Conditions: Stomach Neoplasms
Keywords: programmed cell death 1 (PD-1, PD1) programmed cell death ligand 1 (PD-L1, PDL1) programmed cell death ligand 2 (PD-L2, PDL2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1579
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of pembrolizumab (MK-3745) in combination with chemotherapy (Cisplatin combined with 5-Fluorouracil \[FP regimen\] or oxaliplatin combined with capecitabine \[CAPOX regimen\]) versus placebo in combination with chemotherapy (FP or CAPOX regimens) in the treatment of human epidermal growth factor receptor 2 (HER2) negative advanced gastric or GEJ adenocarcinoma in adult participants.

The primary hypotheses of this study are that pembrolizumab plus chemotherapy is superior to placebo plus chemotherapy in terms of overall survival (OS).

Detailed description:

Arms:
arm 1: Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 2 years) + physicians' choice of either cisplatin 80 mg/m\^2 IV on Day 1 Q3W and 5-fluorouracil (5FU) 800 mg/m\^2/day via continuous IV infusion on Days 1 to 5 Q3W (FP regimen) OR oxaliplatin 130 mg/m\^2 IV on Day 1 Q3W + capecitabine 1000 mg/m\^2 orally twice a day (BID) on Days 1 to 14 Q3W (CAPOX regimen).

Participants who complete up to 35 administrations of pembrolizumab (approximately 2 years) or achieve a complete response (CR) but experience progression of disease (PD), can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year). arm 2: Participants receive placebo on Day 1 Q3W for up to 35 cycles (approximately 2 years) + physicians' choice of either cisplatin 80 mg/m\^2 IV on Day 1 Q3W and 5FU 800 mg/m\^2/day via continuous IV infusion on Days 1 to 5 Q3W (FP regimen) OR oxaliplatin 130 mg/m\^2 IV on Day 1 Q3W + capecitabine 1000 mg/m\^2 orally BID on Days 1 to 14 Q3W (CAPOX regimen).

Interventions: intervention 1: Pembrolizumab intervention 2: Cisplatin intervention 3: 5-fluorouracil intervention 4: oxaliplatin intervention 5: capecitabine intervention 6: Placebo for Pembrolizumab
Intervention descriptions: intervention 1: Administered as an IV infusion on Day 1 Q3W intervention 2: Administered as an IV infusion on Day 1 Q3W intervention 3: Administered as a continuous IV infusion on Days 1-5 Q3W intervention 4: Administered as an IV infusion on Day 1 Q3W intervention 5: Administered orally BID on Days 1 to 14 Q3W intervention 6: Administered as an IV infusion on Day 1 Q3W

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3, randomized, double-blind clinical study of 
pembrolizumab (MK-3475) plus chemotherapy versus 
placebo plus chemotherapy as first-line treatment in 
participants with HER2 negative, previously untreated, 
unresectable or metastatic gastric or gastroesophageal 
junction adenocarcinoma (KEYNOTE-859)
NCT03675737
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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 clinical study of pembrolizumab 
(MK-3475) plus chemotherapy versus placebo plus chemotherapy as first-line treatment in 
participants with HER2 negative, previously untreated, unresectable or metastatic gastric or 
gastroesophageal junction adenocarcinoma (KEYNOTE-859)
Protocol Number: 859-06
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):
EudraCT
2018-001757-27
IND
123,482
Approval Date: 28 September 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 6
28-SEP-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 5
30-NOV-2021
To merge the China mainland extension portion into the Global portion of the 
study due to the short interval between Last Patient In of the Global portion of the 
study and the China mainland extension portion.
Amendment 4
07-JUN-2021
To update the dose modification and toxicity management guidelines for irAEs.
Amendment 3
11-JAN-2021
Amended Statistical Analysis Plan to take into account recently published data, 
specifically the CM649 and ATTRACTION 4-studies.
Amendment 2
12-DEC-2019
Update Statistical Analysis Plan of the study and provide clarification to specific 
sections of the protocol.
Amendment 1
20-NOV-2018
Clarify Inclusion/Exclusion Criteria and update Country-specific requirements
Original Protocol
12-JUL-2018
N/A
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 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.
Section 4.4 Beginning and 
End of Study Definition
Added text regarding the beginning and 
end of the study in European Economic 
Area.
Revision to align with the EU clinical trial regulation 
(CTR) No. 536/2014 of the European Parliament and 
of the Council.
Section 5 Study Population
Added text regarding the collection and 
use of demographic data.
Section 6.1 Study 
Intervention(s) Administered
Updated Use, IMP or NIMP/AxMP 
designation, and footnotes of Table 5.
Section 8.4 Adverse Events 
(AEs), Serious Adverse 
Events (SAEs), and Other 
Reportable Safety Events
Added text regarding the reporting of 
SAEs associated with medication error, 
misuse, and abuse.
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Section # and Name
Description of Change 
Brief Rationale 
Section 10.3: Appendix 3: 
Adverse Events: Definitions 
and Procedures for 
Recording, Evaluating, 
Follow-up, and Reporting
Added the definitions of medication error, 
misuse, and abuse.
Section 8.1.10 Participant 
Blinding/Unblinding
Revised the note regarding PD-L1 results.
Revision to align with the biomarker plan and to clarify 
that PD-L1 results will be masked to the site.
Section 6 Study Intervention
Section 10.7.2 Japan-
specific Information
Added language regarding the IMP and 
NIMP/AxMP designation of 5-FU and 
placebo. Added appropriate cross-
reference in Section 6.
Revision to align with recent changes to the regulations 
issued by the PMDA.
Throughout
Correction of minor typographical, 
editorial, or formatting errors.
Revision to ensure consistency throughout and 
improve readability.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities (SoA)................................................................................22
1.3.1
Initial Treatment Phase ................................................................................22
1.3.2
Second Course (Retreatment) Phase............................................................31
2
INTRODUCTION..........................................................................................................35
2.1
Study Rationale....................................................................................................35
2.2
Background ..........................................................................................................37
2.2.1
Pharmaceutical and Therapeutic Background .............................................38
2.2.2
Preclinical and Clinical Studies ...................................................................38
2.2.3
Ongoing Clinical Studies of Pembrolizumab in Malignancies....................39
2.2.4
Information on Other Study-related Therapy ..............................................40
2.3
Benefit/Risk Assessment......................................................................................41
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................41
4
STUDY DESIGN............................................................................................................44
4.1
Overall Design......................................................................................................44
4.2
Scientific Rationale for Study Design.................................................................46
4.2.1
Rationale for Endpoints ...............................................................................46
4.2.1.1
Efficacy Endpoints.............................................................................46
4.2.1.2
Safety Endpoints................................................................................47
4.2.1.3
Patient-reported Outcomes.................................................................48
4.2.1.3.1
EORTC QLQ-C30 ...................................................................48
4.2.1.3.2
EORTC QLQ-STO22 ..............................................................48
4.2.1.3.3
EuroQoL EQ-5D......................................................................48
4.2.1.4
Planned Exploratory Biomarker Research.........................................48
4.2.1.5
Future Biomedical Research..............................................................50
4.2.2
Rationale for the Use of Comparator/Placebo .............................................50
4.2.2.1
Rationale for the Use of Placebo .......................................................50
4.2.2.2
Rationale for the Use of FP and CAPOX ..........................................51
4.3
Justification for Dose...........................................................................................51
4.3.1
Justification for Pembrolizumab Dose.........................................................51
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4.3.2
Justification for Chemotherapy “Backbone” Dose......................................52
4.4
Beginning and End of Study Definition .............................................................53
4.4.1
Clinical Criteria for Early Study Termination .............................................54
5
STUDY POPULATION ................................................................................................54
5.1
Inclusion Criteria.................................................................................................54
5.2
Exclusion Criteria................................................................................................58
5.3
Lifestyle Considerations......................................................................................61
5.3.1
Meals and Dietary Restrictions....................................................................61
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................61
5.3.3
Activity Restrictions ....................................................................................62
5.3.4
Photosensitivity............................................................................................62
5.4
Screen Failures.....................................................................................................62
5.5
Participant Replacement Strategy......................................................................62
6
STUDY INTERVENTION............................................................................................62
6.1
Study Intervention(s) Administered...................................................................63
6.1.1
Pembrolizumab and Placebo........................................................................65
6.1.2
FP.................................................................................................................65
6.1.3
CAPOX........................................................................................................66
6.1.4
Medical Devices...........................................................................................66
6.2
Preparation/Handling/Storage/Accountability .................................................66
6.2.1
Dose Preparation..........................................................................................66
6.2.2
Handling, Storage, and Accountability........................................................67
6.3
Measures to Minimize Bias: Randomization and Blinding..............................67
6.3.1
Intervention Assignment..............................................................................67
6.3.2
Stratification.................................................................................................67
6.3.3
Blinding........................................................................................................68
6.4
Study Intervention Compliance..........................................................................68
6.5
Concomitant Therapy..........................................................................................68
6.5.1
Rescue Medications and Supportive Care ...................................................70
6.5.1.1
Supportive Care Guidelines for Pembrolizumab ...............................70
6.5.1.2
Supportive Care Guidelines for Combination Therapy .....................71
6.5.1.2.1
Supportive Care Guidelines for Cisplatin................................71
6.5.1.2.2
Supportive Care Guidelines for 5-FU......................................71
6.5.1.2.3
Supportive Care Guidelines for Capecitabine..........................71
6.5.1.2.4
Supportive Care Guidelines for Oxaliplatin ............................71
6.6
Dose Modification (Escalation/Titration/Other)...............................................72
6.6.1
Initial Treatment or First Course..................................................................72
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6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................72
6.6.2.1
Dose Modification and Toxicity Management for Immune-related 
AEs Associated with Pembrolizumab................................................73
6.6.2.2
Dose Modification for Combination Chemotherapy .........................78
6.7
Second Course Phase (Pembrolizumab)............................................................84
6.8
Intervention After the End of the Study............................................................85
6.9
Clinical Supplies Disclosure................................................................................85
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................85
7.1
Discontinuation of Study Intervention...............................................................85
7.2
Participant Withdrawal From the Study...........................................................86
7.3
Lost to Follow-up .................................................................................................87
8
STUDY ASSESSMENTS AND PROCEDURES........................................................87
8.1
Administrative and General Procedures ...........................................................88
8.1.1
Informed Consent.........................................................................................88
8.1.1.1
General Informed Consent.................................................................88
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................88
8.1.2
Inclusion/Exclusion Criteria ........................................................................89
8.1.3
Participant Identification Card.....................................................................89
8.1.4
Medical History ...........................................................................................89
8.1.5
Prior and Concomitant Medications Review...............................................89
8.1.5.1
Prior Medications...............................................................................89
8.1.5.2
Concomitant Medications..................................................................89
8.1.6
Assignment of Screening Number...............................................................90
8.1.7
Assignment of Treatment/Randomization Number.....................................90
8.1.8
Study Intervention Administration ..............................................................90
8.1.8.1
Timing of Dose Administration.........................................................90
8.1.9
Discontinuation and Withdrawal .................................................................91
8.1.9.1
Withdrawal From Future Biomedical Research ................................91
8.1.10
Participant Blinding/Unblinding..................................................................91
8.1.11
Calibration of Equipment.............................................................................92
8.2
Efficacy Assessments ...........................................................................................93
8.2.1
Tumor Imaging and Assessment of Disease................................................93
8.2.1.1
Initial Tumor Scans............................................................................93
8.2.1.2
Tumor Scans During the Study..........................................................94
8.2.1.3
End-of-Treatment and Follow-up Tumor Scans................................94
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8.2.1.4
Second Course (Retreatment) Tumor Scans......................................95
8.2.1.5
RECIST 1.1 Assessment of Disease..................................................95
8.2.1.6
iRECIST Assessment of Disease.......................................................96
8.2.2
Quality-of-Life Assessments .......................................................................99
8.2.2.1
Patient-reported Outcomes.................................................................99
8.3
Safety Assessments...............................................................................................99
8.3.1
Physical Examinations.................................................................................99
8.3.1.1
Full Physical Examination.................................................................99
8.3.1.2
Directed Physical Examination..........................................................99
8.3.1.3
Audiometry (Only in Participants Receiving Cisplatin)..................100
8.3.1.4
Additional Monitoring (Only in Participants Receiving 
Capecitabine) ...................................................................................100
8.3.2
Vital Signs..................................................................................................100
8.3.3
Electrocardiograms ....................................................................................100
8.3.4
Clinical Safety Laboratory Assessments (Hematology, Chemistry and 
Urinalysis)..................................................................................................100
8.3.5
Pregnancy Test...........................................................................................101
8.3.6
Eastern Cooperative Oncology Group (ECOG) Performance Scale .........102
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................102
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................102
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....105
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.105
8.4.4
Regulatory Reporting Requirements for SAE ...........................................105
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................105
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................106
8.4.7
Events of Clinical Interest (ECIs)..............................................................106
8.5
Treatment of Overdose......................................................................................106
8.6
Pharmacokinetics...............................................................................................107
8.7
Pharmacodynamics............................................................................................107
8.8
Future Biomedical Research Sample Collection.............................................107
8.9
Planned MSI Analysis Sample Collection........................................................107
8.10
Planned Genetic Analysis Sample Collection..................................................107
8.11
Biomarkers .........................................................................................................108
8.12
Medical Resource Utilization and Health Economics.....................................108
8.13
Visit Requirements.............................................................................................108
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8.13.1
Screening....................................................................................................109
8.13.1.1
Prescreening Period .........................................................................109
8.13.1.2
Screening Period ..............................................................................109
8.13.2
Treatment Period........................................................................................109
8.13.3
Discontinued Participants Continuing to be Monitored in the Study ........110
8.13.3.1
Safety Follow-up Visit.....................................................................110
8.13.3.2
Efficacy Follow-up Visits................................................................110
8.13.3.3
Survival Follow-up Assessments.....................................................110
8.13.4
Vital Status.................................................................................................111
9
STATISTICAL ANALYSIS PLAN ...........................................................................111
9.1
Statistical Analysis Plan Summary...................................................................111
9.2
Responsibility for Analyses/In-house Blinding ...............................................112
9.3
Hypotheses/Estimation ......................................................................................113
9.4
Analysis Endpoints.............................................................................................113
9.4.1
Efficacy Endpoint ......................................................................................113
9.4.2
Safety Endpoint..........................................................................................113
9.4.3
Patient-reported Outcome (PRO) Endpoint...............................................114
9.5
Analysis Populations..........................................................................................114
9.5.1
Efficacy Analysis Populations...................................................................114
9.5.2
Safety Analysis Populations ......................................................................114
9.6
Statistical Methods.............................................................................................114
9.6.1
Statistical Methods for Efficacy Analyses.................................................114
9.6.1.1
Overall Survival...............................................................................115
9.6.1.2
Progression-free Survival.................................................................115
9.6.1.3
Objective Response Rate .................................................................116
9.6.1.4
Analysis Strategy for Key Efficacy Endpoints................................116
9.6.2
Statistical Methods for Safety Analyses ....................................................117
9.6.3
Summaries of Demographic and Baseline Characteristics ........................118
9.7
Interim Analyses ................................................................................................119
9.7.1
Efficacy Interim Analysis ..........................................................................119
9.7.2
Safety Interim Analysis..............................................................................120
9.8
Multiplicity .........................................................................................................120
9.8.1
OS Hypotheses...........................................................................................121
9.8.2
PFS Hypotheses .........................................................................................124
9.8.3
ORR Hypotheses........................................................................................125
9.8.4
Safety Analyses..........................................................................................125
9.9
Sample Size and Power Calculations ...............................................................125
9.9.1
Overall Survival.........................................................................................126
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9.9.2
Progression-free Survival...........................................................................127
9.9.3
Objective Response Rate ...........................................................................127
9.10
Subgroup Analyses.............................................................................................128
9.11
Compliance (Medication Adherence)...............................................................128
9.12
Extent of Exposure.............................................................................................128
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................129
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......129
10.1.1
Code of Conduct for Clinical Trials...........................................................129
10.1.2
Financial Disclosure...................................................................................131
10.1.3
Data Protection...........................................................................................131
10.1.3.1
Confidentiality of Data ....................................................................132
10.1.3.2
Confidentiality of Participant Records.............................................132
10.1.3.3
Confidentiality of IRB/IEC Information..........................................132
10.1.4
Committees Structure.................................................................................132
10.1.4.1
Executive Oversight Committee......................................................132
10.1.4.2
External Data Monitoring Committee .............................................132
10.1.5
Publication Policy......................................................................................133
10.1.6
Compliance with Study Registration and Results Posting Requirements .133
10.1.7
Compliance with Law, Audit, and Debarmen ...........................................134
10.1.8
Data Quality Assurance .............................................................................134
10.1.9
Source Documents .....................................................................................135
10.1.10
Study and Site Closure...............................................................................135
10.2
Appendix 2: Clinical Laboratory Tests............................................................136
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................138
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................138
10.3.2
Definition of AE ........................................................................................138
10.3.3
Definition of SAE ......................................................................................139
10.3.4
Additional Events Reported in the Same Manner as SAE.........................140
10.3.5
Recording AE and SAE .............................................................................141
10.3.6
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................144
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................146
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................147
10.5.1
Definitions..................................................................................................147
10.5.2
Contraception Requirements......................................................................148
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10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................150
10.7
Appendix 7: Country-specific Requirements..................................................155
10.7.1
Germany-specific Information:..................................................................155
10.7.2
Japan-specific Information: .......................................................................155
10.7.3
UK-specific Information:...........................................................................155
10.7.4
France-specific Information:......................................................................156
10.7.5
Italy-specific Information: .........................................................................157
10.7.6
Czech Republic-specific Information: .......................................................157
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................158
10.9
Appendix 9: Eastern Cooperative Oncology Group Scale.............................162
10.10 Appendix 10: Abbreviations .............................................................................163
11
REFERENCES.............................................................................................................167
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LIST OF TABLES
Table 1
Study Schedule of Activities Initial Treatment Phase ...............................22
Table 2
Study Schedule of Activities Second Course (Retreatment) Phase...........31
Table 3
Ongoing Clinical Studies of Pembrolizumab in the Gastric Cancer 
Indication ......................................................................................................39
Table 4
Adequate Organ Function Laboratory Values ..............................................58
Table 5
Study Interventions.......................................................................................63
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ............................................................74
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines .....................................................................................................77
Table 8
Dose Modification Guidelines for CAPOX Drug-related Adverse Events ..79
Table 9
Dose Modification Guidelines for Oxaliplatin Drug-related Adverse 
Events............................................................................................................79
Table 10
Dose Modification Guidelines for Capecitabine Drug-related Adverse 
Events............................................................................................................80
Table 11
Dose Modification Guidelines for FP Drug-related Adverse Events ...........81
Table 12
Dose Modification Guidelines for Cisplatin Drug-related Adverse 
Events............................................................................................................82
Table 13
Dose Modification Guidelines for 5-FU Drug-related Adverse Events .......83
Table 14
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease..........................................................................................................97
Table 15
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events............................................................................104
Table 16
Censoring Rules for Primary and Sensitivity Analyses of PFS..................116
Table 17
Analysis Strategy for Key Efficacy Endpoints...........................................117
Table 18
Analysis Strategy for Safety Parameters.....................................................118
Table 19
Summary of Interim and Final Analyses Strategy for Efficacy..................120
Table 20
Efficacy Boundaries and Properties for OS Analysis in CPS ≥10 
Participants..................................................................................................122
Table 21
Efficacy Boundaries and Properties for OS Analysis in CPS ≥1 
Participants..................................................................................................123
Table 22
Efficacy Boundaries and Properties for OS Analysis in All Participants...124
Table 23
Efficacy Boundaries and Properties for PFS Analysis ...............................125
Table 24
Assumed Delayed Period and Piecewise Hazard Ratio for OS..................126
Table 25
Assumed Delayed Period and Piecewise Hazard Ratio for PFS.................126
Table 26
Estimated Average Hazard Ratio (AHR) at The Planned Final Analysis ..126
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Table 27
Protocol-required Safety Assessments........................................................136
Table 28
Highly Effective Contraception Methods...................................................149
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LIST OF FIGURES
Figure 1
KEYNOTE-859 Study Design......................................................................21
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator ...................................................................................................98
Figure 3
Multiplicity Graph for Type I Error Control of Study Hypotheses ............121
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, randomized, double-blind clinical study of pembrolizumab (MK-
3475) plus chemotherapy versus placebo plus chemotherapy as first-line treatment in 
participants with HER2 negative, previously untreated, unresectable or metastatic gastric or 
gastroesophageal junction adenocarcinoma (KEYNOTE-859)
Short Title: Pembrolizumab/placebo plus chemotherapy as first-line therapy in participants 
with HER2 negative advanced gastric or GEJ adenocarcinoma
Acronym: KEYNOTE-859
Hypotheses, Objectives, and Endpoints:
In male and female participants at least 18 years of age with human epidermal growth factor 
receptor 2 (HER2) negative, previously untreated, unresectable or metastatic gastric or 
gastroesophageal junction (GEJ) adenocarcinoma:
Primary Objectives
Primary Endpoints
- Objective: To compare the overall survival 
(OS) of the participants following 
administration of pembrolizumab versus 
placebo when each is combined with 
chemotherapy
- Hypothesis (H1): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for OS, in participants with 
programmed cell death ligand 1 (PD-L1) 
combined positive score (CPS) ≥10 
- Hypothesis (H2): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for OS, in participants with 
PD-L1 positive tumors defined by CPS ≥1
- Hypothesis (H3): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for OS, in all participants
- OS: The time from randomization to 
death due to any cause
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Secondary Objectives
Secondary Endpoints
- Objective: To compare the progression-free 
survival (PFS) per Response Evaluation 
Criteria in Solid Tumors version 1.1 
(RECIST 1.1), as assessed by blinded 
independent central review (BICR), 
following administration of pembrolizumab 
versus placebo when each is combined 
with chemotherapy
- Hypothesis (H4): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for PFS, in participants with 
PD-L1 positive tumors defined by CPS ≥10
- Hypothesis (H5): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for PFS, in participants with 
PD-L1 positive tumors defined by CPS ≥1
- Hypothesis (H6): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for PFS, in all participants
- PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first.
- Objective: To compare the objective 
response rate (ORR) per RECIST 1.1, as 
assessed by BICR, following 
administration of pembrolizumab versus 
placebo when each is combined with 
chemotherapy
- Hypothesis (H7): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for ORR, in participants 
with PD-L1 positive tumors defined by 
CPS ≥10 
- Hypothesis (H8): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for ORR, in participants 
with PD-L1 positive tumors defined by
CPS ≥1 
- Hypothesis (H9): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for ORR, in all participants
- Objective response (OR): Complete 
response (CR) or partial response (PR)
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- Objective: To describe the duration of 
response (DOR) per RECIST 1.1, as 
assessed by BICR, following 
administration of pembrolizumab versus 
placebo when each is combined with 
chemotherapy in participants with PD-L1 
CPS ≥10,  PD-L1 CPS ≥1, and in all 
participants
- DOR: The time from first response (CR 
or PR) to subsequent disease progression, 
or death from any cause, whichever 
occurs first
- Objective: To evaluate the safety and 
tolerability of pembrolizumab plus 
chemotherapy versus placebo plus 
chemotherapy
- Adverse events (AEs)
- Study intervention discontinuation due to 
AEs
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Treatment of advanced gastric or GEJ adenocarcinoma
Population
Participants with previously untreated, HER2 negative,
advanced gastric or GEJ adenocarcinoma
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Investigator, Participant
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 6 years from the time the first participant 
provides documented informed consent until the last 
participant’s last study-related telephone call or visit.
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Number of Participants:
Approximately 1542 participants will be randomized with approximately 771 participants in 
each treatment arm to receive pembrolizumab or placebo in combination with chemotherapy. 
After enrollment of the Global portion of the study is complete, the study may remain open 
to enrollment in China mainland alone until the target number of participants from China
mainland have been enrolled to meet local regulatory requirements.
Intervention Groups and Duration:
Intervention 
Groups
Group Name
Intervention 
Name
Dose Strength
Dose 
Frequency
Route 
of 
Admin.
Use
Pembrolizumab
Pembrolizumab 
(MK 3475)
200 mg on 
Day 1 of each 
cycle
Q3W
IV
Experimental
Placebo
Placebo
Day 1 of each 
cycle
Q3W
IV
Placebo
Backbone chemotherapy
FP
Cisplatin
80 mg/m2 on 
Day 1 of each 
cycle
Q3W*
IV
Comparator 
regimen and 
combination 
agent
5 FU
800 mg/m2/day 
continuous on 
Days 1 to 5 of 
each cycle (120 
hours, or per 
local standard)
Q3W
IV
Comparator 
regimen and 
combination 
agent
CAPOX
Oxaliplatin
130 mg/m2 on 
Day 1 of each 
cycle
Q3W*
IV
Comparator 
regimen and 
combination 
agent
Capecitabine
1000 mg/m2
twice daily on 
Days 1 to 14 of 
each cycle
Q3W
Oral
Comparator 
regimen and 
combination 
agent
5 FU 5 fluorouracil; CAPOX capecitabine and oxaliplatin; FP cisplatin and 5 fluorouracil; 
IV intravenous; Q3W every 3 weeks
* Duration of cisplatin or oxaliplatin treatment may be capped at 6 cycles as per local country 
guidelines; however, treatment with 5 FU/capecitabine may continue per protocol.
Investigator decision regarding the type of backbone chemotherapy (FP or CAPOX) should be 
determined prior to randomization.
Participants should continue on the type of backbone chemotherapy chosen prior to randomization 
throughout the study. Exceptions may be permitted after consultation with the Sponsor.
Participants who are randomized to placebo are not allowed to crossover to pembrolizumab 
treatment.
Total 
Number
2 intervention groups
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Duration 
of Partici-
pation
Each participant will participate in the study from the time the participant 
provides documented informed consent through the final protocol-specified 
contact.
After a screening phase of up to 28 days, each participant will be assigned to 
receive study intervention until one of the conditions for study 
discontinuation is met.
Participants who complete study intervention after receiving 35 
administrations of pembrolizumab, and participants who attain a complete 
response (CR) and stop study intervention may be eligible for up to 17 
additional administrations of pembrolizumab (approximately 1 year) on 
experiencing disease progression.
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until any of the conditions for discontinuation are met.  
All participants will be followed for overall survival until death, withdrawal 
of consent, or the end of the study.
Once the participant has achieved the study objective or the study has 
ended, the participant is discontinued from this study and may be enrolled in 
an extension study to continue protocol-defined assessments and treatment.
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.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
KEYNOTE-859 Study Design
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1.3
Schedule of Activities (SoA)
1.3.1
Initial Treatment Phase
Procedures and activities during the Treatment Phase are outlined in Table 1.
Table 1
Study Schedule of Activities Initial Treatment Phase
Study Period:
Screen
-ing
Phase
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 35
Discontin-
uation
Safety 
Follow-
up
Efficacy
Follow-
up
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each 
cycle unless otherwise 
noted.
Posttreatment Period: 
Refer to Section 8.13.3.
Scheduled Timing
Day 
-28 
to -1
At time of 
d/c
30 days 
post 
last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window:
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Administrative Procedures
Informed Consenta
X
Refer to Section 8.1.1.
Reconsent at the First 
Indication of Radiographic 
Progression


