A Phase III, Randomized, Double-blind Trial Comparing Trastuzumab Plus Chemotherapy and Pembrolizumab With Trastuzumab Plus Chemotherapy and Placebo as First-line Treatment in Participants With HER2 Positive Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (KEYNOTE 811)
Phase: PHASE3
Conditions: Gastric Neoplasms, Gastroesophageal Junction Adenocarcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase III, Randomized, Double-blind Trial Comparing 
Trastuzumab Plus Chemotherapy and Pembrolizumab 
With Trastuzumab Plus Chemotherapy and Placebo as 
First-line Treatment in Participants With HER2 Positive 
Advanced Gastric or Gastroesophageal Junction 
Adenocarcinoma (KEYNOTE 811)
NCT03615326
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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 III, Randomized, Double-blind Trial Comparing Trastuzumab Plus 
Chemotherapy and Pembrolizumab With Trastuzumab Plus Chemotherapy and Placebo as 
First-line Treatment in Participants With HER2 Positive Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma (KEYNOTE 811)
Protocol Number: 811-09
Compound Number: MK-3475
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER:   123,482
EudraCT NUMBER: 2018-000224-34
Approval Date:  08 September 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Trial 
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 9
08-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 8
07-APR-2022
Update SAP language for the flexibility of the timing of the interim and final efficacy 
analyses in case of significantly slower than anticipated accrual of PFS and/or OS events.
Amendment 7
24-JUN-2021
To update the pembrolizumab dose-modification and toxicity-management guidelines for 
irAEs and update protocol language to allow option for standard of care treatment beyond 
35 cycles.
Amendment 6
07-JUL-2020
Update SAP language to remove PFS analysis for IA1 in response to Regulatory 
Authority Input.
Amendment 5
20-MAY-2020
Update protocol and SAP language regarding the definition of the curative surgical 
resection and modification of PFS primary censoring rule associated with the curative 
surgical resection, remove the ORR futility analysis for IA1, and add a PFS analysis for 
IA1.
Amendment 4
27-FEB-2019
Update Biomarker Collection Information.
Amendment 3
24-JAN-2019
Response to Regulatory Authority Input.
Amendment 2
16-AUG-2018
Response to Regulatory Authority Input.
Amendment 1
31-MAY-2018
Response to Regulatory Authority Input.
Original Protocol
11-APR-2018
N/A.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 09
Overall Rationale for the Amendment:
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
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.
1.3.2 Second Course 
(Retreatment with 
Pembrolizumab)

Deleted the footnote concerning C1D1 
procedures.

Added in the ‘Notes’ column that a Full Physical 
Examination should be performed within 7 days 
prior to restarting pembrolizumab.

Added in the ‘Notes’ column that PT/INR and 
aPTT tests should be performed within 10 days 
prior to restarting pembrolizumab.

Clarified in the ‘Notes’ column that testing for T3 
(or Free T3), FT4, and TSH should be performed 
within 7 days prior to restarting pembrolizumab. 
To clarify the timing of procedures before 
restarting pembrolizumab and to align with other 
sections of the protocol.
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Section # and Name
Description of Change
Brief Rationale

Added in the ‘Notes’ column that tumor imaging 
should occur within 28 days prior to restarting 
pembrolizumab. 

Updated text in the footnote concerning the 
timing of CBC with Differential, Chemistry 
Panel, and Urinalysis tests.
5.2 Exclusion Criteria
In exclusion criterion number 16, revised pregnancy 
test window from 2472 hours to 24 hours.
To correct a typographical error.
6.5 Concomitant 
Therapy
6.5.1 Specific 
Restrictions

Added “replication-incompetent” to adenoviral 
vaccines.

Clarified that systemic glucocorticoids may be 
used to treat asthma.

To provide clarity regarding allowed types of
COVID-19 vaccines.

