PRO
patient-reported outcomes
PS
performance score
PT
prothrombin time
PTT
partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
QLQ-C30
Quality of Life Questionnaire Core 30
QLQ-CX24
Quality of Life Questionnaire Cervical Cancer Module
RECIST
Response Evaluation Criteria in Solid Tumors
RMST
restricted mean survival time
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan 
SD
stable disease
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SIM
Site Imaging Manual 
SoA
schedule of activities
SOC
System Organ Class
sSAP
supplemental SAP
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus 
T3
triiodothyronine
T4
thyroxine
TB
tuberculosis 
TC
carboplatin/paclitaxel 
TEA
treatment eligibility assessment
TMDD
target-mediated drug disposition 
TP
cisplatin/paclitaxel 
T-regs
regulatory T-cells 
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
084M62


PRODUCT: MK-3475 
152
PROTOCOL/AMENDMENT NO.: 826-08
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10-JUN-2022
Abbreviation
Expanded Term
VOP
verification of progression
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase 
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PRODUCT: MK-3475 
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10-JUN-2022
11
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10-JUN-2022
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