As assessed by the 
investigator.
Informed Consent for 
Future Biomedical 
Research
X
Not required for 
participation in the study.
Eligibility Criteria
X
Participant Identification 
Card
X
Refer to Section 8.1.3.
Medical History and 
Demographics
X
Refer to Section 8.1.4.
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Study Period:
Screen
-ing
Phase
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 35
Discontin-
uation
Safety 
Follow-
up
Efficacy
Follow-
up
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each 
cycle unless otherwise 
noted.
Posttreatment Period: 
Refer to Section 8.13.3.
Scheduled Timing
Day 
-28 
to -1
At time of 
d/c
30 days 
post 
last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window:
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
Refer to Section 8.1.5.
Prior medications: record 
all medications taken 
within 28 days before 
first dose.
Concomitant 
medications: Enter new 
medications started 
during the study through 
the posttreatment Safety 
Follow up. Record 
concomitant medications 
beyond 30 days after 
treatment discontinuation 
if related to SAE or ECI.
Study Intervention
Intervention
Randomization 
X
Site personnel will access 
IRT after confirming the 
participant is eligible for 
randomization.
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Study Period:
Screen
-ing
Phase
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 35
Discontin-
uation
Safety 
Follow-
up
Efficacy
Follow-
up
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each 
cycle unless otherwise 
noted.
Posttreatment Period: 
Refer to Section 8.13.3.
Scheduled Timing
Day 
-28 
to -1
At time of 
d/c
30 days 
post 
last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window:
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Pembrolizumab or Placebo 
Administration
X
X
X
X
X
X
Refer to Section 6.1 for 
administration 
instructions.
Administration to start on 
Day 1 of each cycle, after 
all procedures/ 
assessments have been 
completed.  Sites should 
follow local practice 
guidelines and refer to the 
appropriate appendix, 
where indicated.
FP or CAPOX 
Administration
X
X
X
X
X
X
Efficacy Procedures
Tumor Imaging
X
X
X
X
X
X
Refer to Section 8.2.1.
Baseline tumor imaging 
within 28 days prior to 
randomization.
First on study imaging at 
6 weeks (+ 7 days) after 
randomization, then
every 6 weeks (± 7 days)
(or more frequently if 
clinically indicated).
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Study Period:
Screen
-ing
Phase
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 35
Discontin-
uation
Safety 
Follow-
up
Efficacy
Follow-
up
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each 
cycle unless otherwise 
noted.
Posttreatment Period: 
Refer to Section 8.13.3.
Scheduled Timing
Day 
-28 
to -1
At time of 
d/c
30 days 
post 
last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window:
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
ePROs (EuroQol EQ-5D, 
EORTC QLQ-C30, 
EORTC QLQ-STO22)
X
X
X
X
X
X
(odd 
cycles)
X
X
Refer to Section 8.2.2.
It is strongly 
recommended that ePROs 
are completed prior to 
procedures/ assessments, 
and in the following 
order: EQ 5D then 
EORTC QLQ C30 then 
EORTC QLQ STO22.
Repeat every 2 cycles 
after Cycle 5 (eg,
Cycle 7, Cycle 9).  A visit 
window of ± 7 days will 
apply to PRO visit 
assessments.
Safety Procedures
Height
X
Weight
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Refer to Section 8.3.1.1
Directed Physical 
Examination
X
X
X
X
X
X
Refer to Section 8.3.1.2.
Include additional 
monitoring, as necessary,
for participants receiving 
capecitabine.
Audiometry
X
Only in participants 
receiving cisplatin.
Repeat during the study 
as clinically indicated.
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Study Period:
Screen
-ing
Phase
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 35
Discontin-
uation
Safety 
Follow-
up
Efficacy
Follow-
up
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each 
cycle unless otherwise 
noted.
Posttreatment Period: 
Refer to Section 8.13.3.
Scheduled Timing
Day 
-28 
to -1
At time of 
d/c
30 days 
post 
last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window:
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Vital Signs
X
X
X
X
X
X
X
X
Refer to Section 8.3.2.
Include temperature, 
pulse rate, respiratory 
rate, and blood pressure.
12-lead ECG (local)
X
Refer to Section 8.3.3.
ECOG Performance Status
X
X
X
X
X
X
X
X
Refer to Section 8.3.6
ECOG performance 
status for screening is to
be performed within 
3 days prior to the first 
dose of study 
intervention.
AE/SAE Review
X
X