To allow for systemic treatment of asthma 
exacerbations because asthma exacerbations are 
typically treated with short course of steroids.
10.3.2 Contraception 
Requirements
Added a footnote to define IUS as a progestin 
releasing IUD.
To add clarity. 
10.6.1 UK-specific 
Information
Added a note about allowed COVID-19 vaccines.
To provide clarity regarding allowed types of 
COVID-19 vaccines.
10.6.3 Japan-specific 
Information
6.1 Treatments 
Administered
Clarified the classification of study interventions in 
Japan for Section 6.1 Treatments Administered, 
Table 3 Study Treatments. 
To incorporate changes from the Protocol 
Clarification Letter dated 23-MAY-2022, which 
was released to comply with Japan PMDA 
regulation changes.
Throughout 
Document
Minor administrative, formatting, grammatical, 
and/or typographical changes were made throughout 
the document.
To ensure clarity and accurate interpretation of the 
intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
Protocol Summary .....................................................................................................18
1.1
Synopsis....................................................................................................................18
1.2
Schema .....................................................................................................................22
1.3
Schedule of Activities (SoA) ...................................................................................24
1.3.1
Initial Treatment Phase ........................................................................................24
1.3.2
Second Course (Retreatment with Pembrolizumab)............................................32
2
Introduction................................................................................................................35
2.1
Study Rationale .......................................................................................................35
2.2
Background..............................................................................................................39
2.2.1
Pharmaceutical and Therapeutic Background .....................................................39
2.2.1.1
Pembrolizumab Background.........................................................................39
2.2.2
Preclinical and Clinical Studies ...........................................................................40
2.2.3
Ongoing Clinical Trials of Pembrolizumab in Malignancies ..............................40
2.2.4
Trastuzumab Plus Chemotherapy ........................................................................41
2.2.5
S-1 (Japan SOX Cohort Only) .............................................................................42
2.2.5.1
Comparison between Cisplatin and Oxaliplatin with S-1.............................42
2.3
Benefit/Risk Assessment.........................................................................................43
3
Objectives/Hypotheses and Endpoints.....................................................................43
4
Study Design...............................................................................................................45
4.1
Overall Design .........................................................................................................45
4.2
Scientific Rationale for Study Design....................................................................48
4.2.1
Rationale for Endpoints .......................................................................................48
4.2.1.1
Efficacy Endpoints........................................................................................48
4.2.1.1.1
Primary Efficacy Endpoints...................................................................48
4.2.1.1.2
Secondary Efficacy Endpoints...............................................................49
4.2.1.2
Safety Endpoints...........................................................................................49
4.2.1.3
Patient-reported Outcomes............................................................................49
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4.2.1.3.1
EORTC QLQ-C30.................................................................................49
4.2.1.3.2
EORTC QLQ-STO22 ............................................................................50
4.2.1.3.3
EQ-5D-5L ..............................................................................................50
4.2.1.4
Pharmacokinetic Endpoints ..........................................................................50
4.2.1.5
Planned Exploratory Biomarker Research....................................................50
4.2.1.6
Future Biomedical Research.........................................................................52
4.2.2
Rationale for the Use of Comparator/Placebo .....................................................52
4.2.2.1
Rationale of the Use of Placebo....................................................................52
4.2.2.2
Rationale for the Use of Trastuzumab Plus Pembrolizumab in 
Gastric Cancer...............................................................................................53
4.2.2.3
Rationale for the Use of Trastuzumab, FP and CAPOX in Gastric 
Cancer...........................................................................................................53
4.3
Justification for Dose ..............................................................................................54
4.3.1
Pembrolizumab Dose...........................................................................................54
4.3.2
Standard of Care Chemotherapy Backbone: FP Dose .........................................55
4.3.3
Standard of Care Chemotherapy Backbone: CAPOX Dose................................55
4.3.4
Standard of Care: Trastuzumab Dose ..................................................................55
4.3.5
SOX Dose (Japan SOX Cohort Only) .................................................................55
4.4
Beginning and End of Study Definition ................................................................55
4.4.1
Clinical Criteria for Early Study Termination .....................................................56
5
Study Population........................................................................................................56
5.1
Inclusion Criteria....................................................................................................56
5.2
Exclusion Criteria ...................................................................................................59
5.3
Lifestyle Considerations .........................................................................................62
5.3.1
Meals and Dietary Restrictions............................................................................62
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ......................................................62
5.3.3
Activity Restrictions ............................................................................................63
5.3.4
Photosensitivity....................................................................................................63
5.3.5
Pregnancy.............................................................................................................63
5.4
Screen Failures ........................................................................................................63
5.5
Participant Replacement Strategy.........................................................................63
6
Treatments..................................................................................................................63
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6.1
Treatments Administered.......................................................................................63
6.2
Preparation/Handling/Storage/Accountability ....................................................66
6.2.1
Dose Preparation..................................................................................................66
6.2.2
Handling, Storage and Accountability.................................................................66
6.3
Measures to Minimize Bias: Randomization and Blinding.................................67
6.3.1
Method of Treatment Assignment .......................................................................67
6.3.1.1
Stratification..................................................................................................67
6.3.2
Blinding................................................................................................................67
6.4
Treatment Compliance...........................................................................................67
6.5
Concomitant Therapy.............................................................................................68
6.5.1
Specific Restrictions ............................................................................................68
6.5.2
Rescue Medications and Supportive Care ...........................................................70
6.5.2.1
Supportive Care Guidelines for Cisplatin.....................................................70
6.5.2.2
Supportive Care Guidelines for 5-FU...........................................................70
6.5.2.3
Supportive Care Guidelines for Capecitabine...............................................70
6.5.2.4
Supportive Care Guidelines for Oxaliplatin .................................................70
6.5.2.5
Supportive Care Guidelines for S-1 (Japan SOX Cohort Only)...................70
6.5.2.6
Supportive Care Guidelines for Trastuzumab...............................................71
6.5.3
Curative Surgery ..................................................................................................71
6.6
Dose Modification (Escalation/Titration/Other)..................................................71
6.6.1
Dose Selection (Preparation) ...............................................................................71
6.6.2
Dose Modification and Toxicity Management ....................................................71
6.6.3
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).........................................................................................................72
6.6.4
Dose Modification and Toxicity Management for CAPOX, FP, and 
SOX......................................................................................................................79
6.6.4.1
CAPOX Dose Modification..........................................................................80
6.6.4.2
FP Dose Modification...................................................................................83
6.6.4.3
SOX Dose Modification (Japan SOX Cohort Only).....................................86
6.6.5
Dose Modification and Toxicity Management for Trastuzumab.........................89
6.7
Second Course Phase (Retreatment Period).........................................................91
6.8
Treatment After the End of the Study ..................................................................92
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6.9
Clinical Supplies Disclosure...................................................................................92
7
Discontinuation of Study Treatment and Participant Withdrawal ......................92
7.1
Discontinuation of Study Treatment.....................................................................92
7.2
Participant Withdrawal From the Study..............................................................93
7.3
Lost to Follow-up ....................................................................................................94
8
Study Assessments and Procedures..........................................................................94
8.1
Administrative and General Procedures ..............................................................95
8.1.1
Informed Consent.................................................................................................95
8.1.1.1
General Informed Consent............................................................................95
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research........................................................................................................95
8.1.2
Inclusion/Exclusion Criteria ................................................................................95
8.1.3
Participant Identification Card.............................................................................96
8.1.4
Medical History ...................................................................................................96
8.1.5
Prior and Concomitant Medications Review .......................................................96
8.1.5.1
Prior Medications..........................................................................................96
8.1.5.2
Concomitant Medications.............................................................................96
8.1.5.3
Disease Status and Prior Cancer Treatment History.....................................96
8.1.6
Assignment of Screening Number.......................................................................96
8.1.7
Assignment of Treatment/Randomization Number.............................................97
8.1.7.1
Treatment Eligibility Assessment.................................................................97
8.1.8
Treatment Administration....................................................................................97
8.1.8.1
Timing of Dose Administration....................................................................97
8.1.8.2
Pembrolizumab and Placebo.........................................................................98
8.1.8.3
FP..................................................................................................................98
8.1.8.4
CAPOX.........................................................................................................99
8.1.8.5
Trastuzumab..................................................................................................99
8.1.8.6
SOX (Japan SOX Cohort Only)....................................................................99
8.1.9
Second Course of Therapy.................................................................................100
8.1.10 Discontinuation and Withdrawal .......................................................................100
8.1.10.1 Withdrawal From Future Biomedical Research .........................................100
8.1.11 Participant Blinding/Unblinding........................................................................100
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8.1.12 Calibration of Equipment...................................................................................101
8.2
Efficacy Assessments.............................................................................................102
8.2.1
Tumor Imaging and Assessment of Disease......................................................102
8.2.1.1
Initial Tumor Imaging.................................................................................102
8.2.1.2
Tumor Imaging During the Study...............................................................103
8.2.1.3
End of Treatment and Follow-up Tumor Imaging......................................103
8.2.1.4
Second Course (Retreatment) Tumor Imaging...........................................104
8.2.1.5
RECIST 1.1 Assessment of Disease...........................................................104
8.2.1.6
iRECIST Assessment of Disease................................................................105
8.2.2
Quality of Life Assessments ..............................................................................108
8.2.2.1
Patient-reported Outcomes..........................................................................108
8.3
Safety Assessments................................................................................................109
8.3.1
Physical Examinations.......................................................................................109
8.3.1.1
Full Physical Exam .....................................................................................109
8.3.1.2
Directed Physical Exam..............................................................................109
8.3.1.3
Ophthalmologic Complications due to Capecitabine .................................109
8.3.1.4
Severe Skin Reactions due to Capecitabine................................................109
8.3.2
Vital Signs..........................................................................................................109
8.3.3
Electrocardiograms ............................................................................................110
8.3.4
Echocardiography or Multigated Acquisition Scan...........................................110
8.3.5
Clinical Safety Laboratory Assessments............................................................110
8.3.6
Pregnancy Test...................................................................................................111
8.3.7
Audiometry ........................................................................................................111
8.3.8
Performance Assessments..................................................................................111
8.3.8.1
Eastern Cooperative Oncology Group Performance Scale.........................111
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events .....................................................................................111
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ................................................................112
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events............113
8.4.3
Follow-up of AE, SAE and Other Reportable Safety Event Information..........114
8.4.4
Regulatory Reporting Requirements for SAE ...................................................114
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8.4.5
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs................................................................................114
8.4.6
Pregnancy and Exposure During Breastfeeding ................................................114
8.4.7
Events of Clinical Interest (ECIs)......................................................................115
8.5
Treatment of Overdose.........................................................................................115
8.6
Pharmacokinetics..................................................................................................115
8.7
Biomarkers ............................................................................................................116
8.8
Future Biomedical Research Sample Collection................................................116
8.9
Medical Resource Utilization and Health Economics........................................116
8.10
Visit Requirements................................................................................................117
8.10.1 Screening............................................................................................................117
8.10.1.1 Pre-screening Period...................................................................................117
8.10.1.2 Screening Period.........................................................................................117
8.10.2 Treatment Period................................................................................................117
8.10.3 Participants Discontinued From Study Intervention but Continuing to 
be Monitored in the Study..................................................................................118
8.10.3.1 Safety Follow-up Visit................................................................................118
8.10.3.2 Follow-up....................................................................................................118
8.10.3.3 Survival Follow-up Assessments................................................................118
8.10.4 Survival Status ...................................................................................................118
8.10.5 Post-study...........................................................................................................118
9
Statistical Analysis Plan ..........................................................................................119
9.1
Statistical Analysis Plan Summary......................................................................119
9.2
Responsibility for Analyses/In-house Blinding...................................................121
9.3
Hypotheses/Estimation .........................................................................................121
9.4
Analysis Endpoints................................................................................................121
9.4.1
Efficacy Endpoint ..............................................................................................121
9.4.2
Safety Endpoint..................................................................................................121
9.4.3
PRO Endpoint ....................................................................................................122
9.5
Analysis Populations.............................................................................................122
9.5.1
Efficacy Analysis Populations ...........................................................................122
9.5.2
Safety Analysis Populations ..............................................................................122
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9.6
Statistical Methods................................................................................................122
9.6.1
Statistical Methods for Efficacy Analyses.........................................................122
9.6.1.1
Progression-free Survival............................................................................122
9.6.1.2
Overall Survival..........................................................................................124
9.6.1.3
Objective Response Rate ............................................................................125
9.6.1.4
Duration of Response..................................................................................125
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints...........................................126
9.6.2
Statistical Methods for Safety Analyses ............................................................126
9.6.3
Summaries of Demographic and Baseline Characteristics ................................128
9.7
Interim Analyses ...................................................................................................128
9.7.1
Efficacy Interim Analysis ..................................................................................128
9.7.2
Safety Interim Analysis......................................................................................129
9.8
Multiplicity ............................................................................................................129
9.8.1
Objective Response Rate ...................................................................................130
9.8.2
Progression-free Survival...................................................................................131
9.8.3
Overall Survival.................................................................................................132
9.8.4
Safety Analyses..................................................................................................133
9.9
Sample Size and Power Calculations ..................................................................134
9.9.1
Objective Response Rate ...................................................................................134
9.9.2
Progression-free Survival...................................................................................134
9.9.3
Overall Survival.................................................................................................134
9.10
Subgroup Analyses................................................................................................134
9.11
Extent of Exposure................................................................................................135
10
Supporting Documentation and Operational Considerations.............................136
10.1
Appendix 1:  Regulatory, Ethical and Study Oversight Considerations .........136
10.1.1 Code of Conduct for Clinical Trials...................................................................136
10.1.2 Financial Disclosure...........................................................................................138
10.1.3 Data Protection...................................................................................................138
10.1.4 Confidentiality of Data ......................................................................................139
10.1.5 Confidentiality of Participant Records...............................................................139
10.1.6 Confidentiality of IRB/IEC Information............................................................139
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10.1.7 Committees Structure.........................................................................................139
10.1.7.1 Scientific Advisory Committee...................................................................139
10.1.7.2 Executive Oversight Committee.................................................................140
10.1.7.3 Data Monitoring Committee.......................................................................140
10.1.8 Publication Policy..............................................................................................140
10.1.9 Compliance with Study Registration and Results Posting Requirements .........140
10.1.9.1 Compliance with Law, Audit, and Debarment ...........................................141
10.1.10
Data Quality Assurance ..............................................................................141
10.1.11
Source Documents......................................................................................142
10.1.12
Study and Site Closure................................................................................142
10.2
Appendix 2:  Collection and Management of Specimens for Future 
Biomedical Research.............................................................................................143
10.3
Appendix 3:  Contraceptive Guidance and Pregnancy Testing........................147
10.3.1 Definitions..........................................................................................................147
10.3.2 Contraception Requirements..............................................................................147
10.4
Appendix 4: Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................149
10.4.1 Definition of AE ................................................................................................149
10.4.2 Definition of SAE ..............................................................................................150
10.4.3 Additional Events Reported in the Same Manner as SAE.................................151
10.4.4 Recording AE and SAE .....................................................................................151
10.4.5 Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ..............................................................................................................155
10.5
Appendix 5:  Clinical Laboratory Tests..............................................................156
10.6
Appendix 6:  Country-specific Requirements ....................................................158
10.6.1 UK-specific Information....................................................................................158
10.6.2 Germany-specific Information:..........................................................................158
10.6.3 Japan-specific Information: ...............................................................................158
10.6.4 France-specific Information:..............................................................................159
10.7
Appendix 7:  Abbreviations .................................................................................160
10.8
Appendix 8: Eastern Cooperative Oncology Group Scale................................166
10.9
Appendix 9: Description of the iRECIST Process for Assessment of 
Disease Progression...............................................................................................167
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References.................................................................................................................171
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LIST OF TABLES
Table 1
Ongoing Clinical Trials of Pembrolizumab in Gastric Cancer.............................41
Table 2
Adequate Organ Function Laboratory Values......................................................59
Table 3
Study Treatments..................................................................................................64
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ....................................................................73
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines.............................................................................................................77
Table 6
Recommended Dose Modification Guidelines for CAPOX Drug-related 
Adverse Events .....................................................................................................80
Table 7
Recommended Dose Modification Guidelines for Oxaliplatin Drug-
related Adverse Events .........................................................................................81
Table 8
Recommended Dose Modification Guidelines for Capecitabine Drug-
related Adverse Events .........................................................................................82
Table 9
Recommended Dose Modification Guidelines for FP Drug-related 
Adverse Events .....................................................................................................83
Table 10
Recommended Dose Modification Guidelines for Cisplatin Drug-
related Adverse Events .........................................................................................83
Table 11
Recommended Dose Modification Guidelines for 5-FU Drug-related 
Adverse Events .....................................................................................................85
Table 12
Recommended Dose Modification Guidelines for SOX Drug-related 
Adverse Events (Japan SOX Cohort Only) ..........................................................86
Table 13
Recommended Dose Modification Guidelines for Oxaliplatin Drug-
related Adverse Events .........................................................................................87
Table 14
Recommended Dose Modification Guidelines for S-1 Drug-related 
Adverse Events .....................................................................................................88
Table 15
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease................................................................................................................106
Table 16
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events..........................................................................113
Table 17
Censoring Rules for Primary and Sensitivity Analyses of PFS..........................124
Table 18
Censoring Rules for Duration of Response ........................................................125
Table 19
Analysis Strategy for Key Efficacy Endpoints...................................................126
Table 20
Analysis Strategy for Safety Parameters ............................................................127
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Table 21
Summary of Interim and Final Analyses Strategy..............................................129
Table 22
Possible Alpha-levels and Approximate ORR Difference Required to 
Demonstrate Efficacy for ORR at Interim Analysis 1........................................131
Table 23
Efficacy Boundaries and Properties for Progression-free Survival 
Analyses..............................................................................................................132
Table 24
Efficacy Boundaries and Properties for Overall Survival Analyses...................133
Table 25
Highly Effective Contraception Methods...........................................................148
Table 26
Protocol-required Safety Laboratory Assessments.............................................156
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LIST OF FIGURES
Figure 1
Global Trial Design ..............................................................................................22
Figure 2
Japan-specific SOX Cohort Trial Design .............................................................23
Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator .........................................................................................................108
Figure 4
Type I Error Reallocation Strategy.....................................................................130
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1
Protocol Summary
1.1
Synopsis
Protocol Title:
A Phase III, Randomized, Double-blind Trial Comparing Trastuzumab Plus 
Chemotherapy and Pembrolizumab With Trastuzumab Plus Chemotherapy and 
Placebo as First-line Treatment in Participants With HER2 Positive Advanced Gastric 
or Gastroesophageal Junction Adenocarcinoma (KEYNOTE 811)
Short Title:
Pembrolizumab/Placebo Plus Trastuzumab Plus Chemotherapy in HER2 Positive
Advanced Gastric or GEJ Adenocarcinoma
Objectives/Hypotheses and Endpoints:
In male and female participants at least 18 years of age with previously untreated, locally 
advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)
positive gastric or gastroesophageal junction (GEJ) adenocarcinoma:
Objective/Hypothesis
Endpoint
Primary

Objective:  To compare progression-free 
survival (PFS) between treatment 
groups.

Hypothesis (H1):  Pembrolizumab in 
combination with trastuzumab plus 
chemotherapy is superior to trastuzumab 
plus chemotherapy alone in terms of PFS 
per response evaluation criteria in solid 
tumors (RECIST) 1.1 as assessed by
blinded independent central review
(BICR).

PFS: The time from randomization to 
the first documented disease 
progression or death due to any 
cause, whichever occurs first.

Objective: To compare overall survival 
(OS) between treatment groups.

Hypothesis (H2): Pembrolizumab in 
combination with trastuzumab plus 
chemotherapy is superior to trastuzumab 
plus chemotherapy in terms of OS.

OS: The time from randomization to 
death due to any cause.
This study will be considered to have met its success criteria if the experimental arm is 
superior to the control arm with respect to PFS or OS. 
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Secondary Objectives

Objective:  To compare Objective
Response Rate (ORR) between treatment 
groups.

Hypothesis (H3):  Pembrolizumab in 
combination with trastuzumab plus 
chemotherapy is superior to trastuzumab
plus chemotherapy in terms of ORR per 
RECIST 1.1 as assessed by BICR.

Objective Response: Complete 
response (CR) or partial response 
(PR)

Objective:  To estimate Duration of 
Response (DOR), per RECIST 1.1 as 
assessed by BICR for each treatment 
group.