X
Refer to Section 8.4.
Poststudy Anticancer 
Therapy Status
X
X
Survival Status


X
Refer to Section 8.13.4.
Survival status follow up 
starts after 
investigator determined 
PD or start of new 
anticancer treatment. In 
addition, upon Sponsor 
request, participants may 
be contacted for survival 
status at any time during 
the course of the study
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Study Period:
Screen
-ing
Phase
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 35
Discontin-
uation
Safety 
Follow-
up
Efficacy
Follow-
up
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each 
cycle unless otherwise 
noted.
Posttreatment Period: 
Refer to Section 8.13.3.
Scheduled Timing
Day 
-28 
to -1
At time of 
d/c
30 days 
post 
last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window:
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Laboratory Procedures (LOCAL laboratory)
Pregnancy Test – Serum or 
Urine (WOCBP only)
X
X
X
X
X
X
X
X
X
Refer to Appendix 5.
During Intervention 
Phase: test within
24hours for urine or 
within 72 hours for serum 
prior to first dose and 
repeat prior to each 
treatment cycle and as 
required by local 
guidelines.
HIV, Hepatitis B and C 
Screen (per local 
regulations)
X
PT/INR and aPTT
X
PT/INR should be tested 
at Screening (within 
10 days prior to the first 
dose of study 
intervention). Repeat as 
needed for participants on 
warfarin based 
anticoagulation therapy.
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Study Period:
Screen
-ing
Phase
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 35
Discontin-
uation
Safety 
Follow-
up
Efficacy
Follow-
up
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each 
cycle unless otherwise 
noted.
Posttreatment Period: 
Refer to Section 8.13.3.
Scheduled Timing
Day 
-28 
to -1
At time of 
d/c
30 days 
post 
last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window:
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Hematology (CBC with 
Differential)
X
X
X
X
X
X
X
X
Refer to Section 8.3.4.
Laboratory tests for 
screening are to be 
performed within 10 days 
prior to the first dose of 
study intervention.
Then up to 72 hours prior 
to the scheduled time 
point.
Chemistry Panel
X
X
X
X
X
X
X
X
T3 (or Free T3), Free T4, 
and TSH
X
X
X
X
(even 
cycles)
X
Thyroid function tests 
should be performed at 
Screening, then on Day 1 
of every other cycle 
starting from Cycle 2.
Urinalysis
X
Refer to Section 8.3.4.
Laboratory Procedures (CENTRAL laboratory)
Whole Blood Sample for 
MSI DNA Analysisb
X
Use an EDTA tube. If 
sample is not available at 
Cycle 1, it must be 
collected at a subsequent 
cycle.
Blood for Genetic 
Analysesc
X
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Study Period:
Screen
-ing
Phase
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 35
Discontin-
uation
Safety 
Follow-
up
Efficacy
Follow-
up
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each 
cycle unless otherwise 
noted.
Posttreatment Period: 
Refer to Section 8.13.3.
Scheduled Timing
Day 
-28 
to -1
At time of 
d/c
30 days 
post 
last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window:
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Blood for ctDNA 
Analysesd
X
X
X
X
X
X
Collect predose.
Blood for RNA Analyses
X
X
X
X
Blood for Plasma 
Biomarker Analysis
X
X
X
X
Blood for Serum 
Biomarker Analysis
X
X
X
X
Tumor Tissue Collection
Archival or Newly 
Obtained Tissue 
Collectione
X
X
(optional if 
recurrence)
PD L1 expression status 
must be known prior to 
randomization.
AE adverse event; aPTT activated partial thromboplastin time; CAPOX capecitabine and oxaliplatin; CBC complete blood count; ctDNA circulating tumor deoxyribonucleic acid; 
d/c discontinuation; DNA deoxyribonucleic acid; ECG electrocardiogram; ECI event of clinical interest; ECOG Eastern Cooperative Oncology Group; EDTA ethylenediaminetetraacetic acid; 
ePRO electronic patient reported outcome(s); FBR future biomedical research; FP cisplatin and 5 fluorouracil; HER2 human epidermal growth factor receptor 2; HIV human immunodeficiency 
virus; INR international normalized ratio; IEC Independent Ethics Committee; IRB Institutional Review Board; IRT interactive response technology; MSI microsatellite instability; 
PCR polymerase chain reaction; PD progressive disease; PD L1 programmed cell death ligand 1; RNA ribonucleic acid; PT prothrombin time; SAE serious adverse event; SOP standard 
operating procedure; T3 triiodothyronine; T4 thyroxine; TSH thyroid stimulating hormone; WOCBP woman/women of childbearing potential
a. Results of a test performed prior to the participant signing consent as part of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (ie, 
within 28 days prior to the first dose of study intervention). The form for authorization for release of tumor tissue may be signed prior to the screening period to allow the submission of archival 
tissue sample for determination of HER2 and PD L1 status and is expected to comply with all IRB/IEC requirements.
b. In order to perform MSI analysis by PCR, blood and tumor tissue is required. A blood sample is collected to extract normal DNA for comparison testing to tumor DNA in MSI analysis. Both 
tumor tissue and blood sample are required to perform central MSI testing by PCR.
c. Blood for genetic analyses: This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site 
if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, leftover extracted 
DNA will be stored for FBR if the participant signs the FBR consent. If the planned genetic analyses are not approved, but FBR is approved and consent is given, this sample will be collected for 
the purpose of FBR.
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Study Period:
Screen
-ing
Phase
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 35
Discontin-
uation
Safety 
Follow-
up
Efficacy
Follow-
up
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each 
cycle unless otherwise 
noted.
Posttreatment Period: 
Refer to Section 8.13.3.
Scheduled Timing
Day 
-28 
to -1
At time of 
d/c
30 days 
post 
last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window:
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
d. Following C3D1 collection, the ctDNA samples should be collected at the subsequent imaging, and then every 6 weeks (± 7 days) following the imaging schedule until the end of treatment.
e Archival or newly obtained tissue collection: Baseline tumor tissue for biomarker analysis from a newly obtained core or excisional biopsy (fine needle aspirate not adequate) or prior archival 
tissue specimen must be provided. If submitting unstained slides, the slides should be freshly cut and received at the testing laboratory within 14 days from site slide section date, otherwise a new 
specimen will be requested. It is preferred to have an archival tumor tissue sample taken up to 1 year prior to study randomization, however samples more than 1 year old are acceptable. In the 
absence of more updated histology to confirm metastatic gastric/GEJ adenocarcinoma, we do ask the investigator to confirm their clinical opinion that any recurrence represents recurrence of the 
original gastric/GEJ adenocarcinoma, and not some other new primary malignancy. If the participant signs the FBR consent, any leftover tissue that would ordinarily be discarded at the end of the 
main study will be retained for FBR. Optional biopsy may be collected at recurrence if the participant consents.
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1.3.2
Second Course (Retreatment) Phase
This phase is open only to participants who were originally randomized to receive pembrolizumab plus chemotherapy, and who meet 
the eligibility criteria for retreatment specified in Section 6.7. Procedures and activities are outlined in Table 2.
Table 2
Study Schedule of Activities Second Course (Retreatment) Phase
Study Period:
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 17
Discontin-
uation
Safety 
Follow-up
Efficacy 
Follow-
up
Survival 
Follow-up
Procedures should occur predose 
on Day 1 of each cycle unless 
otherwise noted.
Posttreatment Period: Refer to 
Section 8.13.3.
Scheduled Timing
At time of 
d/c
30 days 
post last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication 
Review
X
X
X
X
X
X
X
X
Refer to Section 8.1.5.2.
Concomitant medications: Enter 
new medications started during 
the study through the 
posttreatment Safety Follow up. 
Record concomitant medications 
beyond 30 days after treatment 
discontinuation if related to SAE 
or ECI.
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Study Period:
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 17
Discontin-
uation
Safety 
Follow-up
Efficacy 
Follow-
up
Survival 
Follow-up
Procedures should occur predose 
on Day 1 of each cycle unless 
otherwise noted.
Posttreatment Period: Refer to 
Section 8.13.3.
Scheduled Timing
At time of 
d/c
30 days 
post last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Study Intervention
Pembrolizumab
X
X
X
X
X
X
Refer to Section 6.1 for 
administration instructions.
To be administered on Day 1 of 
each cycle after all procedures/ 
assessments have been 
completed.
The participant may resume the 
same previously administered 
systemic cytotoxic 
chemotherapy at the discretion 
of the local site investigator.
Efficacy Procedures
Tumor Imaging
X
X
X
X
X
Refer to Section 8.2.1.
Within 28 days prior to 
restarting pembrolizumab
First on treatment image at 
6 weeks (+ 7 days), then every 
6 weeks (± 7 days) (or more 
frequently if clinically indicated)
Safety Procedures
Weight
X
X
X
X
X
X
X
Full Physical 
Examination 
X
X
Refer to Section 8.3.1.1.
Directed Physical 
Examination
X
X
X
X
X
Refer to Section 8.3.1.2.
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Study Period:
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 17
Discontin-
uation
Safety 
Follow-up
Efficacy 
Follow-
up
Survival 
Follow-up
Procedures should occur predose 
on Day 1 of each cycle unless 
otherwise noted.
Posttreatment Period: Refer to 
Section 8.13.3.
Scheduled Timing
At time of 
d/c
30 days 
post last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Vital Signs
X
X
X
X
X
X
X
Refer to Section 8.3.2 
Include temperature, pulse rate, 
respiratory rate, and blood 
pressure.
ECOG Performance 
Status
X
X
X
X
X
X
X
Refer to Section 8.3.6.
Within 3 days prior to restarting 
pembrolizumab.
AE/SAE Review
X


X
Refer to Section 8.4.
Poststudy Anticancer 
Therapy Status
X
X
Survival Status


X
Refer to Section 8.13.4.
Survival follow up starts after 
investigator determined PD or 
start of new anticancer 
treatment. In addition, upon 
Sponsor request, participants 
may be contacted for survival 
status at any time during the 
course of the study.
Laboratory Procedures (LOCAL laboratory)
Pregnancy Test – Serum 
or Urine (WOCBP only)
X
X
X
X
X
X
X
X
Refer to Appendix 5.
During Intervention Phase: Test 
within 24 hours for urine or 
within 72 hours for serum prior 
to restarting pembrolizumab and 
repeat prior to each treatment 
cycle, and as required by local 
guidelines.
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Study Period:
Intervention Phase (Every 3 Weeks)
End-of-
Treatment
Posttreatment
Notes
Treatment Cycle
1
2
3
4
5
6 to 17
Discontin-
uation
Safety 
Follow-up
Efficacy 
Follow-
up
Survival 
Follow-up
Procedures should occur predose 
on Day 1 of each cycle unless 
otherwise noted.
Posttreatment Period: Refer to 
Section 8.13.3.
Scheduled Timing
At time of 
d/c
30 days 
post last 
dose 
Every 
6 weeks 
post last 
dose
Every 
~12 weeks
(telephone)
Window
+3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
PT/INR and aPTT
X
Test within 10 days prior to 
restarting pembrolizumab. 
Repeat as needed for 
participants on warfarin based 
anticoagulation therapy.
Hematology (CBC with 
Differential)
X
X
X
X
X
X 
X
X
Refer to Section 8.3.4.
Within 7 days prior to restarting 
pembrolizumab.
Then up to 72 hours prior to the 
scheduled time point.
Chemistry Panel
X
X
X
X
X
X 
X
X
T3 (or Free T3), Free T4, 
and TSH
X
X
X
X 
(even 
cycles)
X
Thyroid function tests should be 
performed at Cycle 1 Day 1 and 
every other cycle starting from 
Cycle 2.
Urinalysis
X
Refer to Section 8.3.4
Within 7 days prior to restarting 
pembrolizumab
AE adverse event; aPTT activated partial thromboplastin time; CBC complete blood count; d/c discontinuation; ECI event of clinical interest; ECOG Eastern Cooperative Oncology Group; 
INR international normalized ratio; PD progressive disease; PT prothrombin time; SAE serious adverse event; T3 triiodothyronine; T4 thyroxine; TSH thyroid stimulating hormone; 
WOCBP women of childbearing potential
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2
INTRODUCTION
Gastric cancer is the fifth most common cancer in the world and is a major cause of 
cancer-related death [Ferlay, J., et al 2014]. In 2012, there were approximately 952,000 new 
cases of gastric cancer worldwide (631,000 men and 320,000 women) with 723,000 deaths 
(469,000 men and 254,000 women), making it the third-leading cause of cancer death 
globally in both sexes [Ferlay, J., et al 2014]. Gastric cancer incidence varies markedly by 
geographic region. More than 70% of cases occur in developing countries, and half the world 
total occurs in Eastern Asia. In the EU, approximately 82,000 new cases of gastric cancer 
were diagnosed in 2012, with approximately 58,000 deaths attributed to this disease. 
Corresponding numbers in the US showed an estimated 21,000 new cases of gastric cancer 
with nearly 12,000 deaths from this disease.
2.1
Study Rationale
Accumulating evidence demonstrates that combining the PD-1 targeted mAb pembrolizumab 
with current standard of care cytotoxic chemotherapy for the treatment of advanced, 
unresectable and/or metastatic cancer improves clinical outcomes [Robert, C., et al 2015] 
[Gandhi, L., et al 2018]. This has been most recently demonstrated by the randomized, 
double-blind, Phase 3 KEYNOTE-189 study which showed that addition of pembrolizumab 
to standard cytotoxic chemotherapy in the first-line treatment setting of metastatic 
non-squamous non-small cell lung carcinoma (NSCLC) (without sensitizing EGFR or ALK
mutations) resulted in statistically significant improvements in OS and PFS. KEYNOTE-189 
enrolled patients regardless of PD-L1 status. In this PD-L1 “all-comer” population of patients 
with metastatic non-squamous NSCLC, the addition of pembrolizumab to standard cytotoxic 
chemotherapy was associated with a 48% reduction in the risk of disease progression and a 
51% reduction in the risk of death when compared to chemotherapy plus placebo. The 
occurrence of Grade 3 or higher toxicities occurred with similar frequency in both the 
pembrolizumab and placebo arms of the study [Gandhi, L., et al 2018].
Systemic chemotherapy is the mainstay of treatment for advanced and metastatic gastric 
cancer (see NCCN [National Comprehensive Cancer Network 2013] and ESMO 
[Cunningham, D. 2008] treatment guidelines). Platinum/fluoropyrimidine doublet regimens 
containing cisplatin or oxaliplatin and 5-FU or capecitabine are the most commonly used 
regimens worldwide as standard first-line chemotherapy regimens for patients with 
metastatic gastric cancer. Though cytotoxic chemotherapy alone is the mainstay of treatment, 
newer molecularly targeted immunotherapy agents have been added to standard 
chemotherapy regimens to improve clinical outcomes in advanced, metastatic gastric and 
GEJ adenocarcinoma.
The anti-PD-1 monoclonal antibody pembrolizumab has demonstrated durable 
immune-mediated antitumor activity in patients with advanced gastric cancer.
Clinical proof of concept demonstrating activity of pembrolizumab in participants with 
advanced gastric cancer came from Cohort D of the Phase 1b KEYNOTE-012 study. This 
cohort enrolled 39 participants with PD-L1 positive advanced gastric or GEJ adenocarcinoma
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[Muro, K., et al 2016]. Eight of 39 participants had an OR by RECIST 1.1 using BICR for an 
ORR of 22% (95% CI: 10, 39). 
The antitumor activity of pembrolizumab in locally advanced, unresectable and/or metastatic 
gastric or GEJ adenocarcinoma was further characterized in the Phase 2 KEYNOTE-059 
study which involved 3 separate cohorts of participants. 
Cohort 1 tested pembrolizumab monotherapy as third-line and above treatment of advanced 
gastric/GEJ adenocarcinoma, regardless of PD-L1 expression. In this all-comer population of 
highly pre-treated participants for whom there were no alternative effective agents, 
pembrolizumab monotherapy demonstrated durable objective responses with a clinically 
meaningful ORR of 12%. A higher response rate (16%) was observed in the PD-L1 positive 
population [Wainberg, Z. A., et al 2017]. Based on data from KEYNOTE-059, 
pembrolizumab received accelerated approval by the US FDA in September 2017, for 
treatment of third-line and above patients with tumors expressing PD-L1 (CPS ≥1) assessed 
by an FDA-approved test. 
Cohorts 2 and 3 evaluated pembrolizumab in the first-line treatment setting among 
participants with advanced, unresectable and/or metastatic gastric and GEJ adenocarcinoma. 
In both cohorts, ORR was assessed according to RECIST 1.1 by BICR. 
Cohort 2 (n 25) enrolled participants regardless of PD-L1 expression; these participants
received the combination of pembrolizumab and standard of care cytotoxic chemotherapy 
consisting of cisplatin plus a fluoropyrimidine. This combination yielded an ORR of 60% 
(95% CI: 39, 79) and a DCR of 80% (95% CI: 59, 93). Responses were observed regardless 
of PD-L1 status. Median OS in Cohort 2 was 13.8 months (95% CI: 8.6, NR) [Wainberg, Z. 
A., et al 2017]. By historical comparison, this OS result compares favorably with that seen in 
the ML17032 study, which administered cisplatin and 5-FU (treatment regimen known as FP)
or cisplatin and capecitabine (treatment regimen known as XP) alone to patients with 
advanced gastric cancer. Median OS for patients on the ML17032 study who received FP or 
XP alone was 9.3 months and 10.5 months, respectively [Ryu, M. H. and Kang, Y. K. 2009].
Cohort 3 (n 31) enrolled participants with PD-L1 positive [CPS ≥1] gastric/GEJ 
adenocarcinoma; these participants received pembrolizumab monotherapy which yielded an 
ORR of 26% (95% CI: 12, 45) and a median OS of 20.7 months (9.2, 20.7) [Wainberg, Z. A., 
et al 2017].
KEYNOTE-061 was a global Phase 3 study of single-agent pembrolizumab versus 
single-agent paclitaxel in the second-line treatment setting of advanced gastric and GEJ 
adenocarcinoma that progressed after first-line therapy with both a platinum and 
fluoropyrimidine agent. The study initially enrolled participants regardless of PD-L1 status. 
In the most recent analysis of this study [Fuchs, C. S., et al 2018], 67% of enrolled 
participants had PD-L1 CPS ≥1. The ORR associated with single-agent pembrolizumab was 
15.8% (95% CI: 11.0, 21.7); this compared favorably with the ORR associated with 
paclitaxel of 13.6% (95% CI: 9.1, 19.1). Median DOR for pembrolizumab and paclitaxel was 
18.0 months (1.4, 26.0) and 5.2 months (1.3, 16.8), respectively. Median OS, the primary 
endpoint, was 9.1 months with pembrolizumab versus 8.3 months with paclitaxel (HR 0.82, 
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1-sided p 0.042). In participants with previously treated advanced and/or metastatic gastric 
and GEJ adenocarcinoma and PD-L1 CPS ≥1, pembrolizumab reduced numerically, but not 
statistically, the risk of death by 18% versus paclitaxel. The results from KEYNOTE-061, 
taken together with those from KEYNOTE-059, clearly indicate pembrolizumab is active in 
gastric cancer.
Pembrolizumab has been granted accelerated approval for ‘third-line and above’ treatment of 
patients with recurrent, locally advanced or metastatic gastric or GEJ adenocarcinoma whose 
tumors express PD-L1 (CPS ≥1), as determined by an FDA-approved test. Patients are 
required to have evidence of disease progression on or after 2 or more prior lines of therapy, 
including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, 
HER2/neu-targeted therapy. This indication is approved under accelerated approval based on 
tumor response rate and durability of response.
This multicenter study will determine antitumor activity and safety of pembrolizumab in 
combination with standard treatment (FP or capecitabine and oxaliplatin [treatment regimen 
known as CAPOX]) as first-line therapy in participants with advanced, unresectable 
metastatic gastric or GEJ adenocarcinoma. Participants will be eligible regardless of PD-L1 
expression status to ensure inclusion of the entire spectrum of first-line gastric cancers. As 
per internal MSD data, approximately 70% of participants are predicted to have PD-L1 
positive tumor expression.
The study is being powered for biomarker-enriched populations PD-L1 CPS ≥10 and MSI-H. 
The rationale for this change emanates from recently presented data showing clinically 
meaningful improvements in ORR and favorable trends in PFS and OS among CPS ≥10 
patients with the addition of pembrolizumab to standard of care cytotoxic chemotherapy in 
the first-line treatment setting of advanced/metastatic gastric and GEJ adenocarcinoma 
[Tabernero, J., et al 2019]. Internal unpublished data has shown a remarkable treatment effect 
for the combination of pembrolizumab and SOC chemotherapy versus chemotherapy alone 
as first-line treatment of MSI-H advanced/metastatic gastric/GEJ adenocarcinoma.
2.2
Background
PD-1 is a key immune checkpoint receptor that is expressed by activated T cells. Tumors use 
the PD-1 pathway to evade immune surveillance. The PD-1 receptor, on the surface of 
activated T cells, binds to its ligands PD-L1 and PD-L2, which are expressed on tumor cells, 
thereby causing immunosuppression and preventing the immune system from rejecting the 
tumor.
Pembrolizumab is a potent humanized IgG4 mAb with high specificity to the PD-1 receptor, 
thus inhibiting its interaction with PD-L1 and PD-L2. Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for 
advanced malignancies. 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+ 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 CD28 and 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 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 CD3ζ, PKCθ, and ZAP70, which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in gastric and GEJ adenocarcinoma.
Pembrolizumab has been approved by the US FDA for multiple indications, including 
treatment of advanced, metastatic melanoma, cervical cancer, primary mediastinal B-cell 
lymphoma, NSCLC, head and neck squamous cell carcinoma, urothelial carcinoma, gastric 
cancer as well as relapsed/refractory classical Hodgkin Lymphoma and MSI-H (mismatch 
repair deficient) malignancies. For more information, refer to the Investigator’s Brochure.
2.2.2
Preclinical and Clinical Studies
Preclinical studies in mouse models have shown that administration of antibodies blocking 
the PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and leads 
ultimately to tumor rejection. Murine PD-1 or antimouse PD-L1 antibodies have 
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demonstrated antitumor responses as a monotherapy in models of squamous cell carcinoma, 
pancreatic carcinoma, melanoma, and colorectal carcinoma. Blockade of the PD-1 pathway 
effectively promoted CD8+ T-cell infiltration into the tumor and generation of IFNγ, 
granzyme B and perforin, indicating that the mechanism of action involved local infiltration 
and activation of effector T-cell function in vivo [Ropponen, K. M., et al 1997] [Dudley, M. 
E., et al 2005] [Hunder, N. N., et al 2008] [Pölcher, M., et al 2010] [Okazaki, T., et al 2001] 
[Greenwald, R. J., et al 2005]. Studies have confirmed the in vivo efficacy of PD-1 blockade 
as monotherapy as well as in combination with chemotherapy in syngeneic mouse tumor 
models (refer to the Investigator’s Brochure).
Clinical studies have demonstrated efficacy of pembrolizumab in participants with advanced 
melanoma, NSCLC, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, 
triple-negative breast cancer, and gastric adenocarcinoma.
2.2.3
Ongoing Clinical Studies of Pembrolizumab in Malignancies
Clinical studies involving pembrolizumab are currently ongoing in participants with a 
number of advanced solid tumor and hematologic malignancies (Table 3). These studies 
include, but are not limited to, advanced melanoma, NSCLC, and gastric and GEJ 
adenocarcinomas. 
Table 3
Ongoing Clinical Studies of Pembrolizumab in the Gastric Cancer Indication
Study
Phase
Intervention
KN012
1B
Pembrolizumab in PD-L1 positive participants
KN059
2
Pembrolizumab (Cohort 1, 3L treatment), pembrolizumab plus cisplatin and 5-FU 
or capecitabine (Cohort 2, 1L treatment), pembrolizumab (Cohort 3, 1L treatment)
KN061
3
Pembrolizumab versus paclitaxel, 2L treatment
KN062
3
Pembrolizumab versus pembrolizumab plus FP, placebo plus FP, 1L treatment in 
PD-L1 positive participants
KN063
3
Pembrolizumab versus paclitaxel, 2L treatment
KN585
3
3 cycles of neoadjuvant combination treatment, followed by potentially curative 
resection, then adjuvant treatment consisting of an additional 3 cycles of 
combination treatment and 11 cycles of monotherapy
KN811
3
Pembrolizumab plus trastuzumab plus FP/CAPOX versus placebo plus 
trastuzumab plus FP/CAPOX; 1L treatment of HER2-positive advanced 
metastatic gastric/GEJ adenocarcinoma
1L first line; 2L second line; 3L third line; 5 FU 5 fluorouracil; CAPOX capecitabine and oxaliplatin; FP cisplatin 
and 5 fluorouracil; GEJ gastroesophageal junction; HER2 human epidermal growth factor receptor 2; KN KEYNOTE; 
PD L1 programmed cell death ligand 1
For study details, refer to the Investigator’s Brochure and clinicaltrials.gov.
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2.2.4
Information on Other Study-related Therapy
Despite a large number of randomized studies, there is no globally accepted standard 
first-line chemotherapy regimen in HER2 negative, advanced, unresectable and/or metastatic 
gastric and GEJ adenocarcinoma. In general, combination chemotherapy regimens provide 
higher response rates than do single agents. Many patients are recommended to receive a 
fluoropyrimidine-platinum doublet over more toxic triplet chemotherapeutic regimens. 
The fluoropyrimidine/platinum doublet combination is a common first-line therapy for 
metastatic gastric cancer and it is considered “preferred” by the NCCN Gastric Cancer 
Guideline committee [National Comprehensive Cancer Network 2016]. 
Fluoropyrimidine/platinum doublet regimens containing 5-FU or capecitabine and cisplatin 
or oxaliplatin are recognized worldwide as standard first-line chemotherapy regimens for 
patients with metastatic gastric and GEJ adenocarcinoma. 
The ML17032 study was a randomized, Phase 3 study that compared the combination of 
cisplatin and capecitabine (XP) to the combination of cisplatin and 5-FU (FP) as first-line 
treatment in patients with previously untreated advanced gastric cancer [Ryu, M. H. and 
Kang, Y. K. 2009]. No difference was seen in median PFS and the results of this study 
suggest that capecitabine is at least as effective as 5-FU in the treatment of patients with 
advanced gastroesophageal cancers.
The REAL-2 study was a randomized, multicenter, Phase 3 study comparing capecitabine 
with 5-FU and oxaliplatin with cisplatin in 1002 patients with advanced esophagogastric 
cancer [Cunningham, D., et al 2008]. Results from this study suggest that capecitabine and 
oxaliplatin are as effective as 5-FU and cisplatin, respectively, in patients with previously 
untreated esophagogastric cancer.
A meta-analysis of the REAL-2 and ML17032 studies suggested that OS was superior in the 
654 patients treated with capecitabine-based combinations compared with the 664 patients 
treated with fluorouracil-based combinations, although no statistically significant difference 
in PFS between the treatment groups was seen [Okines, A. F., et al 2009].
Most commonly used doublet regimens are XP, FP, CAPOX, and 5-FU/oxaliplatin (known 
as FOLFOX). Choices among these regimens are typically based on patients’ general 
medical condition and comorbidities in consideration of the different toxicity profiles of the 
regimens. This practice pattern is supported by global consensus guidelines for treatment of
advanced gastric cancer which recommend use of any of the doublet regimen discussed 
above [National Comprehensive Cancer Network 2016] [Cunningham, D. 2008].
FP and CAPOX have been studied extensively in advanced gastric cancer and are routinely 
used in clinical practice globally. These 2 regimens are expected to have similar efficacy, and 
these regimens will allow investigators a choice based on each patient’s medical condition.
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from study 
intervention during participation, as clinical studies are designed to provide information 
about the safety and effectiveness of an investigational medicine.
The safety and promising efficacy data described above from multiple studies of 
pembrolizumab, and chemotherapy in the target population, indicate a strong risk:benefit 
ratio.
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying Investigator’s Brochure and ICF documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
In male and female participants at least 18 years of age with human epidermal growth factor 
receptor 2 (HER2) negative, previously untreated, unresectable or metastatic gastric or 
gastroesophageal junction (GEJ) adenocarcinoma:
Objectives
Endpoints
Primary
•
Objective: To compare the OS of the 
participants following administration of 
pembrolizumab versus placebo when each is
combined with chemotherapy
-
Hypothesis (H1): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for OS, in participants 
with PD-L1 CPS ≥10 
-
Hypothesis (H2): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for OS, in participants 
with PD-L1 positive tumors defined by 
CPS ≥1
-