DOR: For participants who 
demonstrate CR or PR, DOR is 
defined as the time from first 
documented evidence of CR or PR 
until disease progression or death 
due to any cause, whichever occurs 
first.

Objective:  To assess the safety and 
tolerability of pembrolizumab in 
combination with trastuzumab plus 
chemotherapy by proportion of adverse 
events (AEs)

Adverse events

Discontinuation of study treatment 
due to AEs
Overall Design:
Study Phase
Phase 3
Clinical Indication
Advanced Gastric or GEJ Adenocarcinoma
Population
Human epidermal growth factor receptor 2 (HER2) positive 
participants with advanced gastric or GEJ adenocarcinoma
Study Type
Interventional
Type of Design
Randomized, Multi-site, Parallel-group
Type of Control
Placebo and active control
Study Blinding
Double-blind
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 5 years from the time the first participant 
provides documented informed consent until the last 
participant’s last study-related contact or visit.
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Number of Participants:
Approximately 692 participants will be randomized in the Global Cohort.  A separate 
cohort of ~ 40 participants will enroll in the Japan-specific SOX (S-1 combination 
product plus oxaliplatin) cohort.
Treatment Groups and Duration:
Treatment Groups
Trastuzumab and pembrolizumab plus either cisplatin plus 5-
FU (FP) or oxaliplatin plus capecitabine (CAPOX)
Trastuzumab and placebo plus FP and CAPOX
Japan-specific SOX Cohort:
Trastuzumab and pembrolizumab plus SOX
Trastuzumab and placebo plus SOX
Duration of 
Participation
Each participant will participate in the trial 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 trial treatment until disease 
progression is radiographically documented and verified by 
BICR, when clinically appropriate, confirmed by the site per 
modified Response Evaluation Criteria in Solid Tumors 1.1 
for immune-based therapeutics (iRECIST), 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 withdraw the participant, 
noncompliance with trial treatment or procedure 
requirements or administrative reasons requiring cessation of 
treatment, or until the participant has received 35 
administrations of pembrolizumab/placebo or until the 
participant has discontinued all other study treatments 
received beyond 35 administrations of 
pembrolizumab/placebo.  Participants have the option to 
receive up to 1 additional year of trastuzumab and 
capecitabine or 5-FU or S-1 beyond 35 administrations of 
pembrolizumab/placebo at the discretion of the investigator 
and after Sponsor consultation.  Participants who stop 
pembrolizumab/placebo treatment after 35 administrations,
for reasons other than disease progression or intolerability, or 
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participants who attain a CR and stop trial treatment, may be 
eligible for up to 17 additional administrations of 
pembrolizumab upon experiencing disease progression if 
they are randomized to the pembrolizumab arm.  
After the end of treatment, each participant will be followed 
for the occurrence of AEs and spontaneously reported 
pregnancy as described in Section 8.4.  
Participants who discontinue for reasons other than 
radiographic disease progression will have post-treatment 
follow-up imaging for disease status until disease 
progression is documented radiographically per RECIST 1.1 
and verified by BICR and confirmed by the site per 
iRECIST (for participants treated with pembrolizumab), 
initiating a non-study cancer treatment, withdrawing 
consent, or becoming lost to follow-up.  All participants will 
be followed by telephone for OS until death, withdrawal of 
consent, or the end of the study. Once the participant has 
achieved the study objective or 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:
Study Governance 
Committees
Committee
Included in this study?
Steering Committee
N
Executive Oversight 
Committee
Y
Data Monitoring 
Committee
Y
Clinical Adjudication 
Committee
N
Study governance considerations are outlined in 
Appendix 1.
A list of abbreviations used in this document can be found in Appendix 7.
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1.2
Schema
The Global Cohort study design is depicted in Figure 1, and the Japan-specific SOX cohort 
study design is depicted in Figure 2.
Figure 1
Global Trial Design
CAPOX  capecitabine/oxaliplatin; FP  cisplatin plus 5 fluorouracil; HER2  human epidermal growth factor receptor 2; 
PD L1  programmed cell death ligand 1; R
randomization.
Figure 1 includes Japan participants using the FP or CAPOX chemotherapy regimens.
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Figure 2
Japan-specific SOX Cohort Trial Design
CDHP  5 chloro 2,4 dihydroxypyridine; 5 FU
5 fluorouracil; HER2  human epidermal growth factor receptor 2; Oxo 
potassium oxonate; PD L1  programmed cell death ligand 1; R  randomization; S1  combination product containing 
tegafur , a prodrug of 5 FU, and 2 types of enzyme inhibitors, CDHP and Oxo; SOX  S 1 plus oxaliplatin.
Figure 2 includes Japan participants using the SOX chemotherapy regimen. This cohort is 
only open in Japan.
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b.
Documented consent must be obtained prior to performing any protocol specified 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 (eg, within 28 days prior to the first dose of trial treatment).  
Authorization for release of tumor tissue form may be signed prior to the Screening Period specified above ( 28 to 1 days) 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. Start of treatment should be within 3 days of randomization.
c.
Cycles can be started within 1 week after ECHO/MUGA, without additional test and without Sponsor consultation, if the following criteria are met: 1) baseline LVEF was 
above 55%; 2) participant did not have any clinically significant LVEF abnormality based on ECHO/MUGA tests; 3) current ECHO/MUGA result is normal and does not 
require trastuzumab to be held; 4) the delay to start treatment is not due to cardiac dysfunction or heart failure. If the investigator wants to start next cycle for longer than 
1 week after ECHO, consultation with Sponsor is required.
d.
In order to perform MSI analysis by PCR, normal and tumor tissue is required. A blood sample (normal/non tumor tissue) 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.
e.
PK/ADA of pembrolizumab: Pre dose trough PK and anti pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, and 8, every 4 cycles thereafter, and until the 
participant completes 35 administrations of pembrolizumab/placebo, discontinues pembrolizumab/placebo or until the participant meets study treatment discontinuation 
criteria, whichever comes first.  Samples should be drawn within 24 hours prior to infusion of pembrolizumab. Additional post dose (peak) PK samples will be drawn within 
30 minutes after end of pembrolizumab infusion at Cycles 1 and 8.  
f.
PK/ADA of trastuzumab: Pre dose trough PK and anti trastuzumab antibody samples will be collected at Cycles 1, 2, 4, and 8, every 4 cycles thereafter, and until the 
participant completes 35 administrations of pembrolizumab/placebo, discontinues trastuzumab or until the participant meets study treatment discontinuation criteria, 
whichever comes first.  Samples should be drawn within 24 hours prior to infusion of trastuzumab. Additional post dose (peak) PK samples will be drawn within 30 minutes 
after end of trastuzumab infusion at Cycles 1 and 8. PK/ADA samples of trastuzumab will be collected for both arms.
g.
It is strongly recommended that electronic patient reported outcomes (ePROs) are administered prior to drug administration, AE evaluation, and disease status notification,
starting with the EQ5D 5L, followed by EORTC QLQ C30, and EORTC QLQ STO22; an exception to this recommendation may occur at the treatment discontinuation visit 
where participants may have already been notified of their disease status or an AE evaluation is known prior to them arriving to the clinic. All ePROs are to be performed at 
Cycles 1, 2, 3, 4, and 5 and every 2 cycles thereafter (eg, Cycle 7, Cycle 9) up to a year or End of Treatment, whichever comes first, and the 30 day post treatment 
discontinuation follow up visit. The End of Treatment visit evaluation needs to be completed for all participants even if the participant completed all ePRO visits up to a year.
If the participant does not complete the ePROs, the MISS MODE form must be completed to capture the reason the assessment was not performed.  A visit window of ± 
7 days will apply to PRO visit assessment.
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2
Introduction
Gastric cancer remains a major health problem worldwide. 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].  There were ~ 1 million new cases of gastric cancer worldwide in 2012 (631,000 men, 
320,000 women), with 723,000 deaths (469,000 men, 254,000 women), making it the third-
leading cause of cancer death globally in both sexes [Ferlay, J., et al 2014].  Age-
standardized incidence rates are about twice as high in men as in women. 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 European Union
(EU), incidence and mortality for gastric cancer were estimated at 82,000 (51,000 in males 
and 31,000 in females) and 58,000 (35,000 in males and 23,000 in females), respectively in 
2012 [Ferlay, J., et al 2014].  In the US, incidence and mortality estimated at 21,000 (13,000 
in males and 8000 in females) and 12,000 (7000 in males and 5000 in females), respectively 
in 2012 [Ferlay, J., et al 2014].
Human epidermal growth factor receptor 2 (HER2, ErbB2) is a transmembrane tyrosine 
kinase receptor and is overexpressed or amplified in 10% to 20% of gastric cancer. Innate 
and adaptive immune mechanisms are emerging as key players in modulation of the effects 
of HER2-targeted agents such as trastuzumab.  A growing body of preclinical and clinical 
evidence shows that the immune system contributes substantially to the therapeutic effects of 
trastuzumab in solid tumors [Bellati, F., et al 2010] [Ferris, R. L., et al 2010].  In addition, 
there is strong rationale in exploring the impact of combining trastuzumab with an anti-PD-1 
inhibitor like pembrolizumab in HER2 positive cancer.
2.1
Study Rationale 
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 (1L) chemotherapy regimens for patients with 
metastatic disease. Trials have demonstrated similar efficacy among these doublet 
chemotherapy regimens in advanced gastric cancer. Patients with HER2 positive tumors
receive a greater benefit when treated with trastuzumab-containing regimens [Kanagavel, D., 
et al 2015]. Estimates of HER2 positive prevalence in gastric cancer range from 6% to 34%
[Ghosn, M., et al 2016] [Kelly, C. M. 2016].
The Trastuzumab for Gastric Cancer (ToGA) trial was the first randomized, prospective,
multicenter, Phase 3 trial to evaluate the efficacy and safety of trastuzumab in HER2 positive
gastric/GEJ adenocarcinoma in combination with cisplatin and a fluoropyrimidine [Bang, Y. 
J., et al 2010]. In this study, 594 patients were randomly assigned to study treatment
(trastuzumab plus chemotherapy, n 298; chemotherapy alone, n 296). Overall survival
(OS), the primary endpoint, was statistically significant in the trastuzumab plus
chemotherapy arm compared with the chemotherapy alone arm (p 0.0045, log-rank test;
hazard ratio [HR], 0.74). The median survival time was 13.8 months in the trastuzumab plus
chemotherapy arm and 11.1 months in the chemotherapy alone arm and the risk of death was
decreased by 26% for patients in the trastuzumab plus chemotherapy arm.
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Based on the ToGA trial, the current standard of care is to use trastuzumab in HER2+
advanced gastric cancer patients in combination with fluoropyrimidine (5-FU or 
capecitabine) and platinum (cisplatin or oxaliplatin) containing doublet regimen. Given 
similar efficacy expected from these regimens, the choice between these regimens is made 
based on patients’ general medical condition and comorbidities in consideration of different 
toxicity profiles of the regimens. This practice pattern is supported by global consensus 
guidelines in treatment of advanced gastric cancer, which recommend use of any of the 
doublets of choice discussed above, plus trastuzumab in patients with HER2 positive gastric 
cancers [National Comprehensive Cancer Network 2016] [Cunningham, D. 2008].
Since the results of the ToGA trial were reported, no further advance has been made in 
treatment of HER2 positive 1L gastric cancer patients. Duration of clinical benefit with 
current standard of care is limited as evidenced by duration of response (DOR) and mean 
progression-free survival (PFS) shorter than 7 months [Bang, Y. J., et al 2010] [Tabernero, J., 
et al 2017]. The majority of these patients develop intrinsic or acquired resistance within 1 
year. Therefore, novel therapeutic approaches to overcome drug resistance are warranted to 
improve the survival outcome of these patients with HER2 positive tumors.
Clinical activity of pembrolizumab in advanced gastric cancer
Immune checkpoint inhibitors such as pembrolizumab have demonstrated durable immune-
mediated antitumor activity in patients with advanced gastric cancer.  Clinical proof of 
concept for pembrolizumab in these patients was demonstrated in Cohort D of the Phase 1b
trial, KEYNOTE-012, which enrolled 39 patients with gastric or GEJ tumors expressing 
PD-L1 assessed using a prototype PD-L1 immunohistochemistry assay [Muro, K., et al 
2016].  Eight of 39 patients had an objective response by RECIST 1.1 using central 
radiologic review for an objective response rate (ORR) of 22% (95% CI: 10, 39).  Cohort 1 
of the Phase II study, KEYNOTE-059 tested pembrolizumab monotherapy in a larger cohort 
of patients whose tumors had progressed on 2 or more lines of systemic therapy (3L+ 
patients). In this study, pembrolizumab monotherapy demonstrated clinically meaningful 
ORR in this heavily treated population for whom there are no other effective agents. Durable 
objective responses were observed in all comer population regardless of PD-L1 status with 
ORR of 12%, while a higher response rate (16%) was observed in the PD-L1 positive 
population [Wainberg, Z. A., et al 2017].  Based on data from KN059, pembrolizumab 
received accelerated approval by the US Food and Drug Administration (FDA) in September 
2017 for treatment of 3L+ patients with tumors expressing PD-L1 (CPS ≥1) assessed by an 
FDA-approved test.  KN059 included 2 additional cohorts where pembrolizumab was tested 
in 1L gastric cancer patients either as monotherapy (Cohort 3) or in combination with a 
fluoropyrimidine and cisplatin (Cohort 2).  Cohort 3 enrolled 31 patients whose tumors 
expressed PD-L1 (CPS ≥1). Cohort 2 enrolled patients irrespective of PD-L1 expression (all-
comers).  In both cohorts, ORR was assessed according to RECIST 1.1 by independent 
central radiological review.  The combination of pembrolizumab with cisplatin and 5-FU or 
capecitabine in Cohort 2 (N 25) yielded an ORR of 60% (95% CI: 39, 79%) and a disease 
control rate (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% confidence interval [CI]: 8.6, 
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NR).  Monotherapy in PD-L1 positive 1L patients (Cohort 3) yielded an ORR of 26% (95% 
CI: 12, 45); median OS was 20.7 months (9.2, 20.7) [Loi, S., et al 2017].
KEYNOTE-061 (NCT02370498) was a global Phase 3 study of pembrolizumab versus 
paclitaxel for previously treated advanced gastric/GEJ cancer. Pembrolizumab reduced the 
risk of death by 18% vs paclitaxel in patients with PD-L1 CPS ≥1, although this difference 
was not statistically significant. Durable benefit of pembrolizumab was demonstrated in this 
trial. After median follow-up of 8 months, 7.8% of patients completed or remained on 
pembrolizumab, vs 0% on paclitaxel. Median OS was 9.1 months with pembrolizumab vs. 
8.3 months with paclitaxel; the difference did not reach statistical significance (HR 0.82, 1-
sided p 0.042). Twelve-month OS rates were 39.8% with pembrolizumab versus 27.1% 
with paclitaxel; 18-month OS rates were 25.7% versus 14.8%. There was no difference in 
PFS or ORR, but pembrolizumab responses were more durable: median duration of response 
was 18 months and 5.2 months for pembrolizumab and paclitaxel, respectively.
Taken together, the data show that pembrolizumab demonstrated durable clinical benefit and 
favorable tolerability in advanced gastric cancer populations.  In the context of the proposed 
trial, it is important to note that pembrolizumab was safe in combination with chemotherapy 
and demonstrated high level of tumor responses regardless of PD-L1 status. 