Hypothesis (H3): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for OS, in all participants
•
OS: The time from randomization 
to death due to any cause
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Objectives
Endpoints
Secondary
•
Objective: To compare the PFS per RECIST 
1.1, as assessed by BICR, following 
administration of pembrolizumab versus 
placebo when each is combined with 
chemotherapy
-
Hypothesis (H4): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for PFS, in participants 
with PD-L1 positive tumors defined by 
CPS ≥10
-
Hypothesis (H5): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for PFS, in participants 
with PD-L1 positive tumors defined by 
CPS ≥1
•
Hypothesis (H6): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for PFS, in all participants
•
PFS: The time from randomization 
to the first documented disease 
progression or death due to any 
cause, whichever occurs first.
•
Objective: To compare the ORR per 
RECIST 1.1, as assessed by BICR, following 
administration of pembrolizumab versus 
placebo when each is combined with 
chemotherapy
-
Hypothesis (H7): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for ORR, in participants 
with PD-L1 positive tumors defined by 
CPS ≥10 
-
Hypothesis (H8): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for ORR, in participants 
with PD-L1 positive tumors defined by 
CPS ≥1 
-
Hypothesis (H9): Pembrolizumab plus 
chemotherapy is superior to placebo plus 
chemotherapy for ORR, in all 
participants
•
OR: CR or PR
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Objectives
Endpoints
•
Objective: To describe the DOR per RECIST 
1.1, as assessed by BICR, following 
administration of pembrolizumab versus 
placebo when each is combined with 
chemotherapy in participants with PD-L1
CPS ≥10,  PD-L1 CPS ≥1, and in all 
participants
•
DOR: The time from first response 
(CR or PR) to subsequent disease 
progression, or death from any 
cause, whichever occurs first
•
Objective: To evaluate the safety and 
tolerability of pembrolizumab plus 
chemotherapy versus placebo plus 
chemotherapy
•
AEs
•
Study intervention discontinuation 
due to AEs
Tertiary/Exploratory
•
Objective: To compare the changes from 
baseline in health-related quality-of-life 
assessments, using the EORTC QLQ-C30 
and the EORTC QLQ-STO22, following 
administration of pembrolizumab versus 
placebo when each is combined with 
chemotherapy
•
EORTC QLQ-C30 scores
•
EORTC QLQ-STO22 scores
•
Objective: To characterize utilities, using the 
EQ-5D™, following administration of 
pembrolizumab versus placebo when each is
combined with chemotherapy
•
EuroQoL EQ-5D-5L scores
•
To compare PFS and ORR using modified 
RECIST 1.1 for iRECIST, as assessed by the 
investigator, following administration of 
pembrolizumab versus placebo when each is 
combined with chemotherapy
•
PFS using iRECIST
•
OR using iRECIST
The study will be considered to have met its primary objective if at least 1 primary 
hypothesis is statistically significant.
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multicenter, double-blinded, 
efficacy and safety study of pembrolizumab or placebo in combination with chemotherapy 
(FP or CAPOX) in participants with previously untreated, HER2 negative, advanced gastric 
or GEJ adenocarcinoma.
Approximately 1542 participants will be randomized with approximately 771 participants in 
each treatment arm to receive pembrolizumab or placebo in combination with chemotherapy. 
After enrollment of the Global portion of the study is complete, the study may remain open 
to enrollment in China mainland alone until the target number of participants from China
mainland have been enrolled to meet local regulatory requirements.
Participants will be stratified by geographic region, PDL1 tumor expression status (CPS <1, 
≥1), and combination chemotherapy (FP or CAPOX). The study is double-blind with respect 
to randomized study intervention (pembrolizumab/placebo). The investigator has 2 choices 
of combination chemotherapy regimen, FP or CAPOX, which must be chosen prior to 
randomization in the study. Participants should continue on the type of chemotherapy 
regimen chosen prior to randomization throughout the study. Exceptions may be permitted 
after consultation with the Sponsor.
Participation in this study will be dependent upon supplying a tumor tissue specimen. Newly 
obtained endoscopic biopsy or core biopsy of a metastatic site, if obtained as part of normal 
clinical practice, is preferred to archived samples. Both formalin solution and FFPE block 
specimens are acceptable. If submitting unstained slides, the slides should be freshly cut and 
received at the testing laboratory within 14 days from site slide section date, otherwise a new 
specimen will be requested. Only participants whose tumors do not express HER2 will be 
eligible for randomization in this study. The specimen will also be evaluated for PD-L1 
expression status, and for other biomarker analyses if local laws or regulations permit.
Study intervention administration will begin on Day 1 of each 3-week dosing cycle. Study 
interventions should begin on the day of randomization or as close as possible to the date on 
which the participant is allocated/assigned.
Participants will have baseline imaging performed at screening, and the first on-study 
imaging will be done at Week 6 (+ 7 days) after randomization. No early window is allowed 
for the initial scheduled Week 6 visit. Subsequently, imaging will be performed every 
6 weeks (± 7 days) after randomization, independent of any treatment delays, to assess 
response to treatment using RECIST 1.1. Study intervention administration will continue
until first evidence of PD, any study intervention-related toxicity specified as a reason for 
permanent discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6, intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the participant, noncompliance with study treatment or 
procedure requirements, administrative reasons requiring cessation of treatment, or until the 
participant has received 35 administrations (approximately 2 years) of treatment. Participants 
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who attain an investigator-determined confirmed CR may consider stopping study 
intervention after receiving at least 8 study intervention administrations in total and at least 
2 additional administrations of study intervention (including 2 doses of pembrolizumab or 
matching placebo and at least 80% of the planned doses of combination chemotherapy) 
beyond the date when the initial CR was declared. Participants who are randomized to 
placebo are not allowed to crossover to pembrolizumab treatment.
RECIST 1.1 responses as assessed by BICR will be used for the efficacy endpoint of PFS. 
RECIST 1.1 will be used by the local site for treatment decisions until verification of PD by 
the iCRO. Treatment should continue until PD has been verified by BICR. Regardless of 
whether PD is verified, if the investigator considers the participant has progressed, but elects 
to implement modified RECIST 1.1 for iRECIST (Section 8.2.1.6, Appendix 8), the 
investigator will assess for confirmation of progression by iRECIST at subsequent time 
points. Images should continue to be submitted to the BICR.
Adverse events will be monitored throughout the study and graded in severity according to 
the guidelines outlined in the NCI CTCAE version 4.0.
Participants who stopped study intervention after achieving SD or better may be eligible to 
receive additional pembrolizumab for up to 17 cycles if they experience radiographic disease 
progression while off study intervention, according to the criteria in Section 6.7. This 
retreatment is termed the Second Course Phase of this study. Participants are unblinded 
individually upon disease progression while off study intervention, and are able to participate 
in the Second Course Phase only if they were receiving pembrolizumab originally, and if the 
study remains open. An objective response or disease progression that occurs during the 
Second Course Phase for a participant will not be counted as an event for the primary 
analysis of either endpoint in this study. The decision to re-treat will be at the discretion of 
the investigator only if no cancer treatment was administered since the last dose of study 
intervention and the participant still meets the safety parameters listed in the 
Inclusion/Exclusion criteria (refer to Section 6.7 for further details). During this phase, the 
participant may resume the same previously administered systemic cytotoxic chemotherapy 
at the discretion of the local site investigator.
After the end of treatment, each participant will have a 30-day follow-up safety assessment 
for AE monitoring (refer to Section 8.4.1 for time periods for reporting of SAEs and 
pregnancy). Participants who discontinue treatment for reasons other than PD will have 
posttreatment follow-up imaging for disease status until PD, initiating a nonstudy cancer 
treatment, withdrawing consent, or becoming lost to follow-up. All participants will be 
contacted approximately every 12 weeks, or more often as needed, for OS until death, 
withdrawal of consent, or the end of the study, whichever comes first.
One interim efficacy analysis is planned in this study. Details about interim analyses are 
provided in Section 9.7. An independent external DMC will monitor the safety and efficacy 
of this study.
This study will be conducted in conformance with GCP.
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After enrollment of the Global portion of the study is complete, the study may remain open 
to enrollment in a possible China mainland extension until the target number of participants 
in China mainland has been enrolled to meet local regulatory requirements. A possible
extension portion of the study will be identical to the global study (eg, inclusion and 
exclusion criteria, study endpoints, primary and secondary objectives, and study procedures). 
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
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint in this study is OS.
OS is the gold standard for a “hard endpoint” in clinical studies in the area of oncology. 
However, OS results, especially in the first-line setting, are often confounded by subsequent 
therapy. In the United States/European Union, gastric cancer is a rare tumor type and most 
patients have advanced or metastatic disease at the time of diagnosis. Because of the multiple 
companies developing this class of drugs for gastric cancer, it is expected that a significant
proportion of control group participants will subsequently be treated with alternative 
immunotherapy outside of this protocol.
Secondary efficacy endpoints include PFS, OR and DOR.
In this study, PFS is to be assessed by BICR. The use of BICR and RECIST 1.1 to assess
PFS is typically considered acceptable by regulatory authorities. Images will be read by an
iCRO blinded to treatment assignment to minimize bias in the response assessments. In 
addition, the final determination of radiologic progression will be based on the central 
assessment of progression, rather than a local site investigator/radiology assessment. 
Real-time verification of radiologic progression, as determined by BICR, will be 
communicated to the site.
The largest meta-analysis (36 studies, 10,484 patients) demonstrated that PFS and time to 
progression were acceptable surrogate markers of OS in patients with advanced gastric 
cancer [Shitara, K., et al 2012]. As such, improvement in PFS, provided the results are 
meaningful, provides evidence for clinical benefit. RECIST 1.1 by BICR will be used to 
determine the dates of progression as this methodology is accepted by regulatory authorities.
OR by RECIST 1.1 criteria, as assessed by BICR, is considered evidence of efficacy and is a 
secondary endpoint for this study. Substantial improvement of OR that is accompanied by 
duration of response will be considered a clinically important measure of benefit. The ORR 
will be calculated as the proportion of participants with OR.
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DOR by RECIST 1.1 criteria, as assessed by BICR, is a commonly accepted endpoint by 
both regulatory authorities and the oncology community to assess durability of responses to 
oncology treatments.
RECIST 1.1 will be used when assessing images for efficacy measures. Although the original 
RECIST 1.1 publication recommends a maximum of 5 target lesions in total and 2 per organ, 
this protocol has implemented an adjustment to RECIST 1.1 to allow a maximum of 10 target 
lesions in total and 5 per organ, if a larger number of target lesions is needed to adequately 
represent the tumor burden. Refer to (Section 8.2.1.5) for additional detail.
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.1.6). 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.
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 .
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of adverse events (AEs)/serious adverse events (SAEs); and changes 
in vital signs and laboratory values. AEs will be assessed as defined by CTCAE, Version 4.0.
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4.2.1.3
Patient-reported Outcomes
The EORTC QLQ-C30 and EuroQoL-5D (EQ-5D) patient-reported outcomes (PROs) are not 
pure efficacy or safety endpoints because they are affected by both disease progression and 
treatment tolerability.
4.2.1.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer-specific, health-related, quality-of-life 
(QoL) instrument, which contains 30 items and measures 5 functional dimensions (physical, 
role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 
6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-
C30 is a psychometrically and clinically validated instrument appropriate for assessing QoL 
in oncology studies [Aaronson, N. K., et al 1993].
4.2.1.3.2
EORTC QLQ-STO22
The EORTC QLQ-STO22 is a disease-specific questionnaire developed and validated to 
address measurements specific to gastric cancer. It is one of multiple disease-specific 
modules developed by the EORTC QLG  designed for use in clinical studies, to be 
administered in addition to the QLQ-C30 to assess disease-specific treatment measurements. 
It contains 22 items with symptoms of dysphagia (4 items), pain or discomfort (3 items), 
upper GI symptoms (3 items), eating restrictions (5 items), emotional (3 items), dry mouth, 
hair loss, and body image.
4.2.1.3.3
EuroQoL EQ-5D
The EuroQoL-5D (EQ-5D) is a standardized instrument for use as a measure of health 
outcome and will provide data to develop health utilities for use in health economic analyses 
[Rabin, R. and de Charro, F. 2001]. The 5 health state dimensions in the EQ-5D include the 
following: mobility, selfcare, 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 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].
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4.2.2
Rationale for the Use of Comparator/Placebo
4.2.2.1
Rationale for the Use of Placebo
The placebo control is necessary to ensure double-blinding since the presence/absence of 
extra infusions would identify treatment assignment. The placebo control also allows 
statistical isolation of the true effect associated with pembrolizumab combination therapy 
from the placebo effect associated with the combination treatment paradigm.
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4.2.2.2
Rationale for the Use of FP and CAPOX
Systemic chemotherapy is the mainstay of treatment for advanced and metastatic gastric 
cancer as evidenced by treatment guidelines issued by the NCCN and ESMO [National 
Comprehensive Cancer Network 2013] [Cunningham, D. 2008]. 
Despite a large number of randomized studies, there is no globally accepted standard 
first-line chemotherapy regimen in HER2 negative, advanced, unresectable and/or metastatic 
gastric and GEJ adenocarcinoma. In general, combination chemotherapy regimens provide 
higher response rates than do single agents. Many patients are recommended to receive a 
fluoropyrimidine-platinum doublet over more toxic triplet chemotherapeutic regimens. 
Platinum/fluoropyrimidine doublet regimens containing cisplatin or oxaliplatin and 5-FU or 
capecitabine are recognized worldwide as standard first-line chemotherapy regimens for
advanced, unresectable, and/or metastatic gastric and GEJ adenocarcinoma. These 
platinum/fluoropyrimidine doublet regimens are considered “preferred” by the NCCN 
Gastric Cancer Guideline committee [National Comprehensive Cancer Network 2016]. 
Most commonly used doublet regimens are XP, FP, CAPOX, and FOLFOX. Choices among 
these regimens are based on a patient’s general medical condition and comorbidities in 
consideration of the different toxicity profiles of the regimens. This practice pattern is 
supported by global consensus guidelines regarding the treatment of advanced gastric cancer 
which recommend use of any of the doublets discussed above [National Comprehensive 
Cancer Network 2016] [Cunningham, D. 2008].
The current study will use FP or CAPOX as the standard of care backbone regimens.
Investigators will have a choice between FP and CAPOX. Use of infusional 5-FU in this 
study provides an alternative fluoropyrimidine treatment to those participants unable to take 
oral capecitabine.
4.3
Justification for Dose
4.3.1
Justification for Pembrolizumab 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
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•
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 non-small 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-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.
4.3.2
Justification for Chemotherapy “Backbone” Dose
FP Regimen
Dose determination for cisplatin and 5-FU in the FP regimen is in accordance with 
prescribing information for gastric cancer per their package inserts. In this study, the dose 
regimen will be cisplatin (80 mg/m2) administered on Day 1 of each treatment cycle (Q3W)
plus 5-FU (800 mg/m2/day) administered as a continuous IV infusion from Day 1 to Day 5 of 
each treatment cycle (Q3W).
The safety and tolerability of pembrolizumab in combination with cisplatin and 
fluoropyrimidine (capecitabine or 5-FU) was evaluated in KEYNOTE-059 Cohort 2. Of the 
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18 participants treated, 64% were men, and the median age was 64 years old. There were no 
treatment-related deaths and only 3 participants (12%) discontinued treatment because of 
chemotherapy-related adverse events (stomatitis [Grade 3], hypoacusis [Grade 2], and
increased creatinine level [Grade 1]); none of the AEs was considered by the investigator to 
be related to pembrolizumab [Wainberg, Z. A., et al 2017]. No participants discontinued 
treatment because of pembrolizumab-related AEs. Twenty-five participants (100%) 
experienced treatment-related AEs of any grade. Nineteen participants (76%) experienced 
Grades 3 to 4 treatment-related AEs; the most common treatment-related Grade 3 to 4 AEs 
were neutropenia, stomatitis, anemia, thrombocytopenia, decreased appetite, and fatigue. 
Immune-related AEs of any grade occurred in 12 participants (48%); the majority of these 
were Grades 1 to 2. The most common immune-mediated AEs were hypothyroidism and 
palmar-plantar erythrodysesthesias. There were no Grade 4 to 5 immune-mediated or 
infusion reactions. Based on these data, the combination of pembrolizumab, cisplatin, and 
fluoropyrimidine (capecitabine or 5-FU) has a manageable safety profile. 
CAPOX Regimen
Dose determination for capecitabine and oxaliplatin in the CAPOX regimen is in accordance 
with prescribing information for gastric cancer per their package inserts. In this study, the 
dose regimen will be oxaliplatin (130 mg/m2 IV) on Day 1 of each treatment cycle (Q3W) 
plus capecitabine (1000 mg/m2 orally twice daily) on Days 1 to 14 of each treatment cycle
(Q3W).
The combination of capecitabine, oxaliplatin, and pembrolizumab is currently being 
evaluated in multiple studies throughout the United States. In an investigator-initiated study 
conducted at Memorial Sloan Kettering Cancer Center in the United States (NCT02954536), 
pembrolizumab was combined with trastuzumab, oxaliplatin, and either 5-FU or 
capecitabine. This study was initiated in November 2016. Based on data from 18 participants
dosed thus far, the combination appears safe, without dose-limiting toxicities or drug-related 
Grade 4 or Grade 5 AEs. The only drug-related Grade 3 events reported were hypokalemia
(2), anemia (2), increased alanine aminotransferase (2), decreased lymphocytes (1), 
dehydration (1), nausea (1), maculopapular rash (1), diarrhea (1), and hyponatremia (1). 
None of the 18 participants has discontinued treatment due to therapy-related AEs. In 
addition, promising anticancer activity was observed, with 14 of 18 patients achieving 
objective responses (internal MSD data). A second investigator-initiated study at Duke 
(KeyLargo study) is a single-arm, Phase 2 study of the combination of pembrolizumab, 
oxaliplatin, and capecitabine in the first-line treatment of metastatic/recurrent 
adenocarcinoma of the esophagus or stomach. This study began enrolling participants in 
January 2018. The doses of capecitabine, oxaliplatin, and pembrolizumab used in the 
KeyLargo study are identical to those in this clinical study.
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 telephone-call or visit, withdraws consent from the study, or 
is lost to follow-up (ie, the participant is unable to be contacted by the investigator).
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Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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
Male/Female participants with previously untreated, HER2 negative, advanced gastric or 
GEJ adenocarcinoma of at least 18 years of age will be enrolled in this study.
As stated in the Code of Conduct for Clinical Trials (Appendix 10.1.1), this study includes
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Sites in France, Germany, Japan, Italy, the Czech Republic and the UK should refer to 
Appendix 7, Country-specific Requirements, for clarifications regarding specific inclusion 
and exclusion criteria.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable 
or metastatic gastric or GEJ adenocarcinoma, with known PD-L1 expression status.
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2. Has HER2 negative cancer.
HER2 negative is defined as: IHC (0, or 1+) or FISH negative (HER2:CEP17 ratio <2
with an average HER2 copy number <4.0 signals/cell). FISH can be replaced with locally 
available ISH methods acceptable as per institutional guidelines (eg, DISH).
Demographics
3. Is Male or Female.
4. Is at least 18 years  of age at the time of providing documented informed consent (or 
acceptable age according to local regulations, whichever is older).
Male Participants
5. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 95 days after the last dose of chemotherapy:
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 5]) as detailed below:
•
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
Contraceptive use by men 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 drugs is more stringent than the requirements above, the 
local label requirements should be followed.
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Female Participants
6. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and 
at least one of the following conditions applies 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 using 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 180 days after the last dose of chemotherapy or 120 days after the last dose of 
pembrolizumab, whichever is last, 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 investigator should evaluate the potential for contraceptive method failure 
(ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention. 
-
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours for urine or within 72 hours for serum
before the first dose of study intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
-
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.5.
-
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
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 drugs is more stringent than the 
requirements above, the local label requirements should be followed.
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Informed Consent
7. The participant (or legally acceptable representative) has provided 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
8. Has measurable disease per RECIST 1.1 as assessed by investigator assessment. Lesions 
situated in a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
Note: The exact same image acquisition and processing parameters should be used 
throughout the study.
9. Has provided archival tumor tissue sample or newly obtained core, incisional or 
excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are 
preferred to slides. Newly obtained biopsies are preferred to archived tissue.
Note: If submitting unstained cut slides, newly cut slides should be received by the 
testing laboratory within 14 days from the date slides are cut (details pertaining to tumor 
tissue submission can be found in the Procedures Manual).
10. Has provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis.
Note: Tumor PD-L1 expression status must be available prior to randomization.
11. Has provided tumor tissue sample for MSI biomarker analysis. 
12. Has an ECOG performance status of 0 or 1 (within 3 days prior to the start of study 
intervention) (refer to Appendix 9).
13. Has adequate organ function, as defined in the following table (Table 4). Specimens must 
be collected within 10 days prior to the start-of-study intervention.
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Table 4
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 × ULN OR
≥60 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Cisplatin and oxaliplatin product label should be followed 
for acceptable creatinine clearance rates.
Participants are required to have a minimum creatinine 
clearance (CrCl) of 30 mL/min.
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Albumin
≥ 2.5 g/dL
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time 
(aPTT)
≤1.5 × ULN unless participant is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR = glomerular filtration rate; ULN = upper 
limit of normal.
1Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
2Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has squamous cell or undifferentiated gastric cancer.
2. Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior 
to randomization, or anticipation of the need for major surgery during the course of study 
intervention.
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Note: If participant has had major surgery, they must have recovered adequately from the 
toxicity and/or complications from the treatment prior to starting study intervention.
3. Has pre-existing peripheral neuropathy >Grade 1.
4. Is a WOCBP who has a positive urine pregnancy test within 24 hours for urine or within 
72 hours for serum prior to randomization or treatment allocation (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 screening pregnancy test and 
the first dose of study intervention, another pregnancy test (urine or serum) must be 
performed and must be negative in order for participant to start receiving study 
intervention. 
Prior/Concomitant Therapy
5. Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ 
cancer. Participants may have received prior neoadjuvant and/or adjuvant therapy as long
as it was completed at least 6 months prior to randomization.
6. 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 coinhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
7. Has received prior systemic anticancer therapy including investigational agents within 
4 weeks prior to randomization.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline.
8. Has received prior radiotherapy within 2 weeks prior to start of study intervention. 
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 noncentral nervous system (CNS)
disease.
9. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of 
study intervention. Administration of killed vaccines is allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
10. 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 the first dose of study 
intervention.
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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.
Diagnostic Assessments
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study intervention.
12. Has a known additional malignancy that is progressing or has required active treatment 
within the past 5 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
13. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
intervention.
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
15. 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.
16. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
17. Has an active infection requiring systemic therapy.
18. Has a known history of HIV infection. 
Note: No HIV testing is required unless mandated by local health authority.
19. 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.
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20. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
21. Has a history or current evidence of any condition (eg, known deficiency of the enzyme 
dihydropyrimidine dehydrogenase), 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.
22. Participants with hypokalemia (serum potassium less than the lower limit of normal).
23. Participants with hypomagnesemia (serum magnesium less than the lower limit of 
normal).
24. Participants with hypocalcemia (serum calcium less than the lower limit of normal).
25. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions 
26. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 180 days after 
the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, 
whichever is last.
27. Has had an allogenic tissue/solid organ transplant.
28. Has a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents 
(including, but not limited to, infusional 5-fluorouracil or oral capecitabine) and/or to any 
of their excipients.
29. Grade ≥2 audiometric hearing loss.
Note: For participants taking cisplatin.
5.3
Lifestyle Considerations
No lifestyle restrictions are necessary.
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
No restrictions are necessary.
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5.3.3
Activity Restrictions
No restrictions are necessary.
5.3.4
Photosensitivity
Investigators are advised to counsel participants assigned to receive capecitabine or 5-FU 
about the risk of photosensitivity and to take sun protection measures accordingly.
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.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention(s) provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Country-specific requirements are noted in Appendix 7.
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 5.
Table 5
Study Interventions
Group Name Group Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Adminis-
tration
Regiment/
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
Pembro
lizumab
Experi
mental
Pembrolizumab 
(MK 3475)
Biological/
Vaccine
Vial
25 mg/mL 
vial
100 mg vial
200 mg on 
Day 1 of each 
cycle
IV 
Infusion
Q3W up to 
35 cycles
Test product
IMP
Provided centrally 
by the Sponsor
Placebo
Placebo 
Comparator
Placebo (refer 
to Pharmacy 
Manual)
Drug
Solution 
for 
infusion
N/A
On Day 1 of 
each cycle
IV 
Infusion
Q3W up to 
35 cycles
Placebo
IMP
Provided locally by 
the study site, 
subsidiary, or 
designee
FP Backbone Chemotherapy
Cisplatin
Other
Cisplatin
Drug
Ampule
1 mg/mL vial 
20 mg vial or 
50 mg vial
80 mg/m2 on 
Day 1 of each 
cycle
IV 
Infusion
Q3W up to 
35 cycles *
Comparator 
regimen and 
combination 
agent
NIMP
Provided centrally 
by the Sponsor or 
locally by the study 
site, subsidiary, or 
designee
5 FU
Other
5 FU
Drug
Ampule
25 mg/mL 
vial
50 mg/mL 
vial
800 mg/m2/day 
continuous on 
Days 1 to 5 of 
each cycle 
(120 hours, or 
per local 
standard)
IV 
Infusion
Q3W up to 
35 cycles
Comparator 
regimen and 
combination 
agent
NIMP
Provided centrally 
by the Sponsor or 
locally by the study 
site, subsidiary, or 
designee
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Group Name Group Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Adminis-
tration
Regiment/
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
CAPOX Backbone Chemotherapy
Oxaliplatin
Other
Oxaliplatin
Drug
Ampule
5 mg/mL vial
50 mg vial or 
100 mg vial
130 mg/m2 on 
Day 1 of each 
cycle
IV 
Infusion
Q3W up to 
35 cycles *
Comparator 
regimen and 
combination 
agent
NIMP
Provided centrally 
by the Sponsor or 
locally by the study 
site, subsidiary, or 
designee
Capecitabine
Other
Capecitabine
Drug
Tablet
150 mg tablet
500 mg tablet
1000 mg/m2
Oral
Twice daily 
on Days 1 
to 14 of 
each cycle 
(Q3W)
Comparator 
regimen and 
combination 
agent
NIMP
Provided centrally 
by the Sponsor or 
locally by the study 
site, subsidiary, or 
designee
5 FU 5 fluorouracil; CAPOX capecitabine and oxaliplatin; EEA European Economic Area; FP cisplatin and 5 fluorouracil; IMP investigational medicinal product; 
IV intravenous; NIMP/AxMP noninvestigational medicinal product/auxiliary medicinal product; Q3W every 3 weeks
The classification of IMP and NIMP/AxMP is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
classification/definition of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
* Duration of cisplatin or oxaliplatin treatment may be capped at 6 cycles as per local country guidelines. Treatment with 5 FU/capecitabine may continue per protocol.
Investigator decision regarding the type of backbone chemotherapy (FP or CAPOX) should be determined prior to randomization. 
Participants should continue on the type of backbone chemotherapy chosen prior to randomization throughout the study. Exceptions may be permitted after consultation with the 
Sponsor.
In this protocol, placebo for pembrolizumab is diluent alone (normal saline and/or dextrose); diluent is used for blinding purposes and does not contain active ingredients.
Participants who are randomized to placebo are not allowed to crossover to pembrolizumab treatment.
Note: The unit dose strength of chemotherapy may vary depending on the source. The table captures the current available unit dose strengths but could vary depending on 
availability.
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All study interventions will be administered on an outpatient basis.
All products indicated in  Table 5 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 6.1.1 for details regarding administration of the study intervention.
Refer to Section 8.1.8.1 for details regarding the order of administration of study 
intervention.
A cycle of treatment is 3 weeks (21 days) long and is set relative to pembrolizumab/placebo.
Use of nonexperimental standard of care chemotherapies and supportive medications should 
follow the appropriate package insert and locoregional practice guidelines, as mandated by 
local health regulatory agencies. Please consult the specific appendix, where appropriate.
6.1.1
Pembrolizumab and Placebo
Pembrolizumab or placebo must be administered on Day 1 of each 3-week cycle for up to 
35 cycles after all procedures/assessments have been completed. Pembrolizumab or placebo 
will be administered as a 30-minute IV infusion Q3W. Sites must make every effort to target 
infusion timing to be as close to 30 minutes as possible. However, given the variability 
between infusion pumps, a window of -5 minutes and +10 minutes is permitted (ie, infusion 
time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. Pembrolizumab will 
be dosed and administered by blinded and qualified study site personnel. 
The placebo will be prepared by the unblinded pharmacist (refer to the Pharmacy Manual). 
The placebo will be dosed and administered by blinded and qualified study site personnel in 
the same manner as the investigational product (pembrolizumab).
6.1.2
FP
Cisplatin 80 mg/m2 will be administered as a 60- to 120-minute IV infusion or per the site’s 
standard practice on Day 1 of each treatment cycle. Duration of cisplatin treatment may be 
capped at 6 cycles as per local country guidelines.
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5-fluorouracil 800 mg/m2/day will be administered as a continuous IV infusion from Day 1 to 
Day 5 (120 hours) of each treatment cycle, after completion of all procedures and 
assessments according to the SoA in Section 1.3.
Investigators are advised to counsel participants assigned to receive 5-FU about risk of 
photosensitivity and to take sun protection measures accordingly. Participants receiving 
cisplatin should be monitored for audiological complications (Section 8.3.1.3).
6.1.3
CAPOX
Oxaliplatin 130 mg/m2 will be administered as a 60- to 120-minute IV infusion or per the 
site’s standard practice on Day 1 of each treatment cycle.
Capecitabine will be administered orally as a 1000 mg/m2 dose twice daily from Day 1 to 
Day 14 of each treatment cycle. The evening dose of capecitabine should be taken 
approximately 12 hours after the morning dose. Capecitabine should be taken with food, or 
within 30 minutes after food/meal, with approximately 200 mL of water. Sites may follow 
local practice patterns regarding calculation of capecitabine milligram dose. Refer to the 
product label for additional guidance on administration procedures for capecitabine.
Note: If the participant is enrolled later in the day, it is acceptable for the first dose to be 
taken on Day 1, and twice daily dosing can continue on Days 2 to 14; the final dose will be 
taken in the morning of Day 15.
Investigators are advised to counsel participants assigned to receive capecitabine about the 
risk of photosensitivity and to take sun protection measures accordingly. Participants 
receiving capecitabine should be carefully monitored for ophthalmological complications and 
skin reactions (Section 8.3.1.4).
6.1.4
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Dose preparation must be done by separate unblinded study personnel. Dose 
administration must be done by blinded study personnel.
Concomitant chemotherapeutic/immunotherapeutic agents will be prepared and administered 
as per the approved product label(s). The BSA in m2 should be calculated per local guidance.
The dose of oxaliplatin and cisplatin shall not be recalculated by body weight fluctuation in 
principle, but for 10% or higher fluctuation of body weight, recalculation is possible at the 
discretion of the investigator. When recalculating, BSA in m2 should be calculated per local 
guidance.
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6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. For those study interventions taken home, the participant must be 
instructed on appropriate storage and handling, per the label.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to pembrolizumab or placebo, respectively.
6.3.2
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Geographical region