Mechanistic rationale for the use of pembrolizumab for the treatment of HERer2+ 
gastric cancer in combination with trastuzumab plus chemotherapy
A growing body of preclinical and clinical evidence shows that the immune system 
contributes substantially to the therapeutic effects of trastuzumab in solid tumors.  HER2 
positive cancers have high levels of T-cell infiltration [Loi, S., et al 2013].  The immune 
system plays a key role in the mechanism of action of trastuzumab, an anti-HER2 mAb, 
through ADCC and recruitment of natural killer (NK) cells.  Specifically, evidence indicates
association between immune signature/extent of tumor-infiltrating lymphocytes and response 
to trastuzumab [Kohrt, H. E., et al 2012] [Kohrt, H. E., et al 2014].
Trastuzumab upregulates immune cell function, eg, NK cell degranulation and cytotoxicity, 
which in turn can enhance antitumor immune responses.  However, trastuzumab also 
increases tumor expression of PD1/PD-L1, which has been described as a mechanism of 
resistance to trastuzumab [Park, Y. H. 2011] [Clynes, R. A. 2000] [Loi, S., et al 2014] 
[Stagg, J., et al 2011] [Loi, S., et al 2013]. These observations led to the hypothesis that 
using a dual antibody strategy, combining a tumor-targeting antibody with a second antibody 
that activates the host innate immune system, in combination with standard cytotoxic 
chemotherapy will improve the therapeutic effects of antibodies against metastatic HER2-
expressing tumors.
This hypothesis was tested in a clinical trial recently presented at the San Antonio Breast 
Cancer Symposium [Loi, S., et al 2017].  In this trial, the combination of pembrolizumab and 
trastuzumab was tested in HER2 positive metastatic breast cancer patients who experienced 
progression during prior trastuzumab-based therapy.  The combination was well tolerated 
without a dose-limiting toxicity (DLT) during dose escalation and notably without a cardiac 
event (n 58).  In this trastuzumab-resistant population, promising response rates were 
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observed (ORR of 15.2% and DCR of 24%), thus establishing clinical proof of concept for 
treating patients with a combination of anti-HER2 and anti-PD-1 antibodies.
Although the combination of pembrolizumab, trastuzumab, and chemotherapy has not been
studied extensively, 2 investigator-initiated trials were designed to test whether 
pembrolizumab can be added to current 1L gastric cancer standard-of-care regimen 
(chemotherapy plus trastuzumab) in HER2 positive patients to improve efficacy in a safe 
manner.  Early results from these 2 studies are promising.  Some safety data available from 
2 investigator-initiated trials have demonstrated an acceptable safety profile for this 
combination.
In 1 investigator-initiated trial conducted at Memorial Sloan Kettering Cancer Center in the 
US (NCT02954536), pembrolizumab was combined with trastuzumab, oxaliplatin, and either 
5-FU or capecitabine. Based on data from 18 patients dosed thus far, the combination has 
been safe, with no dose-limiting toxicity (DLT) and no drug-related Grade 4 or Grade 5 
adverse events (AEs) observed. The only drug-related Grade 3 events reported were 
hypokalemia (2), anemia (2), alanine aminotransferase increased (2), lymphocyte decrease 
(1), dehydration (1), nausea (1), rash maculopapular (1), diarrhea (1), and hyponatremia (1). 
There has been no discontinuation of treatment due to drug-related AEs. In addition, 
promising anti-cancer activity was observed, with 14/18 patients achieving objective 
responses (internal MSD data).
In the second investigator-initiated trial, which is ongoing in Korea (NCT02901301), the trial
characteristics and regimens are similar except that this trial used cisplatin instead of
oxaliplatin. Similar preliminary safety results have been observed. Based on results from 
8 patients dosed to date, there have been no DLTs and no drug-related Grade 4 or Grade 5 
AEs in this trial; 4 events of Grade 3 neutropenia have been reported. There has been no
discontinuation of therapy due to drug-related AEs. Among 8 evaluable patients, 6 patients 
experienced objective responses (internal MSD data).
While sample size is limited, these early results are promising relative to the 47% ORR 
observed consistently with current standard of care in HER2 positive gastric cancer patients.  
It is also reassuring that results appear consistent between 2 separate trials conducted in 
different regions.
Taken together, accumulating evidence strongly suggests that combining pembrolizumab 
with current standard-of-care regimen in HER2 positive gastric cancer may improve clinical 
outcome.  Synergistic interaction of pembrolizumab with chemotherapy and trastuzumab 
presents an opportunity to improve survival and duration of clinical benefit.  Given the 
results of these 2 trials combining trastuzumab with pembrolizumab in HER2 positive 
cancer, we propose this multicenter, randomized, double-blind Phase 3 study to determine 
antitumor activity and safety of pembrolizumab and trastuzumab in combination with 
chemotherapy (capecitabine and oxaliplatin [CAPOX], or cisplatin and 5-FU [FP]) compared 
to trastuzumab in combination with chemotherapy in participants with HER2 positive gastric 
cancer (KEYNOTE-811).
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2.2
Background
Pembrolizumab is a potent and highly selective humanized monoclonal antibody of the 
IgG4/kappa isotype designed to directly block the interaction between programmed cell 
death receptor-1 (PD-1) and programmed cell death ligands 1 and 2 (PD-L1 and PD-L2).
Pembrolizumab was approved in September 2014 by the US FDA for the treatment of 
melanoma and for non small cell lung cancer (NSCLC) in October 2015.  In June 2016, the
European Medicines Agency also approved pembrolizumab for NSCLC. In August 2016, 
pembrolizumab received FDA approval for head and neck squamous cell carcinoma.  In 
March 2017, pembrolizumab received FDA approval for the treatment of adults and children 
with relapsed or refractory classical Hodgkin lymphoma, or who have relapsed after 3 or 
more prior lines of therapy.  Recently, pembrolizumab was approved by the FDA for the 
treatment of adult and pediatric patients with unresectable or metastatic microsatellite 
instability-high or mismatch repair deficient in solid tumors that have progressed following 
prior treatment and who have no satisfactory alternative treatment options, or colorectal 
cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and 
irinotecan, and as 3L therapy for PD-L1 positive gastric cancer.  For more information, refer 
to the Investigator’s Brochure (IB).
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Pembrolizumab 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 cluster of differentiation 
(CD)8+ T cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T cells 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.  Programmed cell death-1 (encoded by the gene 
Pdcd1) is an immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004].  Programmed cell 
death-1 and its family members are type I transmembrane glycoproteins containing an Ig-
variable type (IgV type) domain responsible for ligand binding and a cytoplasmic tail 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
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tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif, and an 
immunoreceptor tyrosine-based switch motif.  Following T-cell stimulation, PD-1 recruits 
the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-based switch 
motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such 
as CD3 zeta, protein kinase C-theta, and zeta-chain-associated protein kinase, that are 
involved in the CD3 T-cell signaling cascade [Hunder, N. N., et al 2008] [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].
Refer to the IB/approved labeling for detailed background information on pembrolizumab.
2.2.2
Preclinical and Clinical Studies
Preclinical studies show that monoclonal antibodies against PD1 or CTLA-4 could boost 
substantially the therapeutic activity of anti-HER2 in immunocompetent mice [Bianchini, G. 
2014] [Stagg, J., et al 2011] [Wang, Q., et al 2012].  In particular, Stagg and colleagues
report that optimum activity of anti-HER2 treatment needs type I and type II interferons, and 
interferon γ can also enhance MHC class I and PD-L1 expression on tumor cells [Stagg, J., et 
al 2011].
Pembrolizumab was recently approved as 3L therapy in PD-L1 positive gastric cancer 
patients (KN059, Cohort 1). Additionally, the combination of pembrolizumab with cisplatin 
and 5-FU or capecitabine (KN059, Cohort 2) demonstrated an ORR of 68.0% (95% CI: 
46.5%, 85.1%) and a DCR of 72.0% (95% CI: 50.6%, 87.9%).  In the KN012 study for 
heavily treated gastric cancer [Muro, K., et al 2014], the ORR was 30.8% (95% CI: 17.0%, 
47.6%) and DCR was 43.6%1 (95% CI (27.8%, 60.4%). Pembrolizumab was generally 
tolerated with promising efficacy in gastric cancer.
2.2.3
Ongoing Clinical Trials of Pembrolizumab in Malignancies
Ongoing clinical studies are being conducted in advanced melanoma, NSCLC, a number of 
advanced solid tumor indications including gastric and GEJ adenocarcinomas and 
hematologic malignancies (Table 1). For study details, please refer to the IB. 
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Table 1
Ongoing Clinical Trials of Pembrolizumab in Gastric Cancer
Study
Phase
Treatment
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, second line treatment
KN062
3
Pembrolizumab versus pembrolizumab plus FP, placebo plus FP, 1L treatment
KN063
3
Pembrolizumab versus paclitaxel, second line 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
KN859
3
Pembrolizumab plus cisplatin and 5-FU or oxaliplatin and capecitabine versus cisplatin 
and 5-FU or oxaliplatin and capecitabine, 1L treatment
LEAP-15
3
Pembrolizumab, lenvatinib plus cisplatin and 5-FU or oxaliplatin and capecitabine 
versus cisplatin and 5-FU or oxaliplatin and capecitabine, 1L treatment
1L  first line; 3L  third line; 5 FU 5 fluorouracil; FP cisplatin plus 5 fluorouracil; PD L1  programmed cell death ligand 
1.
2.2.4
Trastuzumab Plus Chemotherapy
The fluoropyrimidine/platinum combination is a common first-line therapy for metastatic 
HER2 positive gastric cancer and it is considered “preferred” by the NCCN Gastric Cancer 
Guideline committee [National Comprehensive Cancer Network 2016].  
Platinum/fluoropyrimidine doublet regimens containing cisplatin or oxaliplatin and 5-FU or 
capecitabine are recognized worldwide as standard first-line chemotherapy regimens for 
participants with metastatic disease. Most commonly used doublet regimens are capecitabine 
plus cisplatin (XP), 5-FU plus cisplatin (FP), capecitabine plus oxaliplatin (CAPOX), and 5-
FU plus oxaliplatin. There are only a few head to head comparisons between these regimens, 
and these trials have demonstrated similar efficacy among these doublet chemotherapy 
regimens in advanced gastric cancer. As such, choices among these regimens are made 
based on patients’ general medical condition and comorbidities in consideration of different 
toxicity profiles of the regimens. This practice pattern is supported by global consensus 
guidelines in treatment of advanced gastric cancer, which recommend use of any of the 
doublet of choice discussed above, plus trastuzumab in patients with HER2 positive gastric 
cancers [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, in combination with trastuzumab in patients with HER2 positive
advanced gastric cancers [Ryu, M. H., et al 2015] [Gong, J., et al 2016] [Bang, Y. J., et al 
2010]. 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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2.2.5
S-1 (Japan SOX Cohort Only)
S-1 is a combination product containing tegafur, a prodrug of 5-FU, and 2 types of enzyme 
inhibitors, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo), in a molar 
ratio of 1:0.4:1. CDHP increases 5-FU concentration by reversible inhibition of 
dihydropyrimidine dehydrogenase, an enzyme that degrades 5-FU, while Oxo, densely 
distributed in gastrointestinal tissues, prevents gastrointestinal toxicity of 5-FU by inhibiting 
its local activation.  S-1 has been developed to enhance therapeutic efficacy in comparison 
with conventional 5-FU products and also to reverse the resulting increase in adverse drug 
reactions.
S-1 has been marketed in Japan since 1999. As of January 2017, S-1 is approved for the 
treatment of gastric cancer, head and neck cancer, colorectal cancer, non small cell lung 
cancer, breast cancer, pancreatic cancer and/or biliary tract cancer. It is approved under the 
trade name of TS-1, S-1, TS-ONE, or Teysuno, in over 45 countries including the European 
countries (mainly the European Union/European Economic Area) and Asian countries 
(mainly Japan). To date, cumulative postmarketing exposure to S-1 is estimated to be 
1,771,593 patients in Japan since first approval in 1999, approximately 126,964 patients in 
other Asian countries, and 3966 patients from the European Economic Area, Israel, and 
Russia since marketing on 14-MAR-2012.
In Japan, combination therapy with fluorinated pyrimidine anticancer agents and platinum 
containing drugs has been recommended as standard treatment. The Japan Clinical 
Oncology Group 9912 Study (5-FU versus irinotecan plus cisplatin versus S-1) revealed 
noninferiority of S-1 monotherapy to continuous IV 5-FU infusion, which was the standard 
treatment at that time, in terms of OS [Boku, N., et al 2009].  The SPIRITS Study (S-1 versus
S-1 plus cisplatin) demonstrated that S-1 plus cisplatin therapy significantly prolonged OS 
compared with S-1 monotherapy [Koizumi, W., et al 2008]. The ToGA trial involving 
HER2- positive gastric cancer patients showed that trastuzumab added to capecitabine or 5-
FU plus cisplatin therapy significantly prolonged OS [Bang, Y. J., et al 2010].
2.2.5.1
Comparison between Cisplatin and Oxaliplatin with S-1
When cisplatin and oxaliplatin are compared, hydration for the prevention of renal toxicity 
before administration is required for cisplatin; thus, whether or not cisplatin can be replaced 
with oxaliplatin has been studied. Because the REAL-2 trial (epirubicin plus cisplatin plus
5-FU versus epirubicin plus cisplatin plus capecitabine versus epirubicin plus oxaliplatin plus
5-FU versus epirubicin plus oxaliplatin plus capecitabine) revealed the noninferiority of the 
oxaliplatin group to the cisplatin group in terms of OS, the efficacy of cisplatin and 
oxaliplatin is considered to be equivalent [Cunningham, D., et al 2008]. In Japan, the G-
SOX study (S-1 plus cisplatin versus S-1 plus oxaliplatin) was conducted to demonstrate the 
noninferiority of S-1 plus oxaliplatin (SOX) therapy to S-1 plus cisplatin therapy [Yamada, 
Y., et al 2015]. While the noninferiority of SOX therapy to S-1 plus cisplatin therapy in 
terms of PFS was shown, the OS result was slightly above the upper limit (1.15) of the 
noninferiority margin (OS, 13.1 months versus 14.1 months; HR, 0.969 [95% CI, 0.812 to 
1.157]). Nonetheless, an ex-post facto (retrospective) analysis using a method to combine 1 
subject excluded at the time of the primary analysis revealed that the upper limit of the 
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hazard ratio was below 1.15 (HR, 0.958 [95% CI, 0.803 to 1.142]). In 2009, the Japanese 
Gastric Cancer Association submitted a request for the expansion of the indication for 
oxaliplatin for unresectable advanced or recurrent gastric cancer. On the basis of results of 
REAL-2 trial and G-SOX study, the clinical usefulness of combination therapy with other 
anticancer agents and oxaliplatin for unresectable advanced or recurrent gastric cancer was 
determined to be a medically and pharmacologically known fact; thus, it was included in 
health insurance treatment in September 2014. In addition, the SOPP study (S-1 plus
cisplatin versus SOX) conducted in South Korea showed the noninferiority of SOX therapy 
to S-1 plus cisplatin therapy in terms of PFS [Ryu, M. H., et al 2015]. Consequently, the 
SOX Q3W regimen is likely to be used as a standard first-line chemotherapy regimen for 
patients with metastatic gastric cancer.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
The safety and promising efficacy data as described above from multiple studies of 
pembrolizumab, chemotherapy, and trastuzumab in our target population indicate a strong 
risk/benefit ratio.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and Informed Consent forms (ICFs).
3
Objectives/Hypotheses and Endpoints
In male and female participants at least 18 years of age with previously untreated, locally 
advanced unresectable or metastatic HER2 positive gastric or GEJ adenocarcinoma: 
Objective/Hypothesis
Endpoint
Primary