Europe/Israel/North America/Australia

Asia
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
Rest of the World (including South America)
2. PD-L1 tumor expression status (CPS <1, ≥1)
3. Combination chemotherapy (FP, CAPOX)
6.3.3
Blinding
A double-blinding technique will be used. Pembrolizumab and placebo will be prepared 
and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified study site 
personnel. The participant and the investigator who is involved in the study intervention
administration or clinical evaluation of the participants are unaware of the group 
assignments.
6.4
Study Intervention Compliance
Administration of study medication(s) will be witnessed by the investigator and/or study 
staff. The total volume of study medication infused will be compared with the total volume 
prepared to determine compliance with each dose administered.
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record. 
Refer to Section 6.6.2 for dose modification and toxicity management for irAEs associated 
with pembrolizumab and for other allowed dose interruption of pembrolizumab.
For those study interventions taken at home, the site will validate compliance with study 
intervention at each site visit according to their standard operating procedure.
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 intervention may be required. The 
investigator is to discuss prohibited medication 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.
Listed below are concomitant therapies prohibited during the course of the study:
•
Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol.
•
Immunotherapy not specified in this protocol.
•
Chemotherapy not specified in this protocol.
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•
Investigational agents other than pembrolizumab.
•
Radiation therapy.
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion and, if possible without compromising participant safety, 
after consultation with the Sponsor.
•
Live or live-attenuated vaccines within 30 days prior to the first dose of study 
intervention and while participating in the study. Administration of killed vaccines is 
allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
Country-specific requirements are noted in Appendix 7.
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE
that is suspected to have an immunologic etiology. Inhaled or topical steroids are 
allowed, and systemic steroids at doses ≤10 mg/day prednisone or equivalent are allowed.
The use of systemic steroids at a dose >10 mg/day of prednisone (or equivalent) may be 
approved after consultation with the Sponsor.
Note 1: For the purpose of preventing chemotherapy-induced nausea/vomiting, the 
administration of dexamethasone should be limited to those instances when the 
participant is receiving high (or moderate) emetic risk chemotherapy. The dose and 
duration of dexamethasone administration should be limited to the lowest needed to 
prevent and/or treat chemotherapy-related nausea and emesis.
Note 2: Antiemetic prophylaxis with corticosteroids per NCCN or institutional guideline 
is permitted.
•
For participants receiving 5-FU or capecitabine:
-
Brivudine, Sorivudine analogs, and other inhibitors of the enzyme DPD.
•
For participants receiving cisplatin:
-
Phenytoin should not be started with cisplatin therapy.
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.
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Concomitant Medications to be used with caution:
•
Cimetidine, metronidazole, and interferons may increase levels of 5-FU.
•
Participants who are taking phenytoin in conjunction with 5-FU should be examined 
regularly due to a potential elevation in phenytoin plasma levels. Hepatotoxic effects (rise 
in alkaline phosphatase, transaminase or bilirubin levels) are commonly observed under 
the treatment with 5-FU and levamisole.
•
Drugs known to prolong the QTc interval should be used with caution. Please refer to the 
website https://www.crediblemeds.org prior to administration of oxaliplatin.
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.  All concomitant medications administered during SAEs or ECIs are to 
be recorded. SAEs and events of clinical interest (ECIs) are defined in Section 8.4.7.
6.5.1
Rescue Medications and Supportive Care
6.5.1.1
Supportive Care Guidelines for Pembrolizumab
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 6 and Table 7
in Section 6.6.2 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.
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6.5.1.2
Supportive Care Guidelines for Combination Therapy
6.5.1.2.1
Supportive Care Guidelines for Cisplatin
Participants should be well-hydrated while taking cisplatin.
Prevention and/or treatment of nausea and vomiting should be managed with:
1. IV EMEND (fosaprepitant) 150 mg IV or oral EMEND (aprepitant) 3-day pack 
125 mg on Day 1, 80 mg on Day 2, 80 mg on Day 3
2. Plus Aloxi (palonosetron) 0.25 mg IV
Nausea may also be managed with:
1. Zofran (ondansetron) 8 mg twice a day
2. Or Compazine (prochlorperazine) 10 mg 3 to 4 times per day
Additionally, use of steroids for cisplatin associated antiemetic support is allowed and is to 
follow the NCCN or institutional guidelines. However, caution must be exercised to prevent 
the overuse of steroids. For the purpose of preventing chemotherapy-induced 
nausea/vomiting, the administration of dexamethasone should be limited to those instances 
when the participant is receiving high (or moderate) emetic risk chemotherapy. The dose and 
duration of dexamethasone administration should be limited to the lowest needed to prevent
and/or treat chemotherapy-related nausea and emesis. 
Refer to the product label or local standards of care for additional cisplatin supportive 
measures.
6.5.1.2.2
Supportive Care Guidelines for 5-FU
Refer to the product label or local standards of care for 5-FU supportive measures.
6.5.1.2.3
Supportive Care Guidelines for Capecitabine
Refer to the product label or local standards of care for capecitabine supportive measures.
6.5.1.2.4
Supportive Care Guidelines for Oxaliplatin
Refer to the product label or local standards of care for oxaliplatin supportive measures.
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6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Initial Treatment or First Course
The Initial Treatment or First Course of pembrolizumab consists of 35 treatments. 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 8.13.3. Participants may be retreated in the Second Course Phase (Retreatment) for 
up to an additional 17 cycles (approximately 1 year).
For participants who have attained a confirmed CR and have received at least 2 doses of 
pembrolizumab monotherapy and been treated for at least 8 cycles (at least 24 weeks)  or 
received 2 cycles of the combination including 2 doses of pembrolizumab or matching 
placebo and at least 80% of the planned doses of combination chemotherapy beyond the date 
when the initial CR was declared, the treatment may be stopped. These participants may be 
eligible for Second Course described in Section 6.7.
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
The investigator may attribute each toxicity event to oxaliplatin, cisplatin, 5-FU, 
capecitabine, or pembrolizumab/placebo alone and use a stepwise dose reduction according 
to Table 6 and Table 7 (pembrolizumab), Table 8 (CAPOX), Table 9 (oxaliplatin), Table 10
(capecitabine), Table 11 (FP), Table 12 (cisplatin), and Table 13 (5-FU). Dose modification 
should be performed with the following taken into consideration:
•
Treatment for each new cycle may be delayed if the scheduled off-drug periods are not 
adequate to allow for recovery to the guideline for restarting each study intervention. 
•
Pembrolizumab/placebo dose reductions are not permitted. Pembrolizumab/placebo
treatment may be interrupted or discontinued due to toxicity.
•
If a dose reduction for toxicity occurs with any study intervention, the dose may not be 
reescalated. 
•
Participants can have a maximum of 3 dose modifications to oxaliplatin and 2 dose 
modifications to infusional 5-FU, capecitabine, and cisplatin for drug-related toxicities
throughout the course of the study. 
•
If a participant experiences several toxicities and there are conflicting recommendations, 
follow the most conservative dose adjustment recommended (dose reduction appropriate 
to the most severe toxicity). 
•
Reduction of 1 chemotherapy agent and not the other agent is appropriate if, in the 
opinion of the investigator, the toxicity is clearly related to 1 of the treatments. If, in the 
opinion of the investigator, the toxicity is related to the combination of both 
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chemotherapy agents, both drugs may be considered to be reduced according to 
recommended dose modifications. If the toxicity is related to the combination of 3 agents, 
chemotherapy may be considered to be reduced, interrupted, or discontinued;
pembrolizumab/placebo should be interrupted or discontinued according to the 
recommended dose modifications.
•
Both groups may have chemotherapy discontinued and continue to receive
pembrolizumab/placebo.
The CTCAE version 4.0 must be used to grade the severity of AEs. All dose modifications 
should be based on the AE requiring the greatest dose modification. Dose modifications are 
detailed in Table 6 and Table 7 (pembrolizumab), Table 8 (CAPOX), Table 9 (oxaliplatin), 
Table 10 (capecitabine), Table 11 (FP), Table 12 (cisplatin), and Table 13 (5-FU). 
Exceptional circumstances to following the dose modification tables below may be 
considered after consultation with the Sponsor.
If toxicity is not otherwise specified, investigators should refer to the label or local guidelines 
for dose adjustments.
In addition, participants should receive appropriate supportive care measures as deemed 
necessary by the treating investigator. Suggested supportive care measures are included in 
Table 6 and Table 7 (pembrolizumab) and Section 6.5.1.
6.6.2.1
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 6.
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Table 6
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 7.
Table 7
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 hrs
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 
study intervention 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
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.
6.6.2.2
Dose Modification for Combination Chemotherapy
Dose modifications for CAPOX combination, oxaliplatin, and capecitabine are detailed in
Table 8, Table 9, and Table 10, respectively. Dose modifications for FP combination, 
cisplatin, and 5-FU are detailed in Table 11, Table 12, and Table 13, respectively. See the 
agents’ respective package inserts for more details.
Dose delays and treatment restarts will be made at the discretion of the site investigator 
according to institutional guidelines or local standard practice. 
Oxaliplatin administration must be discontinued in the case of QT/QTc interval prolongation 
> 500 msec. Continuous ECG (telemetry) monitoring in a hospital setting under the care of a 
cardiologist will be required in the case of QT/QTc prolongation >500 msec.
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Table 8
Dose Modification Guidelines for CAPOX Drug-related Adverse Events
Dose Level 0
Dose Level -1
Dose Level -2
Dose Level -3
Dose Level -4
Oxaliplatin
130 mg/m2
100 mg/m2
75 mg/m2
50 mg/m2
Discontinue
Capecitabine
1000 mg/m2 twice daily
750 mg/m2 twice daily
500 mg/m2 twice daily
Discontinue
Discontinue
Table 9
Dose Modification Guidelines for Oxaliplatin Drug-related Adverse Events
Category
Toxicity
Hold Oxaliplatin 
Treatment for 
Grade
Timing for Restarting 
Oxaliplatin Treatment
Dose for Restarting 
Oxaliplatin Treatment
Discontinue Oxaliplatin
Hematologica
Neutropeniab
2-3c
Neutrophil count
resolves to ≥1,500/mm3
No Reduction
If the criteria for starting 
the course are not met at 
Day 22, reduce by 1 DL
If >3 DL reductions exceeded
4c
Neutrophil count
resolves to ≥1,500/mm3
Reduce by 1 DL
If >3 DL reductions exceeded
Febrile Neutropenia
3c
Toxicity resolves
Reduce by 1 DL
If >3 DL reductions exceeded
4
c
n/a
Discontinue
Permanently discontinue 
oxaliplatin
Thrombocytopenia
3-4c
Platelet count resolves to 
≥75,000/mm3
Reduce by 1 DLd
If >3 DL reductions exceeded
Non-
hematologica
Creatinine Increased
≥1.5 mg/dLc
<1.5 mg/dL
No reduction
If >3 DL reductions exceeded
Peripheral Sensory 
Neuropathye
3-4c
Grade 0-2
Reduce by 1 DL
If >3 DL reductions exceeded
All Other Non-
hematologic Toxicitiesa
3-4c
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
If >3 DL reductions exceeded
Laboratory Adverse
Eventsf
3-4c
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
If >3 DL reductions exceeded
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Category
Toxicity
Hold Oxaliplatin 
Treatment for 
Grade
Timing for Restarting 
Oxaliplatin Treatment
Dose for Restarting 
Oxaliplatin Treatment
Discontinue Oxaliplatin
AE adverse event; DL dose level; G CSF granulocyte colony stimulating factor; n/a not applicable
a Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion.
b See the package insert of each of the G CSF drugs for administration of G CSF for neutropenia.
c Permanent discontinuation should be considered for any severe or life threatening event. Consult Sponsor before restarting treatment after Grade 4 drug related AE.
d Dose reduction at Grade 3 is at the discretion of the investigator but not required.
e Administration may be interrupted or reduced at the discretion of the investigator.
f Allow continuous treatment for laboratory AEs that are asymptomatic and deemed to be not clinically significant.
Table 10
Dose Modification Guidelines for Capecitabine Drug-related Adverse Events
Category
Toxicity
Hold Capecitabine
Treatment for
Grade
Timing for Restarting
Capecitabine Treatment
Dose for Restarting 
Capecitabine Treatment
Discontinuation of Capecitabine
Hematologica
Neutropenia
3b
Neutrophil count resolves to
>1,000/mm3
No Reduction
*consider G-CSF
Toxicity does not resolve within
4-5 weeks of last oral intake or if
>2 DL reductions exceeded
4
b
Neutrophil count resolves to
>1,000/mm3
Reduce by 1 DL
*consider G-CSF
Toxicity does not resolve within
4-5 weeks of last oral intake or if
>2 DL reductions exceeded
Febrile Neutropenia
3
b
Toxicity resolves
Reduce by 1 DL
Toxicity does not resolve within
4-5 weeks of last oral intake or if
>2 DL reductions exceeded
4
b
n/a
Discontinue
Permanently discontinue 
Thrombocytopenia
3-4b
Platelet count resolves to 
≥75,000/mm3
Reduce by 1 DL
Toxicity does not resolve within
4-5 weeks of last oral intake or if
>2 DL reductions exceeded
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Category
Toxicity
Hold Capecitabine
Treatment for
Grade
Timing for Restarting
Capecitabine Treatment
Dose for Restarting 
Capecitabine Treatment
Discontinuation of Capecitabine
Non-
hematologic
Diarrhea, Mucositis,
or Hand-foot 
Syndrome
2-3
Toxicity resolves to Grade 0-
1
Reduce by 1 DL
Toxicity does not resolve within
4-5 weeks of last oral intake or if
>2 DL reductions exceeded
4
n/a
Discontinue
Permanently discontinue 
All Other Non-
hematologic 
Toxicitiesc
3-4b
Toxicity resolves to Grade 0-
1
Reduce by 1 DL
Toxicity does not resolve within
4-5 weeks of last oral intake or if
>2 DL reductions exceeded
Laboratory Adverse
Eventsd
4b
Toxicity resolves to Grade 0-
1
Reduce by 1 DL
Toxicity does not resolve within
4-5 weeks of last oral intake or if
>2 DL reductions exceeded
AE adverse event; DL dose level; G CSF granulocyte colony stimulating factor; n/a not applicable
a Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion.
bPermanent discontinuation should be considered for any severe or life threatening event. Consult Sponsor before restarting treatment after Grade 4 drug related AE.
c Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion. Permanently discontinue from agent for persistent Grade 2 adverse reactions 
for which treatment has been held and did not recover to Grade 0 1 within 12 weeks of the last dose.
d Allow continuous treatment for laboratory AEs that are asymptomatic and deemed to be not clinically significant.
Table 11
Dose Modification Guidelines for FP Drug-related Adverse Events
Dose Level 0
Dose Level -1
Dose Level -2
Dose Level -3
Cisplatin
80 mg/m2
60 mg/m2
40 mg/m2
Discontinue
5-FU
800 mg/ m2
600 mg/m2
400 mg/m2
Discontinue
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Table 12
Dose Modification Guidelines for Cisplatin Drug-related Adverse Events
Category
Toxicity
Hold Cisplatin
Treatment for
Grade
Timing for Restarting
Cisplatin Treatment
Dose for Restarting
Cisplatin Treatment
Discontinue Cisplatin
Hematologica
Neutropenia
3b
Neutrophil count resolves
to >1,000/mm3
No Reduction
*consider G-CSF
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
4
b
Neutrophil count resolves
to >1,000/mm3
Reduce by 1 DL
*consider G-CSF
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
Febrile 
Neutropenia
3
b
Toxicity resolves
Reduce by 1 DL
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
4
b
n/a
Discontinue
Permanently discontinue cisplatin
Thrombocytopenia
3-4b
Platelet count resolves to 
≥75,000/mm3
Reduce by 1 DL
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
Non-
hematologic
Creatinine
Increased
2
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
3-4b
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
Ototoxicity
3-4b
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
Sensory 
Neuropathy
3-4b
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
All Other Non-
hematologic 
Toxicitiesc
3-4b
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
Laboratory
Adverse Eventsd
4b
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within 4 weeks of
last infusion or if >2 DL reductions exceeded
AE adverse event; DL dose level; G CSF granulocyte colony stimulating factor; n/a not applicable
a Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion.
b Permanent discontinuation should be considered for any severe or life threatening event. Consult Sponsor before restarting treatment after Grade 4 drug related AE.
c Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion. Permanently discontinue from agent for persistent Grade 2 adverse reactions for which 
treatment has been held and did not recover to Grade 0 1 within 12 weeks of the last dose.
d Allow continuous treatment for laboratory AEs that are asymptomatic and deemed to be not clinically significant.
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Table 13
Dose Modification Guidelines for 5-FU Drug-related Adverse Events
Category
Toxicity
Hold 5-FU 
Treatment for
Grade
Timing for Restarting
5-FU Treatment
Dose for Restarting 
5-FU Treatment
Discontinue
5-FU
Hematologica
Neutropenia
3b
Neutrophil count resolves
to >1,000/mm3
No Reduction
*consider G-CSF
Toxicity does not resolve within 4-5 weeks of
last infusion or if >2 DL reductions exceeded
4
b
Neutrophil count resolves
to >1,000/mm3
Reduce by 1 DL
*consider G-CSF
Toxicity does not resolve within 4-5 weeks of
last infusion or if >2 DL reductions exceeded
Febrile
Neutropenia
3
b
Toxicity resolves
Reduce by 1 DL
Toxicity does not resolve within 4-5 weeks of
last infusion or if >2 DL reductions exceeded
4
b
n/a
Discontinue
Permanently discontinue 
Thrombocytopenia
3-4b
Platelet count resolves to 
≥75,000/mm3
Reduce by 1 DL
Toxicity does not resolve within 4-5 weeks of
last infusion or if >2 DL reductions exceeded
Non-
hematologic
Diarrhea, 
Mucositis, or 
Hand-foot 
Syndrome
2-3
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within 4-5 weeks of
last infusion or if >2 DL reductions exceeded
4
n/a
Discontinue
Permanently discontinue 
All Other Non-
hematologic 
Toxicitiesc
3-4bb
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within 4-5 weeks of
last infusion or if >2 DL reductions exceeded
Laboratory
Adverse Eventsd
4b
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within 4-5 weeks of
last infusion or if >2 DL reductions exceeded
AE adverse event; DL dose level; G CSF granulocyte colony stimulating factor; n/a not applicable
a Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion.
b Permanent discontinuation should be considered for any severe or life threatening event. Consult Sponsor before restarting treatment after Grade 4 drug related AE.
c Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion. Permanently discontinue from agent for persistent Grade 2 adverse
reactions for which treatment has been held and did not recover to Grade 0 1 within 12 weeks of the last dose.
d Allow continuous treatment for laboratory AEs that are asymptomatic and deemed to be not clinically significant.
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6.7
Second Course Phase (Pembrolizumab)
All participants who stop study intervention with SD or better may be eligible for up to an 
additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress 
after stopping study intervention from the initial treatment phase. 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:
EITHER
•
Stopped initial study intervention after attaining an investigator determined confirmed 
CR based on RECIST 1.1, and
-
Was treated with at least 8 cycles of study intervention before discontinuing 
treatment, and
-
Received at least 2 treatments with pembrolizumab beyond the date when the initial 
CR was declared
OR
•
Had SD, PR, or CR and stopped study intervention after completion of 35 administrations 
(approximately 2 years) of study intervention for reasons other than disease progression 
or intolerability
AND
•
Experienced an investigator-determined radiographic disease progression by RECIST 1.1 
after stopping initial treatment, and
-
Upon unblinding at the time of centrally verified disease progression were found to 
have received pembrolizumab, and
-
No new anticancer treatment was administered after the last dose of study 
intervention, 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 for the primary analysis of either endpoint in this 
study.
Country-specific requirements are noted in Appendix 7.
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6.8
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.9
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
Refer to Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
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 (SoA) and 
Section 8.13.3.
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.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
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•
The participant interrupts pembrolizumab administration for more than 12 consecutive 
weeks unless written Sponsor approval to continue is received.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
Noncompliance with study treatment or procedure requirements.
•
The participant has a confirmed positive serum pregnancy test.
•
Prohibited concomitant medication requiring withdrawal (refer to Section 6.5). 
•
Confirmed radiographic disease progression outlined in Section 8.13 (exception if the 
Sponsor approves treatment continuation)
•
Any progression or recurrence of any malignancy, or occurrence of another malignancy 
that requires active treatment
•
Recurrent Grade 2 pneumonitis
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study 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.
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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 Trial File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before 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.
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The maximum amount of blood collected from each participant at each treatment cycle/visit 
will be approximately 6.0 mL to 48.0 mL. Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a 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 consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant 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 dated 
signature or by the participant’s legally acceptable representative’s dated signature.
The participant or his/her legally acceptable representative will be asked to sign consent at 
the point of initial radiographic disease progression.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, 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.
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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 intervention/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 important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout or run-in treatment including placebo run-in).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before first dose. Treatment for the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. Concomitant medications will be 
recorded for 30 days after the last dose of study intervention (or longer if related to an SAE 
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or ECI). In addition, new medications started during the Second Course 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.
Any participant who is rescreened will retain the original screening number assigned at the 
initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 8.13.1.2. 
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/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 intervention should begin within 3 days after randomization.
8.1.8.1
Timing of Dose Administration
Study intervention in both groups will begin on Day 1 of each 3-week dosing cycle after all 
procedures/assessments have been completed, as detailed in Section 1.3 (SoA). Study 
interventions may be administered up to 3 days before or after the scheduled Day 1 of each 
cycle due to administrative reasons (except Cycle 1, which may be administered up to 3 days 
after the scheduled Day 1).
All study interventions may be administered on an outpatient basis.
Study interventions will be administered in the order presented below:
1. Pembrolizumab or placebo infusion
2. Cisplatin or oxaliplatin infusion
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3. 5-FU infusion or capecitabine
Refer to Section 6.1 for details on study intervention administration.
Refer to Section 6.6 for information on allowed dosing interruptions.
Refer to Section 7 for criteria for discontinuation of study intervention.
Refer to Section 6.7 for details of Second Course pembrolizumab therapy.
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 .
8.1.9.1
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
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
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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 
intensity/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.
Treatment identification information is to be unblinded ONLY in the following situation:
1. For the welfare of the participant, if necessary. 
2. Participants requiring Second Course who completed 35 cycles and stopped first 
course study intervention with SD or better and has to discontinue for any reason 
other than disease progression, intolerability, or CR (per protocol requirement). Such 
participants must have experienced radiographic disease progression while off study 
intervention according to the criteria in Section 6.7.
Every effort should be made to avoid unblinding. Only the principal investigator or delegate 
and the respective participant’s code should be unblinded.
Note: The PD-L1 result will be masked to the site.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
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 
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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
Throughout this section, the term 'scan' refers to any medical imaging data used to 
assess tumor burden and may include cross-sectional imaging (such as CT or MRI), 
medical photography, or other methods as specified in this protocol.
The process for scan collection and transmission to the iCRO can be found in the Site 
Imaging Manual. Tumor scans are strongly preferred to be acquired by CT. For the abdomen 
and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is 
contraindicated, or when mandated by local practice. Magnetic resonance imaging is the 
strongly preferred modality for imaging the brain. The same scan technique regarding 
modality, ideally the same scanner, and the use of contrast should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the assessment of response or progression based 
on scans. 
In general, scans should include the chest, abdomen, and pelvis.
Note: for the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility.
Participant eligibility will be determined using investigator assessment. All scheduled scans
for all participants from the sites will be submitted to the iCRO. In addition, scans (including 
via other modalities) that are obtained at an unscheduled time point to determine disease 
progression, as well as scans obtained for other reasons, but which demonstrates radiologic 
progression, should also be submitted to the iCRO.
When the investigator identifies disease progression, the iCRO will verify this progression
and email the results to the study site and Sponsor (Section 8.2.1.5 and Figure 2). In 
clinically stable participants, scans are to continue until disease progression has been verified 
by BICR. If initial investigator-assessed progression was not verified by BICR, each 
subsequent scan must be submitted to the iCRO. Once progression is verified by BICR, 
subsequent scans (if acquired) should not be submitted to the iCRO.
8.2.1.1
Initial Tumor Scans
The screening scans must be submitted to the iCRO for retrospective review.
Tumor scans performed as part of routine clinical management are acceptable for use as 
screening tumor scans if they are of acceptable diagnostic quality and performed within 28
days prior to the date of randomization and can be assessed by the iCRO.
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8.2.1.2
Tumor Scans During the Study
The first on-study imaging assessment should be performed at 6 weeks (42 days +7 days]) 
from the date of randomization. Subsequent tumor scans should be performed every 6 weeks 
(42 days ±7 days) or more frequently if clinically indicated. Scan timing should follow 
calendar days and should not be adjusted for delays in cycle starts. Scans are to be performed 
until disease progression is identified by the investigator and verified by BICR, the start of 
new anticancer treatment, withdrawal of consent, or death.
Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular scan 
schedule, starting with the next scheduled time point. Participants who receive additional 
scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 
weeks later; scans may resume at the subsequent scheduled time point.
When radiological disease progression is identified by the investigator in clinically stable 
participants, disease progression is to be confirmed by another set of scans performed 4 to 8 
weeks later, per iRECIST guidelines Section 8.2.1.6.
If disease progression is not confirmed, clinically stable participants are to continue study 
intervention until progression is confirmed. Participants are to return to their regular scan 
schedule. If the next scheduled scan will occur in less than 4 weeks, this scheduled scan may 
be skipped.
If disease progression is confirmed, study intervention will be discontinued. Exceptions are 
detailed in Section 8.2.1.6.
8.2.1.3
End-of-Treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4 week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization (refer to Section 8.2.1.2).
Scans are to be continued until one of the following conditions are met:

disease progression as defined by RECIST 1.1verified by BICR

the start of a new anticancer treatment

pregnancy

death
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
withdrawal of consent

the end of the study
Participants who are clinically stable and treated past radiographic progression may continue 
to be assessed until progression is confirmed according to the rules of iRECIST, when 
clinically appropriate.
8.2.1.4
Second Course (Retreatment) Tumor Scans
Tumor scans must be performed within 28 days prior to restarting study intervention with 
pembrolizumab. If disease progression has been verified by BICR for the First Course, the 
Second Course may be initiated. The disease progression scan may be used as the Second 
Course baseline scan if performed within 4 weeks prior to dosing and  meets the scan 
standards.
The first scan should be performed at 6 weeks (42 days +7 days) after the restart of study 
intervention. Subsequent tumor scans are to be performed every 6 weeks (42 days ±7 days) 
or more frequently, if clinically indicated.
Scans are to be performed until disease progression, the start of a new anticancer treatment, 
withdrawal of consent, death, completion of Second Course, or notification by the Sponsor, 
whichever occurs first. 
If participants discontinue study intervention, tumor scans are to be performed at 
discontinuation (±4 week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor their disease status by acquiring tumor scans every 6 weeks (
42 days ±7 days) until the start of a new anticancer treatment, disease progression, death, or 
the end of the study, whichever occurs first.
Response assessments and progressive disease are determined by investigator site 
assessment. only. 
The only Second Course scan to be provided to the iCRO is the baseline scan if it is also the 
final scan for the Initial Treatment or First Course.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
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The initial tumor scan showing site-assessed disease progression should be submitted 
immediately to the iCRO for BICR verification of disease progression. The site will be 
notified if the iCRO verifies disease progression using RECIST 1.1. Figure 2 illustrates the 
scan flow involving verification of disease progression for clinically stable participants.
8.2.1.6
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 intervention 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 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 
iCRO 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 intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 8, 
study intervention should be discontinued; however, if 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 (SoA) and submitted to the iCRO.
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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 14 and illustrated as a flowchart in Figure 2.
Table 14
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. 
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.
May continue 
study intervention
at the assessment 
of the investigator 
and after the 
participant’s 
reconsent.
Submit the 
imaging to BICR 
for verification. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
First radiologic 
evidence of PD by 
RECIST 1.1 that has 
been verified by 
BICR.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.
May continue 
study intervention
at the 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging by 
site by iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor imaging 
confirms PD (iCPD) 
by iRECIST per 
investigator 
assessment.
No additional 
imaging 
required.
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
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.
Continue study 
intervention at the 
investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor imaging 
shows iSD, iPR, or 
iCR by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
intervention at the 
investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
intervention if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
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Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
BICR=blinded independent central review; iCPD=iRECIST confirmed progressive disease; iCR=iRECIST 
complete 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
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 iCRO, 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 iCRO with verification of progression
request until RECIST 1.1 progression is verified by BICR.
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
CIV=central imaging vendor (ie, iCRO); iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 
for immune-based therapeutics; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid 
Tumors 1.1
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8.2.2
Quality-of-Life Assessments
8.2.2.1
Patient-reported Outcomes
The EuroQoL EQ-5D and EORTC QLQ-C30 questionnaires will be administered by trained 
site personnel and completed electronically by participants in the following order: EuroQoL 
EQ-5D first, then EORTC QLQ-C30, then EORTC QLQ-STO22. The questionnaires should 
be administered prior to dosing at Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, and every 
2 cycles thereafter (eg, Cycle 7, Cycle 9, etc.), at the Treatment Discontinuation Visit, and at 
the 30-day Safety Follow-up Visit.  A visit window of ± 7 days will apply to PRO visit 
assessments.
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. 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 Study 
Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or medically qualified designee (consistent with local requirements) will 
perform a complete physical examination per institutional standards during the screening 
period. Height and weight will also be measured and recorded. Clinically significant 
abnormal findings should be recorded as medical history. The time points for full physical 
examinations are described in Section 1.3 (SoA). After the first dose of study intervention, 
new clinically significant abnormal findings should be recorded as AEs.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination, as defined in Section 1.3 (SoA), 
the investigator or medically qualified designee (consistent with local requirements) will 
perform a directed physical examination per institutional standards prior to the administration 
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of the study intervention. New clinically significant abnormal findings should be recorded as 
AEs.
8.3.1.3
Audiometry (Only in Participants Receiving Cisplatin)
In participants receiving cisplatin, audiometry testing will be performed at screening by the 
investigator or medically qualified designee (consistent with local requirements). 
Assessments may be repeated during the study, as clinically indicated. After the first dose of 
study intervention, new clinically significant abnormal findings should be recorded as AEs.
Country-specific requirements are noted in Appendix 7.
8.3.1.4
Additional Monitoring (Only in Participants Receiving Capecitabine)
Participants receiving capecitabine should be carefully monitored for ophthalmological 
complications such as keratitis and corneal disorders, especially if they have a prior history 
of eye disorders. Treatment of eye disorders should be initiated, as clinically appropriate.
Capecitabine can induce severe skin reactions such as SJS and TEN. Capecitabine should be 
permanently discontinued in participants who experience a severe skin reaction during 
treatment.
After the first dose of study intervention, new clinically significant abnormal findings should 
be recorded as AEs.
8.3.2
Vital Signs
Vital signs (temperature, pulse rate, respiratory rate, and blood pressure) will be assessed by 
the investigator or medically qualified designee (consistent with local requirements) as 
specified in Section 1.3 (SoA). After the first dose of study intervention, new clinically 
significant abnormal findings should be recorded as AEs.
8.3.3
Electrocardiograms
A standard 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) at screening. Clinically significant 
abnormal findings should be recorded as medical history. Assessments may be repeated 
during the study, as clinically indicated.
Note: A 6-lead ECG is allowed per institutional standard.
Country-specific requirements are noted in Appendix 7.
8.3.4
Clinical Safety Laboratory Assessments (Hematology, Chemistry and 
Urinalysis)
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
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•
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 Section 1.3 (SoA).
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Study 
Procedures Manual. 
Refer to Section 1.3 (SoA) for the timing of laboratory assessments.
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.5
Pregnancy Test
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
according to Section 1.3 (SoA) and at the end of relevant systemic exposure for all arms.
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
at monthly intervals during intervention.
-
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted
for the time required to eliminate systemic exposure after the last dose of study 
intervention as noted in section 5.1. The length of time required to continue pregnancy 
testing for pembrolizumab is 120 days.
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-
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.
Country-specific requirements are noted in Appendix 7.
8.3.6
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or medically qualified designee (consistent with local requirements) will 
assess ECOG status (see Appendix 9) at the time points specified in Section 1.3 (SoA).
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.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up 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.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc., the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
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 treatment allocation/randomization must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
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protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of study intervention allocation/randomization through 30 
days following cessation of study intervention must be reported by the 
investigator.
•
All AEs meeting serious criteria, from the time of study intervention
allocation/randomization through 90 days following cessation of study 
intervention or 30 days following cessation of study intervention if the participant 
initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.
•
All pregnancies and exposure during breastfeeding, from the time of study 
intervention allocation/randomization through the time required to eliminate 
systemic exposure following cessation of study intervention as described in 
Section 5.1 and Section 8.3.5 or 30 days after cessation of study intervention if 
the participant initiates new anticancer 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 15.
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Table 15
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event:
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-Specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-specified 
Follow-up Period
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:
-  participant has been 
exposed to any protocol-
specified intervention (eg, 
procedure, washout or run-
in treatment including 
placebo run-in)
Exception: A positive 
pregnancy test at the time 
of initial screening is not a 
reportable event unless the 
participant has received 
study intervention.
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
DILI=drug-induced liver injury; ECI=event of clinical interest
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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.
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 the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Any pregnancy complication will be reported as an AE or SAE.
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The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus. 
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1. Specifically, the suspected/actual events covered in this exception include 
any event that is disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest (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: 
1.
An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2.
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) for pembrolizumab and an as any dose exceeding the 
prescribed dose by ≥20% for other study treatments.
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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.
Treatment of overdose of other study treatments should follow the prescribed information in 
the relevant package insert.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
CCI
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All-cause hospitalizations and emergency room visits must be reported in the electronic case 
report form (eCRF), from the time of treatment allocation/randomization through 90 days 
following cessation of study intervention, or 30 days following cessation of study 
intervention, if the participant initiates new anticancer therapy, whichever is earlier.
8.13
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
CCI
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8.13.1
Screening
8.13.1.1
Prescreening Period
The Prescreening Period may be utilized to determine biomarker eligibility based on HER2
and PD-L1 expression status using an archival tumor biopsy sample. An archival tissue 
sample taken up to 1 year prior to study randomization is preferred. After signing an 
authorization form for release of tumor tissue, participants will be assigned a screening 
number. Characterization of HER2 and PD-L1 status will be performed at a prescreening
visit for participants with an available archival tumor biopsy sample. If the participants are 
HER2 negative, documented consent for the main study will need to be obtained.
Participants who do not have an archival tumor biopsy sample available will not enter the 
prescreening Period as eligibility based on HER2 expression status will be determined in the 
main study screening period.
8.13.1.2
Screening Period
Within 28 days prior to treatment randomization, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5. Documented 
informed consent must be provided prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing 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.
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 are met. Participants who are rescreened will retain their original 
screening number.
If a site decides to rescreen a participant more than once, a Sponsor consultation will be 
required.
8.13.2
Treatment Period
Visit requirements are outlined in Section 1.3 (SoA). Specific procedure-related details are 
provided in Section 8.1 through Section 8.13. Unless otherwise specified, 
assessments/procedures are to be performed prior to administration of study intervention. 
Unless otherwise specified, the window for each visit is ± 3 days.
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8.13.3
Discontinued Participants Continuing to be Monitored in the Study
8.13.3.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits, 1 after the Initial Treatment or First Course Period and 1 after the Second 
Course.
8.13.3.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin Efficacy
Follow-up and should be assessed every 6 weeks (42 days ± 7 days) to monitor disease 
status. Every effort should be made to collect information regarding disease status until the 
start of new anticancer therapy, disease progression, death, withdrawal of consent, 
pregnancy, end of study, or if the participant begins retreatment with pembrolizumab, as 
detailed in Section 6.7. Information regarding poststudy anticancer treatment will be 
collected if new treatment is initiated. Participants who completed all efficacy assessments 
and/or will not have further efficacy assessments must enter Survival Follow-up.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.7 will move from Efficacy Follow-up to Second Course when they 
experience disease progression. Details are provided in Section 1.3 (SoA) for retreatment 
with pembrolizumab.
8.13.3.3
Survival Follow-up Assessments
Participant Survival Follow-up contact will occur 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:
1. For participants who discontinue treatment intervention and who will not enter 
Efficacy Follow-up, the first Survival Follow-up contact will be scheduled 12 weeks 
after the Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
2. For participants who completed assessments in Efficacy Follow-up, the first Survival 
Follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
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8.13.4
Vital Status
To ensure current and complete vital status for survival data is available at the time of 
database locks, updated vital status for survival data may be requested during the study by 
the Sponsor. For example, updated vital status for survival data may be requested before but 
not limited to, an eDMC review, interim and/or final analysis. Upon Sponsor notification, all 
participants who do not/will not have a scheduled study visit or study contact during the 
Sponsor-defined time period will be contacted for their vital status for survival data
(excluding participants that have a previously recorded death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized will be 
documented in an sSAP and referenced in the Clinical Study Report for the study. Separate 
analysis plans may be developed for PK/modeling analysis, biomarker analysis, and genetic 
data analysis. Post hoc exploratory analyses will be clearly identified in the Clinical Study 
Report.
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9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
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The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment.
Blinding issues related to the planned interim analysis 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
9.4.1
Efficacy Endpoint
Primary
•
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause.
Secondary
•
Progression-free survival (PFS) per RECIST 1.1 assessed by BICR
PFS is defined as the time from randomization to the first documented disease 
progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. 
See Section 9.6.1 for the censoring rules. 
•
Objective Response Rate (ORR) per RECIST 1.1 by BICR
OR defined as a CRor a PR.
•
Duration of Response (DOR) per RECIST 1.1 by BICR
For participants who demonstrated CR or PR, DOR is defined as the time from first 
response (CR or PR) to subsequent disease progression or death from any cause, 
whichever occurs first.
Exploratory
Methods related to exploratory objectives will be described in the sSAP.
9.4.2
Safety Endpoint
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events, laboratory values, and vital signs. 
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9.4.3
Patient-reported Outcome (PRO) Endpoint
The PRO endpoints (eg, score change from baseline over time), which include EORTC 
QLQ-C30, EORTC QLQ-STO22, and EQ-5D-5L scores, are described in Section 3. Details 
will be provided in the sSAP.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The ITT population will serve as the population for primary efficacy analysis (PFS, OS, and 
ORR). All randomized participants, whether or not treatment was administered, will be 
included in this population. Any participant who receives a randomization number will be 
considered to have been randomized. Participants will be included in the treatment group to 
which they are randomized. 
The ITT CPS ≥10 population in the primary analysis will include participants whose 
CPS ≥10 status can be determined from 3 sources: 1) Participants are prospectively identified 
as having tumors with CPS ≥10 at enrollment; 2) Participants with archived specimens are 
rescored and determined to be CPS ≥10 retrospectively; and 3) Participants who could not be 
rescored at CPS10 cutoff retrospectively are categorized as CPS ≥10 based on raw scores 
from testing at study entry.
9.5.2
Safety Analysis Populations
The 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 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
For most participants, this will be the study intervention group to which they are randomized. 
Participants who receive incorrect study intervention for the entire treatment period will be 
included in the treatment group corresponding to the study intervention actually received. 
Any participant who receives the incorrect study intervention for 1 or more cycles but 
receives the correct study intervention for the remaining cycles will be analyzed according to 
the participant’s randomized treatment group, and a narrative will be provided for any events 
that occur during the cycle for which the participant was incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required.
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participants without documented PD or death. The censoring rules for primary and sensitivity 
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9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention 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 months and number of 
cycles or administrations, as appropriate.
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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 of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH
GCP]) and 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 (eg, 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 (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
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 to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
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 fraud, scientific/research misconduct, or serious GCP noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified 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. Ethics Committee Review (Institutiona Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), 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 to identify potentially eligible participants.
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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 (eg, 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 
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.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF 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.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The 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.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
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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 
Analyses) 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
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. 
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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 
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.
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Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants' documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 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.
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 27 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.
Table 27
Protocol-required Safety Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNa
Potassium
AST/SGOT
Total Bilirubin 
(and direct bilirubin, if total 
bilirubin is elevated above the 
upper limit of normal)
Albumin
Bicarbonateb
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose 
Calcium
Alkaline Phosphatase
Magnesium
Thyroid function tests (T3 [or 
free T3c], free T4, and TSH)
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, nitrite, leukocyte esterase by dipstick
Microscopic examination (if blood or protein is clinically significant)
Other 
Screening 
Tests
• Follicle-stimulating hormone and estradiol (as needed in women of nonchildbearing 
potential only)
• Serum or urine pregnancy test (as needed for WOCBP). Refer to Appendix 5
• Coagulation panel (PT/INR, aPTT)d
• Serology (HIV antibody, HBsAg, and hepatitis C virus RNA), if applicable
• Tuberculosis, if applicable
ALT alanine aminotransferase; aPTT activated partial thromboplastin time; AST aspartate aminotransferase; 
BUN blood urea nitrogen; HBsAg hepatitis B surface antigen; HIV human immunodeficiency virus; INR International 
Normalized Ratio; PT prothrombin time; RBC red blood cell; RNA ribonucleic acid; SGOT serum glutamic
oxaloacetic transaminase; SGPT serum glutamic pyruvic transaminase; T3 triiodothyronine; T4 thyroxine; 
TSH thyroid stimulating hormone; WBC white blood cell; WOCBP women of childbearing potential
a Urea is acceptable if BUN is not available as per institutional standard.
b If the test is considered part of standard of care.
c T3 is preferred over free T3. If not available, free T3 may be tested.
d PT/INR should be tested as needed for participants on warfarin-based anticoagulation therapy.
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The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (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, or are 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.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of 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.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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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.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same 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)
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•
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
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 AE that changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs//worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL
-
Grade 4: Life threatening consequences; urgent intervention indicated
-
Grade 5: Death related to AE
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Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
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 AE:
-
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 studies 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 study is a single-dose drug study; or (4) Sponsor’s 
product(s) is/are only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
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-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose drug study); or (3) Sponsor’s product(s) is/are used 
only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE 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 
IRB/IEC.
•
Consistency with study intervention 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 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
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
Not applicable.
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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.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with one 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 FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or HRT. However, in the absence of 12 
months of amenorrhea, confirmation with 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
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol-defined time frame in Section 5.1:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
-
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM).
•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom cannot be used together.
-
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
consistent and correct use of a highly effective method of contraception as described in 
Table 28 during the protocol-defined time frame in Section 5.1.
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Table 28
Highly Effective Contraception Methods
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
•
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.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Germany-specific Information:
1. Exclusion Criterion 18: HIV testing is mandatory.
2. Exclusion Criterion 19: Hepatitis B and C testing is mandatory.
3. Exclusion Criterion 20: TB testing is mandatory.
4. Sites in Germany will perform a systematic search for DPD deficiency for participants 
who have been naïve to 5-fluorouracil or capecitabine. This research should be performed 
before any administration of 5-fluorouracil or capecitabine.
10.7.2
Japan-specific Information:
1. Inclusion Criterion 7: Document agreement is necessary for both the participant and their 
substitute if the participant is under 20 years of age.
Section 6.1 Study Interventions Administered
The classification of Investigational Medicinal Product (IMP) and Non-Investigational 
Medicinal Product (NIMP) in Section 6.1 is based upon guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). As country 
differences with respect to the definition/classification of IMP/NIMP may exist, local 
legislation is followed. Local legislation in Japan requires that the agent 5-FU for this study 
is considered as IMP. Diluent placebo (normal saline and/or dextrose) for this study is not 
considered as IMP in Japan.
10.7.3
UK-specific Information:
1. Exclusion Criterion 18: HIV testing is mandatory.
2. Exclusion Criterion 19: Hepatitis B and C testing is mandatory.
3. Section 6.5 Concomitant Therapy 
Listed below are specific concomitant therapies or vaccinations that are prohibited during 
the study (exceptions noted):
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
4. Pregnancy testing must be performed through 120 days after the last dose of study 
medication.
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10.7.4
France-specific Information:
Sites in France will perform a systematic search for DPD deficiency for participants who 
have been naïve to 5-fluorouracil or capecitabine. This research should be performed before 
any administration of 5-fluorouracil or capecitabine
For participants receiving oxaliplatin:

A 12-lead ECG must be performed before and after intravenous administration of 
oxaliplatin.
For participants receiving cisplatin:

Audiometry testing must be performed every 3 months.
For participants receiving cisplatin, capecitabine, oxaliplatin and 5-fluorouracil:

Please refer to the updated SmPC for these marketed products or the website 
http://base-donnees-publique.medicaments.gouv.fr, which presents the updated 
version of the SmPC of the medicines.
France-specific Inclusion Criteria
IC #5: In France, men participating in the study must use an effective method of 
contraception during study intervention and at least 6 months after stopping study 
intervention with oxaliplatin and cisplatin. 
France-specific Exclusion Criteria:
30. Participants with QT/QTc interval longer than 450 msec for men and longer than 470 
msec for women on the inclusion ECG.
31. Participants with clinically significant active heart disease or myocardial infarction within 
the last 6 months or cardiorespiratory pathology, which precludes hyperhydration for 
cisplatin therapy.
32. Participants receiving 5-FU or capecitabine who require treatment with phenytoin or with 
sorivudine or its chemically related analogs, such as brivudine.
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10.7.5
Italy-specific Information:
1. Participants with significant cardiovascular impairment, including myocardial infarction, 
within 6 months of the first dose of study intervention should be excluded.
2. Due to clinically significant interaction between brivudine and fluoropyrimidines, recent 
or concomitant treatment with brivudine (or the analog sorivudine) is contraindicated. 
Participants on such treatment or with less than 4 weeks since last dose of brivudine (or 
sorivudine) should be excluded from enrollment.
3. Sites Italy will perform a systematic search for DPD deficiency for participants who have 
been naïve to 5-fluorouracil or capecitabine. This research should be performed before 
any administration of 5-fluorouracil or capecitabine.
10.7.6
Czech Republic-specific Information:
1. Exclusion Criterion 18: HIV testing is mandatory.
2. Exclusion Criterion 19: Hepatitis B and C testing is mandatory.
3. Prohibited Concomitant Medications: Live vaccines are prohibited through 3 months 
after the end of study intervention.
4. Section 6.7 Second Course Phase: Eligibility for retreatment (termed Second Course 
Phase) is at the medical discretion of the site Principal Investigator provided the study 
remains open and the participant meets the conditions listed in Section 6.7.
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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 14 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 intervention 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 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 
iCRO 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 Non-target.
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 or if RECIST 1.1 PD has not been 
verified centrally, 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 iCRO.
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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 
non-target 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 non-target 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 Scale
ECOG Grade
ECOG 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 housework, 
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
[ECOG-ACRIN Cancer Research Group 2016]
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
5-FU
5-fluorouracil
AE
adverse event 
AHR
average hazard ratio
ALK
anaplastic lymphoma kinase
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic transaminase)
APaT
All Participants as Treated
aPTT
activated partial thromboplastin time
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review
BSA
body surface area
CAPOX
capecitabine and oxaliplatin
CBC
complete blood count
CD28
cluster of differentiation 28
CD3ζ
cluster of differentiation 3 zeta
CI
confidence interval
CNS
central nervous system 
CPS
combined positive score
CPS1
combined positive score ≥1
CR
complete response
CrCl
creatinine clearance
CRF
case report form 
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trials Facilitation and Coordination Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DCR
disease control rate
DILI
drug-induced liver injury
DL
dose level
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
DPD
dihydropyrimidine dehydrogenase
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunoassay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-C30
EORTC Quality-of-Life Questionnaire C30
EORTC QLQ-STO22
EORTC Quality-of-Life Questionnaire STO22
ePRO
electronic patient-reported outcome(s)
EQ-5D™
EQ-5D™ is a trademark of the EuroQoL Research Foundation
EQ-5D-5L
EuroQoL 5 Dimension Questionnaire
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Abbreviation
Expanded Term
ESMO
European Society for Medical Oncology
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials (database)
FA
final analysis
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
FISH
fluorescence in situ hybridization
FOLFOX
5-FU/oxaliplatin
FP
cisplatin and 5-fluorouracil
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
G-CSF
granulocyte colony-stimulating factor
GEJ
gastroesophageal junction
GFR
glomerular filtration rate
GI
gastrointestinal
H
hypothesis
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HER2/neu
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
iCRO
Imaging Contract Research Organization
IEC
Independent Ethics Committee
IFNγ
interferon-gamma
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV-type
immunoglobulin-variable–type
IHC
immunohistochemistry
IL-10
interleukin 10
IND
Investigational New Drug 
INR
international normalized ratio
iPR
iRECIST partial response
irAE
immune-related adverse event
IRB
Institutional Review Board 
iRECIST
modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRT
interactive response technology
iSD
iRECIST stable disease
ISH
in situ hybridization
iUPD
iRECIST unconfirmed progressive disease
IUS
Intrauterine system
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Abbreviation
Expanded Term
ITT
Intention-to-Treat
IV
intravenous
IVD
in vitro diagnostic
M&N
Miettinen and Nurminen [method]
mAb
monoclonal antibody
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MSI
microsatellite instability
MSI-H
microsatellite instability - high
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NR
not reached
NSAID
nonsteroidal anti-inflammatory
NSCLC
non-small cell lung carcinoma
OR
objective response
ORR
objective response rate
OS
overall survival
PBPK
physiologically-based pharmacokinetics
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression-free survival
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PR
partial response
PRO
patient-reported outcome(s)
PT
prothrombin time
Q2W
every 2 weeks
Q3W
every 3 weeks
QLG
Quality-of-Life Group
QoL
quality-of-life
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RNA
ribonucleic acid
SAE
serious adverse event 
SD
stable disease
SJS
Stevens-Johnson syndrome
SmPC
Summary of Product Characteristics
SoA
Schedule of Activities
SOC
standard of care
SOP
standard operating procedure
sSAP
supplementary Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TB
tuberculosis; Bacillus tuberculosis
TEN
Toxic Epidermal Necrolysis
TMDD
target-mediated drug disposition
T-regs
regulatory T-cells
TSH
thyroid-stimulating hormone
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Abbreviation
Expanded Term
ULN
upper level of normal
US
United States [of America]
WOCBP
woman/women of childbearing potential 
XP
cisplatin and capecitabine 
ZAP70
zeta-chain-associated protein kinase
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11
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