Objective:  To compare PFS between 
treatment groups.

Hypothesis (H1):  Pembrolizumab in 
combination with trastuzumab plus 
chemotherapy is superior to trastuzumab 
plus chemotherapy alone in terms of PFS 
per RECIST 1.1 as assessed by blinded 
independent central review (BICR).

PFS: The time from randomization to 
the first documented disease 
progression or death due to any cause, 
whichever occurs first.
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Objective/Hypothesis
Endpoint

Objective: To compare OS between 
treatment groups.

Hypothesis (H2): Pembrolizumab in 
combination with trastuzumab plus
chemotherapy is superior to trastuzumab 
plus chemotherapy alone in terms of OS.

OS: The time from randomization to 
death due to any cause.
Secondary

Objective:  To compare ORR between 
treatment groups.
Hypothesis (H3):  Pembrolizumab in 
combination with trastuzumab plus 
chemotherapy is superior to trastuzumab 
plus chemotherapy alone per RECIST 1.1 
as assessed by BICR in terms of ORR.

Objective Response (OR): Complete 
response (CR) or partial response (PR)

Objective:  To estimate DOR, per 
RECIST 1.1 as assessed by BICR for 
each treatment group.

DOR: The time from first response 
(CR or PR) to subsequent disease 
progression or death from any cause, 
whichever occurs first.

Objective:  To assess the safety and 
tolerability of pembrolizumab in 
combination with trastuzumab plus 
chemotherapy by proportion of adverse 
events (AEs).

Adverse events

Discontinuation of study treatment due 
to AEs
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4
Study Design
4.1
Overall Design
This is a Phase 3, randomized, placebo-controlled, multi-site, double-blind study in 
participants diagnosed with previously untreated, locally advanced unresectable or metastatic 
HER2 positive gastric or GEJ adenocarcinoma.
Approximately 692 participants will be randomized in the Global Cohort in a 1:1 ratio to 
receive pembrolizumab or placebo each in combination with chemotherapy plus trastuzumab.  
The investigator has 2 chemotherapy regimen choices, FP or CAPOX, which must be chosen
prior to randomization in the trial. All participants will receive trastuzumab. Participants
should continue on the fluoropyrimidine and platinum chosen prior to randomization 
throughout the study.  Exceptions may be permitted after consultation with the Sponsor.  
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Participants will be stratified by geographic region, PD-L1 status, and chemotherapy 
treatment prior to randomization.
A Japan-specific SOX cohort will enroll and treat an additional approximately 40 participants 
with trastuzumab, SOX, and either pembrolizumab or placebo.  These participants will be 
stratified by PD-L1 status prior to randomization and their data analyzed separately from the 
Japanese Global Cohort participants, who will be randomized as part of the Global Cohort 
and follow the FP or CAPOX treatment regimens to which they are assigned.
Trial treatment in all arms will begin on Day 1 of each 3-week dosing cycle.  Trial treatment 
should begin on the day of randomization or as close as possible to the date on which the 
participant is allocated/assigned.
Participation in this trial will be dependent upon supplying a tumor tissue specimen.  Only 
participants whose tumors express HER2 positive as determined by the central laboratory 
will be eligible for randomization in this study.  A newly obtained biopsy of a metastatic 
site is preferred to archived samples.  Both formalin solution and formalin-fixed, paraffin 
embedded 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.  The specimen will be evaluated at a 
central laboratory facility for expression status of PD-L1 and for other biomarker analyses.
Participants will undergo the first imaging evaluation at Week 6 (+7 days) after participant
has been randomized. Subsequently, participants will be evaluated every 6 weeks (42 days 
± 7 days), independent of any treatment delays, with radiographic imaging to assess response 
to treatment using RECIST.1.1.  Study treatment will continue until first evidence of
progressive disease (PD).  RECIST 1.1 responses as assessed by BICR will be used as the 
primary efficacy endpoint; ie, PFS.  RECIST 1.1 will be used by the local site for treatment 
decisions.  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 iRECIST (Appendix 9), 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 National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0.
The primary and key secondary objectives of the study are described in Section 3.
Treatment will continue until confirmed disease progression, clinical progression, 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 withdraw the 
participant, participant withdraws consent, pregnancy of the participant, noncompliance with 
trial treatment or procedure requirements, completion of 35 cycles of treatment with 
pembrolizumab/placebo or until the participant has discontinued all other standard of care 
chemotherapy received beyond 35 administrations of pembrolizumab/placebo, achievement 
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of a CR, or administrative reasons. Note: Participants have the option to receive up to 
1 additional year of trastuzumab and capecitabine or 5-FU or S-1 beyond 35 administrations 
of pembrolizumab/placebo at the discretion of the investigator and after Sponsor 
consultation.
Participants who have evidence of PD by imaging and are clinically stable may continue to 
be treated at the discretion of the investigator.  In addition, participants who attain an 
investigator-determined confirmed CR may consider stopping pembrolizumab/placebo 
treatment after receiving at least 8 trial administrations in total and at least 2 additional
administrations of pembrolizumab/placebo after achieving confirmed CR.
Participants who have achieved SD or better may be eligible for up to 17 additional 
pembrolizumab cycles if they experience radiographic disease progression after completing 
35 administrations of pembrolizumab/placebo treatment 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 treatment and are able to 
participate in the Second Course Phase only if they were receiving pembrolizumab
originally, and if the study remains open. Response or progression in the Second Course 
Phase will not count toward the PFS of the primary endpoint in this trial.  The decision to 
retreat will be at the discretion of the investigator only if no cancer treatment was 
administered since the last dose of study treatment and the participant still meets the safety 
parameters listed in the Inclusion/Exclusion criteria (refer to Section 6.7 for further details).  
After the end of treatment, each participant will have a 30-day follow-up assessment for AE
monitoring (serious adverse events and events of clinical interest (ECI) will be collected for 
90 days after the end of treatment or 30 days after the end of treatment if the participant
initiates new anticancer therapy, whichever is earlier).  Participants who discontinue 
treatment for reasons other than PD will have post-treatment follow-up for disease status 
until PD, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to 
follow-up.  All participants will be contacted every 12 weeks (±14 days), or more often as 
needed, for OS until death, withdrawal of consent or the end of the trial, whichever comes 
first.
Details about interim analyses are in Section 9.7. An independent, external Data Monitoring 
Committee (DMC) will monitor the safety and efficacy of this study.
This study will be conducted in conformance with Good Clinical Practices (GCP).
NOTE:  Protocol operational items specific to Japan and Germany are found in
Section 10.6, Appendix 6, Country-specific Requirements.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities (SoA), Section 1.3. 
Details of each procedure are provided in Section 8.
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4.2
Scientific Rationale for Study Design 
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
Primary Efficacy Endpoints 
The primary efficacy endpoints in this trial are OS and PFS; the latter 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 a central imaging vendor 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 determination of radiologic 
progression as determined by central review will be communicated to the site.
OS is the gold standard for a “hard endpoint” in clinical studies in the area of oncology.  
However, OS results, especially in 1L setting, are often confounded by subsequent therapy.
In the US/EU, gastric cancer is a rare tumor type and most patients have advanced or 
metastatic disease at the time of diagnosis. Because of the limited number of patients in 
Western countries and the multiple companies developing this class of drugs for gastric 
cancer, a high crossover rate is expected for control arm participants who are treated in 
subsequent trials outside of this protocol.
The largest meta-analysis (36 trials, 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. This trial will use a dual endpoint of OS 
and PFS.  RECIST 1.1 by BICR will be used to determine the dates of progression as this 
methodology is accepted by regulatory authorities.
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (Section 8.2.1.5).  Although traditional RECIST 
1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ.
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.1.6).  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 PD by RECIST 1.1 but not by the immune-related response criteria 
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[Wolchok, J. D., et al 2009] had longer OS 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 FDA and the European 
Medicines Agency [Seymour, L., et al 2017].  The unidimensional measurement of target 
lesions, qualitative assessment of non-target 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.
4.2.1.1.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints in this trial will be OR and DOR.  
Objective Response by RECIST 1.1 criteria as assessed by BICR is considered evidence of
efficacy and is a secondary endpoint for this trial.  Substantial improvement of OR that is 
accompanied by duration of response will be considered clinically important surrogate of 
benefit.
Duration of Response by RECIST 1.1 criteria and assessed by BICR is a commonly accepted 
endpoint by both regulatory authorities and the oncology community to assess durability of 
responses to oncology treatments.
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anti-cancer
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. 
Adverse events will be assessed as defined by CTCAE, Version 4.0.
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4.2.1.4
Pharmacokinetic Endpoints
Blood samples will be obtained to measure pharmacokinetics (PK) of serum pembrolizumab 
and trastuzumab. Blood samples will also be obtained to measure anti-drug antibodies
(ADA) of pembrolizumab and trastuzumab in both arms.  Simultaneous PK sampling is 
required for interpretation of ADA analysis. 
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4.2.2
Rationale for the Use of Comparator/Placebo
4.2.2.1
Rationale of 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 Trastuzumab Plus Pembrolizumab in Gastric 
Cancer
As noted in Section 2.2.4, treatment with trastuzumab results in beneficial, yet limited, 
clinical improvement for patients with HER2 positive esophagogastric (EG) cancer.  
Antibody-dependent cell-mediated cytotoxicity by NK cells contributes to the efficacy of 
trastuzumab [Kohrt, H. E., et al 2012] [Kohrt, H. E., et al 2014].  Junttila et al demonstrated 
that combining a trastuzumab-based bispecific antibody HER2-TDB with anti-PD-L1 yielded 
a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates 
and durability of therapeutic response [Junttila, T. T., et al 2014].
Preclinical studies show that monoclonal antibody against PD-1 boost substantially the 
efficacy of anti-HER2 treatment.  Stagg et al demonstrated synergistic activity of anti-PD-1 
and trastuzumab.  Combining trastuzumab with anti-PD-1 antibody showed greater tumor 
regression over trastuzumab alone in positive mouse model.
Data from ongoing KN014-PANACEA trial Phase Ib/II trial evaluating the efficacy of 
pembrolizumab and trastuzumab in participants with trastuzumab-resistant, HER2-positive, 
metastatic breast cancer (NCT02129556) indicate that the combination of pembrolizumab 
and trastuzumab is generally safe and effective.
Two Phase 2 MISP trials have been initiated to evaluate the trastuzumab/pembrolizumab 
combination plus chemo in HER2+ EG cancer.  In the first study, performed at Memorial 
Sloan Kettering Cancer Center, no DLT or significant AEs were reported in the first 14 
participants enrolled. In the second study, performed in Korea, no DLT or significant AEs 
were reported in the first 9 participants enrolled (Section 2.1).
Based on these data showing synergistic effect, we hypothesize that enhanced NK cell 
degranulation and cytotoxicity using PD-1 blockade will result in synergistic activity of 
pembrolizumab in combination with trastuzumab.  We further hypothesize that using a dual 
antibody strategy, combining a tumor-targeting antibody with a second antibody that 
activates the host innate immune system, in combination with standard cytotoxic 
chemotherapy will improve the therapeutic effects of antibodies against metastatic HER2-
expressing EG tumors.
4.2.2.3
Rationale for the Use of Trastuzumab, FP and CAPOX in Gastric Cancer
Systemic chemotherapy is the mainstay of treatment for advanced and metastatic gastric 
cancer (NCCN/ESMO guidelines).  Platinum/fluoropyrimidine doublet regimens containing 
cisplatin, 5-FU, or capecitabine are recognized worldwide as standard first-line 
chemotherapy regimens for participants with metastatic disease.  Most commonly used 
doublet regimens are cisplatin plus capecitabine, FP, CAPOX), and 5-FU plus oxaliplatin. 
There are only a few head to head comparisons between these regimens, and these trials have 
demonstrated similar efficacy among these doublet chemotherapy regimens in advanced 
gastric cancer. As such, choices among these regimens are made based on patients’ general 
medical condition and comorbidities in consideration of different toxicity profile of the 
regimens. This practice pattern is supported by global consensus guidelines in treatment of 
advanced gastric cancer, which recommend use of any of the doublet of choice discussed 
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above, plus trastuzumab in patients with HER2 positive gastric cancers [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, in combination with trastuzumab in patients with HER2+ advanced gastric cancers 
[Ryu, M. H., et al 2015] [Gong, J., et al 2016] [Bang, Y. J., et al 2010]. These 2 regimens are 
expected to have similar efficacy, and these regimens will allow investigators a choice based 
on each patient’s medical condition.
The current trial will use FP or CAPOX plus trastuzumab as the standard of care backbone 
regimens. Investigators will have a choice between FP plus trastuzumab and CAPOX plus 
trastuzumab. As discussed above, these 2 regimens are routinely used in clinical practice 
globally, in combination with trastuzumab in patients with HER2 positive advanced gastric 
cancers [Ryu, M. H., et al 2015] [Gong, J., et al 2016] [Bang, Y. J., et al 2010]. These 2
regimens are expected to have similar efficacy, and these regimens will allow investigators 
choices based on patients’ medical conditions. It is important to note that these 2 regimens 
used in investigators’ led trials discussed earlier, and they were safe in combination with 
pembrolizumab with promising early efficacy results.
The current trial will have a Japan-specific SOX cohort (N 40) that will allow use of SOX.
Japanese investigators will use SOX plus trastuzumab as backbone therapy in this cohort. 
This cohort will be analyzed separately from the main protocol data and will not be included 
in the analysis of the primary endpoints.
4.3
Justification for Dose 
4.3.1
Pembrolizumab Dose
The planned dose of pembrolizumab for this study is 200 mg Q3W. 
Based on the totality of data generated in the Keytruda development program, 200 mg Q3W 
is an appropriate dose of pembrolizumab for adults across all indications. As outlined below, 
this dose is justified by: 

Clinical data from 8 randomized studies in melanoma and NSCLC indications
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2)

Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W

Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
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treated, PD-L1 enriched and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). 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.  Studies in other cancer types confirmed 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.  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
Standard of Care Chemotherapy Backbone: FP Dose
Cisplatin (80 mg/m2 administered on Day 1 of each treatment cycle, Q3W) plus 5-FU 
(800 mg/m2/day administered from Day 1 to Day 5 of each treatment cycle Q3W, 120 hours
or per local standard). 
4.3.3
Standard of Care Chemotherapy Backbone: CAPOX Dose
Oxaliplatin 130 mg/m2 on Day 1 of each cycle (Q3W) over 2 hours plus capecitabine 
1000 mg/m2 twice daily (BID) on Days 1-14 of each cycle (Q3W).
4.3.4
Standard of Care: Trastuzumab Dose
Trastuzumab 8 mg/kg loading dose and then 6 mg/kg maintenance thereafter (Q3W).
4.3.5
SOX Dose (Japan SOX Cohort Only)
S-1 <1.25 m2 body surface area (BSA) 40 mg BID; 1.25 to <1.5 m2 BSA 50 mg BID; ≥1.5 
m2 BSA 60 mg bid on Days 1-14 of each cycle (Q3W), plus oxaliplatin 130 mg/m2 on Day 1 
of each cycle (Q3W) over 2 hours.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related contact or visit, withdraws from the 
study or is lost to follow-up (ie, the participant is unable to be contacted by the investigator).
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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
5.1
Inclusion Criteria
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Male/female participants who are at least 18 years of age on the day of signing the 
informed consent with histologically or cytologically confirmed diagnosis of previously 
untreated, locally advanced unresectable or metastatic HER2 positive gastric or GEJ 
adenocarcinoma.
2. Be HER2-positive defined as either IHC 3+ or IHC 2+ in combination with ISH+ (or 
FISH), as assessed by central review on primary or metastatic tumor.  ISH positivity is 
defined as a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of signals 
for CEP17.  If the ratio is <2.0 but the HER2 gene copy number is >6 the participant may 
be considered ISH-positive.
3. Have measurable disease as defined by RECIST 1.1 by scans with IV contrast as 
determined by the site investigator. Tumor 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.
Male participants:
4. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least:

180 days after the last dose of chemotherapy; no male contraception is needed for 
pembrolizumab and trastuzumab.

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
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
Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 3]) as detailed below:
o
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 are more stringent than the 
requirements above, the local label requirements should be followed.
Female participants:
5. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least 1 of the following conditions applies: 

Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
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 3 during the intervention period and for at 
least 120 days after the last dose of pembrolizumab, and 210 days after trastuzumab, 
180 days after the last dose of chemotherapy, whichever is longest, 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.
o
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 
as required by local regulations) within 24 hours before the first dose of study 
intervention.
o
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 8.3.6 and Appendix 3.

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.
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Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed.
Informed Consent
6. The participant (or legally acceptable representative if applicable) provides documented
informed consent for the trial. 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.
In Japan, document agreement is necessary for both the participant and their substitute 
when participants are under 20 years of age.
Other Inclusions
7. Have a performance status of 0 or 1 on the ECOG Performance Scale within 3 days prior 
to the first dose of trial treatment.
8. Have a life expectancy of greater than 6 months.
9. Participants must have a 12-lead electrocardiogram (ECG) and echocardiogram (ECHO) 
or multigated acquisition (MUGA) scan performed by the investigator or other qualified 
person to evaluate cardiac function prior to enrollment in the study. Adequate cardiac 
function will be assessed by:

Left ventricular ejection fraction (LVEF) ≥55% as determined by MUGA scan or 
ECHO. Note: Participants with EF 50 to 54 may still be eligible with discussion with 
Sponsor AND after consultation with cardiology AND after being medically 
optimized; and

QT interval calculated according to the Fridericia method (QTcF) value ≤470 msec 
for males and ≤480 msec for females (mean of 3 measurements corrected for heart 
rate using Fridericia’s formula).
10. Have provided tumor tissue sample deemed adequate for PD-L1 and MSI biomarker 
analysis. The PD-L1 result must be determined as positive or negative.
11. Have adequate organ function as defined in the following table (Table 2). Specimens 
must be collected within 10 days prior to the start of study treatment.
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/mcL
Platelets
≥100,000/mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L1
Renal
Creatinine OR
Measured or calculated2 creatinine 
clearance
(Glomerular filtration rate can also be used 
in place of creatinine or CrCl)
≤1.5 × upper limit of normal (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
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 OR
≤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
≤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; PT prothrombin time; ULN upper limit of normal.
1 Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. 
2 Creatinine 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:
1. Has had previous therapy for locally advanced unresectable or metastatic gastric/GEJ 
cancer. Participants may have received prior neoadjuvant or adjuvant therapy as long as 
it was completed at least 6 months prior to randomization and there was no evidence of 
progression within the timeframe.
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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 
treatment.
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting study treatment.
3. Has had radiotherapy within 14 days of randomization. Participants must have recovered 
from all radiation-related toxicities, not require corticosteroids, and not have had 
radiation pneumonitis.  A 1-week washout is permitted for palliative radiation (≤2 weeks 
of radiotherapy) to non-CNS disease.
4. Has a known additional malignancy that is progressing or has required active treatment 
within the past 5 years.  Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer.
5. 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 
treatment. 
6. 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, etc.) is not considered a form of systemic 
treatment and is allowed.  
7. 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 the first dose of trial drug.
8. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
9. Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis). No testing 
for TB is required unless mandated by local health authority.
Note: For Germany and the UK, TB testing is mandatory.
10. Has an active infection requiring systemic therapy.
11. Has poorly controlled diarrhea (eg, watery stool, uncontrollable bowel movement with 
drugs, Grade ≥2 and number of defecations, ≥5/day).
12. Accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs
within 2 weeks prior to enrollment. If the participant is receiving diuretic drugs for other 
reasons, it is acceptable.
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13. Has a history or current evidence of any condition (eg, known deficiency of the enzyme 
dihydropyrimidine dehydrogenase, hearing impairment, etc.), therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the participant’s 
participation for the full duration of the trial, or is not in the best interest of the participant
to participate, in the opinion of the treating investigator. Participants with a 
contraindication to standard-of-care therapy should be excluded, ie:

Participants with a history of a severe and unexpected reaction to a fluoropyrimidine-
containing treatment.

Participants with severe dyspnea at rest related to advanced disease stage or oxygen-
dependent complications.

Participants presenting with clinically significant dehydration should avoid a 
cisplatin-containing regimen.

Participants with hypokalemia, hypomagnesemia, or hypocalcemia.

Participants with evidence of neutropenia should not be assigned to an 
oxaliplatin-containing regimen as recommended by the local package insert.

Participants with severe leukopenia should not be assigned to a 
capecitabine-containing regimen.
14. Has peripheral neuropathy > Grade 1.
15. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the trial.
16. A WOCBP who has a positive urine pregnancy test within 24 hours prior to 
randomization or treatment allocation (see Appendix 3). If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
Note:  In the event that 24 hours have elapsed between the screening pregnancy test and 
the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for participant to start receiving study 
medication.
17. Removed.
18. Has active or clinically significant cardiac disease including:

Symptomatic congestive heart failure (CHF) (ie, New York Heart Association Class 
II or higher)

History or current evidence of clinically significant cardiac arrhythmia requiring anti-
arrhythmic therapy other than beta blockers or digoxin and/or conduction abnormality 
within 6 months prior to start of study treatment except atrial fibrillation and 
paroxysmal supraventricular tachycardia

Active coronary artery disease
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
Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before 
randomization

Myocardial infarction within 6 months before randomization
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).  
No testing for HIV is required unless mandated by local health authority.
Note: For Germany and the UK, HIV testing is mandatory.
20. 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. No testing for hepatitis B and hepatitis C is required unless mandated 
by local health authority.
Note: For Germany and the UK, hepatitis B and C testing is mandatory.
21. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, trastuzumab, study 
chemotherapy agents and/or to any excipients, murine proteins, or platinum-containing 
products.
22. Has had an allogeneic tissue/solid organ transplant.
Prior/Concomitant Therapy
23. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 
40, CD137)
24. Has received a live or live attenuated vaccine within 30 days prior to the first dose of 
study treatment. Note: Killed vaccines are allowed.
Prior/Concurrent Clinical Study Experience
25. 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 
treatment.
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.
5.3
Lifestyle Considerations
No 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.
5.3.5
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.  If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor.  All 
pregnancies must be reported and followed as described in Section 8.4.
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 adverse events (AEs) or serious adverse 
events (SAEs) meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the study will not be 
replaced.
6
Treatments
Study treatment is defined as any investigational treatment(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 treatment(s) provided by the Sponsor] will be packaged to support 
enrollment as required. Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
6.1
Treatments Administered
The treatments to be used in this study are outlined in Table 3.
Country-specific requirements are noted in Appendix 6.
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Table 3
Study Treatments
Arm Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)c
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment
Period/
Vaccination 
Regimen
Use
IMP and 
NIMP/AxMP Sourcing
Pembrolizumab
Experimental
Pembrolizumab 
(MK 3475)
Biological/
Vaccine
Vial
25 mg/mL
200 mg
IV 
Infusion
Day 1 of each 
cycle (Q3W)
Test Product
IMP
Central
Placebo
Placebo 
Comparator
Placebo
Drug
Solution for 
Infusion
N/A
N/A
IV 
Infusion
Day 1 of each 
cycle (Q3W)
Placebo
IMP
Local
FPa
Experimental
Cisplatinb
Drug
Vial
1 mg/mL
80 mg/m2
IV 
Infusion
Day 1 of each 
cycle (Q3W)
Background 
Treatment
NIMP/AxMP
Central or 
Local
FPa
Experimental
5 FUb
Drug
Vial
25 mg/mL
50 mg/mL
800 mg/m2
IV 
Infusion
Continuous on 
Days 1 to 5 of 
each cycle 
(Q3W) 
(120 hours, or 
per local 
standard)
Background 
Treatment
NIMP/AxMP
Central or 
Local
CAPOXd
Experimental
Oxaliplatinb
Drug
Vial
5 mg/mL
130 mg/m2
IV 
Infusion
Day 1 of each 
cycle (Q3W) 
over 2 hours
Background 
Treatment
NIMP/AxMP
Central or 
Local
CAPOXd
Experimental
Capecitabineb
Drug
Tablet
150 mg 
or
500 mg
1000 mg/m2
Oral
BID on Days 1 to 
14 of each cycle 
(Q3W)
Background 
Treatment
NIMP/AxMP
Central or 
Local
SOX (Japan 
Only)
Experimental
S 1b
Drug
Capsule
20 mg
or
25 mg
40 mg (<1.25 
m2 BSA) 
50 mg (1.25 to 
<1.5 m2 BSA)
60 mg (≥1.5 
m2 BSA)
Oral
BID Days 1 to 14 
of each cycle 
(Q3W)
Background 
Treatment
NIMP/AxMP
Local
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Arm Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)c
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment
Period/
Vaccination 
Regimen
Use
IMP and 
NIMP/AxMP Sourcing
SOX (Japan 
Only)
Experimental
Oxaliplatinb
Drug
Vial
5 mg/mL
130 mg/m2
IV 
Infusion
Day 1 of each 
cycle (Q3W) 
over 2 hours
Background 
Treatment
NIMP/AxMP
Local
All Cohorts
Experimental
Trastuzumabb
Drug
Vial
60 mg vial 
(Japan only)
150 mg vial
420 mg vial
440 mg vial
600 mg vial
8 mg/kg 
loading dose, 
6 mg/kg 
maintenance 
IV 
Infusion
Day 1 of each 
cycle (Q3W)
Background 
Treatment
NIMP/AxMP
Central or 
Local
5 FU 5 fluorouracil; BID twice daily; BSA body surface area; CAPOX capecitabine/oxaliplatin; CDHP 5 chloro 2,4 dihydroxypyridine; CR complete response; FP cisplatin 
plus 5 fluorouracil; IMP investigational medicinal product; IV intravenous; NIMP non investigational medicinal product; Oxo
potassium oxonate; AxMP 
auxiliary medicinal 
product, Q3W every 3 weeks; S 1 combination product containing tegafur, a prodrug of 5 FU, and 2 types of enzyme inhibitors, CDHP and Oxo; SOX S 1 plus oxaliplatin
Definitions of IMP, NIMP, and AxMP are based on guidance issued by the European Commission. Regional and/or country differences of the definition of IMP and NIMP/AxMP
may exist.  In these circumstances, local legislation is followed.
Pembrolizumab/trastuzumab will be administered until disease progression, completion of 35 cycles, or other discontinuation criteria are met.
Participants have the option to receive up to 1 additional year of trastuzumab and capecitabine or 5 FU or S 1 beyond 35 administrations of pembrolizumab/placebo at the 
discretion of the investigator and after Sponsor consultation. Pembrolizumab/placebo treatment is not allowed beyond 35 administrations in the initial treatment course. 
Participants who stop pembrolizumab/placebo treatment after 35 administrations, for reasons other than disease progression or intolerability, or participants who attain a CR and 
stop trial treatment, may be eligible for up to 17 additional administrations of pembrolizumab upon experiencing disease progression if they are randomized to the pembrolizumab 
arm.
a FP: Duration of cisplatin treatment may be capped at 6 cycles as per local country guidelines; however, treatment with 5 FU may continue per protocol.
b Chemotherapy options and trastuzumab are used in both the experimental and placebo arms.
c The strength of treatment may vary depending on the source.  The table captures the current available strengths but could vary depending on availability.
d CAPOX: duration of oxaliplatin may be capped at 6 or 8 cycles as per local country guidelines; however, treatment with capecitabine may continue per protocol.
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All supplies indicated in Table 3 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number where possible (eg, not applicable in the case where 
multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study treatment.
Use of 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.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
The rationale for selection of dose of pembrolizumab to be used in this trial is provided in 
Section 4.3.1.  Details on preparation and administration of pembrolizumab are provided in 
the pharmacy manual.
Dose preparation must be done by separate unblinded trial personnel.  Dose administration 
must be done by blinded trial personnel.
Preparation of trastuzumab, cisplatin, 5-FU, and capecitabine should follow the local product 
label.  The BSA in m2 should be calculated per local guidance.
6.2.2
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment 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.
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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 
treatments in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Method of Treatment Assignment
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study treatment arms. Participants will be assigned 
randomly in a 1:1 ratio to pembrolizumab and placebo, respectively.
6.3.1.1
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Geographic region (Global Cohort only) 

Europe/Israel/North America/Australia

Asia

Rest of the World (including South America)
2. PD-L1 status (positive versus negative)
3. Chemotherapy regimen (FP or CAPOX)
Japan-specific SOX cohort
1. PD-L1 status (positive versus negative)
6.3.2
Blinding 
A double-blinding technique will be used. Study medications will be prepared and/or 
dispensed according to the specifications in the pharmacy manual. The participant and the 
investigator who is involved in the study treatment administration or clinical evaluation of 
the participants are unaware of the group assignments.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.4
Treatment Compliance
Interruptions from the protocol-specified treatment plan for greater than 12 weeks between
pembrolizumab doses for non-study medication-related or administrative reasons require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
For those medications taken at home, the site will validate compliance with study medication 
at each site visit according to their standard operating procedure.
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6.5
Concomitant Therapy
6.5.1
Specific Restrictions
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 treatment may be required. The 
investigator should discuss any questions regarding this with the Sponsor 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 treatment requires the mutual agreement of the investigator, the Sponsor and the 
participant.
The following medications and vaccinations are prohibited during the course of the study:

Anticancer immunotherapy, chemotherapy, or biological therapy not specified in this 
protocol

Investigational agents other than pembrolizumab

Radiation therapy
Note: Palliative radiation therapy to a symptomatic lesion (eg, bony metastasis), or to the 
brain may be permitted 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 treatment,
while participating in the study, for at least 90 days after the last study treatment, and per 
local standard of care.  Note: Killed vaccines are allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy. 
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.

Systemic glucocorticoids except when used for the following purposes:
o
To modulate symptoms from an AE that is suspected to have an immunologic 
etiology
o
For the prevention of emesis
o
To premedicate for IV contrast allergies
o
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses 
>10mg/day prednisone equivalent)
o
For chronic systemic replacement, not to exceed 10 mg/day prednisone equivalent
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
Other glucocorticoid use except when used for the following purposes:
o
For topical use or ocular use
o
Intraarticular joint use
o
For inhalation in the management of asthma or chronic obstructive pulmonary disease

For participants receiving 5-FU, S-1 or capecitabine:
o
Brivudine, sorivudine analogs, and other inhibitors of the enzyme dihydropyrimidine
dehydrogenase

For participants receiving cisplatin:
o
Phenytoin should not be started with cisplatin therapy.

Pre-cisplatin treatment with corticosteroids per NCCN or institutional guideline is 
permitted.
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 unless 
otherwise specified.
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.
For participants receiving cisplatin:

Concomitant administration of nephrotoxic (eg, cephalosporins, aminoglycosides,
Amphotericin B or contrast media) or ototoxic (eg, aminoglycosides) medicinal products 
will potentiate the toxic effect of cisplatin. 
For participants receiving oxaliplatin:

Caution is advised when oxaliplatin treatment is co-administered with other medicinal 
products known to cause QT interval prolongation. In case of combination with such 
medicinal products, the QT interval should be closely monitored. 

Caution is advised if medicinal products associated with rhabdomyolysis are 
administered concomitantly with 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 electronic case report form
(eCRF) including all prescription, over-the-counter products, herbal supplements, and IV 
medications and fluids.  If changes occur during the study period, documentation of drug 
dosage, frequency, route, and date should also be included on the eCRF.
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All concomitant medications received within 28 days prior to the first dose of study treatment
and up to 30 days after the last dose of study treatment should be recorded.  Concomitant
medications administered 30 days after the last dose of study treatment should be recorded 
for SAEs and ECIs as defined in Section 8.4.7.
6.5.2
Rescue Medications and Supportive Care
6.5.2.1
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 
Day 1, 80 mg Day 2, 80 mg Day 3
2. Plus Aloxi (palonosetron) 0.25 mg IV
Nausea may also be managed with:
1. Zofran (ondansetron) 8 mg BID
2. Or Compazine (prochlorperazine) 10 mg 3-4 times per day
Additionally, use of steroids for cisplatin associated anti-emetic support is allowed and is to 
follow the NCCN or institutional guidelines.  However, caution must be exercised to prevent 
the overuse of steroids.
Please refer to the product label or local standards of care for additional cisplatin supportive 
measures.
6.5.2.2
Supportive Care Guidelines for 5-FU
Please refer to the product label or local standards of care for 5-FU supportive measures.
6.5.2.3
Supportive Care Guidelines for Capecitabine
Please refer to the product label or local standards of care for capecitabine supportive 
measures.
6.5.2.4
Supportive Care Guidelines for Oxaliplatin
Please refer to the product label or local standards of care for oxaliplatin supportive 
measures.
6.5.2.5
Supportive Care Guidelines for S-1 (Japan SOX Cohort Only)
Please refer to the product label or local standards of care for S-1 supportive measures.
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6.5.2.6
Supportive Care Guidelines for Trastuzumab
Please refer to the product label or local standards of care for trastuzumab supportive 
measures.
6.5.3
Curative Surgery
In general, surgical resection in participants who have metastatic disease is not encouraged,
except in exceptional cases as the benefit of surgery is unknown in this setting. However, if it 
is determined that participants are eligible for a potential curative surgical resection, in the 
event of strong tumor response, please contact the Sponsor for guidance. Participants who 
have curative surgery while on study will be defined as participants who have had tumor 
resection and postresection imaging restaging to include at minimum contrasted CT chest, 
abdomen, pelvis, plus imaging of any part of the body previously known to have tumor, all of 
which must show no residual disease in the participant. Contrasted MRI or PET CT may be 
allowed, if appropriate, for restaging imaging. Participants who have surgery should continue 
imaging as detailed in the SoA (Section 1.3) until PD, or they otherwise meet the 
discontinuation criteria (Section 8.2.1.2 and Section 8.2.1.3).
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Dose Selection (Preparation)
The rationale for selection of dose of pembrolizumab to be used in this trial is provided in 
Section 4.3.1.  Details on preparation and administration of pembrolizumab are provided in 
the pharmacy manual.
Preparation of oxaliplatin, cisplatin, 5-FU, capecitabine, and S-1 should follow the local 
product label.  The BSA in m2 should be calculated per local guidance.  The dose of 
chemotherapy and trastuzumab should be recalculated for fluctuation of body weight ≥10%
at the beginning of a cycle only.  For weight fluctuation <10%, recalculation may be done at 
the discretion of the investigator. When recalculating, BSA in m2 should be calculated per 
local guidance.
6.6.2
Dose Modification and Toxicity Management
The investigator may attribute each toxicity event to oxaliplatin, cisplatin, S-1 (Japan only), 
5-FU, capecitabine, trastuzumab, or pembrolizumab alone and use a stepwise dose reduction 
according to Table 4 through Table 14.  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 treatment.  

Pembrolizumab and trastuzumab dose reductions are not permitted.  Pembrolizumab or 
trastuzumab treatment may be interrupted or discontinued due to toxicity.  

If a dose reduction for toxicity occurs with any agent, the dose may not be re-escalated.  

Participants can have a maximum of 2-dose modifications for toxicities (if applicable) to
5-FU, cisplatin, capecitabine, and S-1 (Japan only), a maximum of 3-dose modifications 
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to oxaliplatin 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 on 1 of the treatments.  If, in 
the opinion of the investigator, the toxicity is related to the combination of both 
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 and/or trastuzumab should be interrupted or discontinued according to 
the recommended dose modifications.

Both groups may have trastuzumab and/or the chemotherapy discontinued and continue
to receive pembrolizumab/placebo.
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be 
used to grade the severity of adverse events.  All dose modifications should be based on the 
AE requiring the greatest dose modification.  Dose modifications are detailed in Table 4
through Table 14.  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 oxaliplatin, cisplatin, 5-FU, capecitabine, trastuzumab, and S-1 (Japan only) 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 4 (pembrolizumab) and Section 6.5.2.
6.6.3
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab and IO Combination Therapy
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 1 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 4.
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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 5. 
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Table 5
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 hours
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 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 
treatment.
Participant may be premedicated 1.5 h 
(±30 minutes) prior to infusion of 
pembrolizumab 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 
treatment.
No subsequent dosing
CTCAE=Common Toxicity Criteria for Adverse Events; IV=intravenous; NCI= National Cancer Institute; NSAID=non-steroidal anti-inflammatory drug; 
po=per OS (orally).
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the CTCAE v4.0 at http://ctep.cancer.gov.
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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.
6.6.4
Dose Modification and Toxicity Management for CAPOX, FP, and SOX
Please refer to criteria for dose modification and discontinuation in Table 6, Table 7, and 
Table 8 for CAPOX; Table 9, Table 10, and Table 11 for FP; and Table 12, Table 13, and 
Table 14 for SOX. 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. If a dose reduction for 
toxicity occurs with any agent, the dose may not be re-escalated.
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.
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).  
If a toxicity is not otherwise specified, investigators should refer to the label or local 
guidelines for dose adjustments.
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6.6.4.1
CAPOX Dose Modification
Table 6
Recommended 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 bid
750 mg/m2 bid
500 mg/m2 bid
Discontinue
Discontinue
bid=twice daily; CAPOX=capecitabine/oxaliplatin
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Table 7
Recommended 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
Hematologic1
Neutropenia5
2-32
Neutrophil count
resolves to
≥1500/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
42
Neutrophil count
resolves to
≥1500/mm3
Reduce by 1 DL
If >3 DL reductions exceeded
Febrile neutropenia
3-42
Toxicity resolves
Reduce by 1 DL
If >3 DL reductions exceeded
Thrombocytopenia
3-42
Platelet count 
resolves to 
≥75,000/mm3
Reduce by 1 DL3
If >3 DL reductions exceeded
Non-
hematologic1
Creatinine increased
≥1.5 mg/dL2
<1.5 mg/dL
No reduction
If >3 DL reductions exceeded
Peripheral sensory 
neuropathy4
3-42
Grade 0-2
Reduce by 1 DL
If >3 DL reductions exceeded
All other non-
hematologic 
toxicities1
3-4
2
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
If >3 DL reductions exceeded
Laboratory Adverse
Events6
3-4
2
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
If >3 DL reductions exceeded
AE adverse event; DL dose level; G CSF granulocyte colony stimulating factor
1 Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion.
2 Permanent discontinuation should be considered for any severe or life threatening event.  Consult Sponsor before restarting treatment after Grade 4 drug related AE.
3 Dose reduction at Grade 3 is at the discretion of the investigator but not required.
4 Administration may be interrupted or reduced at the discretion of the investigator.
5 See the package insert of each G CSF drugs for administration of G CSF for neutropenia.
6Allow continuous treatment for non clinical significant lab AE, such as low MG, CA, or K, that is asymptomatic and deemed to be safe by the investigator.
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Table 8
Recommended 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
Hematologic
Neutropenia
2-31
Neutrophil count resolves
to >1500/mm3
No Reduction
*consider G-CSF
Toxicity does not resolve within
4-5 weeks of last administration
or if >2 DL reductions exceeded
4
1
Neutrophil count resolves
to >1500/mm3
Reduce by 1 DL
*consider G-CSF
Toxicity does not resolve within
4-5 weeks of last administration
or if >2 DL reductions exceeded
Febrile
Neutropenia
2-3
1
Toxicity resolves
Reduce by 1 DL
Toxicity does not resolve within
4-5 weeks of last administration
or if >2 DL reductions exceeded
4
1
N/A
Discontinue
Permanently discontinue 
Thrombocytopenia
2-41
Platelet count resolves to 
≥75,000/mm3
Reduce by 1 DL
Toxicity does not resolve within
4-5 weeks of last administration
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 administration
or if >2 DL reductions exceeded
4
N/A
Discontinue
Permanently discontinue 
All other non-
hematologic 
toxicities
2-41
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within
4-5 weeks of last administration
or if >2 DL reductions exceeded
Laboratory Adverse
Events2
41
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within
4-5 weeks of last administration
or if >2 DL reductions exceeded
AE adverse event; DL dose level; G CSF granulocyte colony stimulating factor; N/A not applicable
1Permanent discontinuation should be considered for any severe or life threatening event. Consult Sponsor before restarting treatment after Grade 4 drug related AE.
2Allow continuous treatment for non clinical significant lab AE, such as low MG, CA, or K, that is asymptomatic and deemed to be safe by the investigator.
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6.6.4.2
FP Dose Modification
Table 9
Recommended 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
5 FU 5 fluorouracil; FP  cisplatin plus 5 fluorouracil
Table 10
Recommended 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
Hematologic3
Neutropenia
31
Neutrophil count resolves
to >1000/mm3
No
Reduction
*consider G-
CSF
Toxicity does not resolve within 4 weeks
of last infusion or if >2 DL reductions
exceeded
4
1
Neutrophil count resolves
to >1000/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
1
Toxicity resolves
Reduce by 1
DL
Toxicity does not resolve within 4 weeks
of last infusion or if >2 DL reductions
exceeded
4
1
N/A
Discontinue
Permanently discontinue cisplatin
Thrombocytopenia
1-4
1
Platelet count resolves to 
≥100,000/mm3
Reduce by 1
DL
Toxicity does not resolve within 4 weeks
of last infusion or if >2 DL reductions
exceeded
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Category
Toxicity
Hold Cisplatin
Treatment for Grade
Timing for Restarting
Cisplatin Treatment
Dose for
Restarting
Cisplatin
Treatment
Discontinue Cisplatin
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
3-41
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
3-41
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
3-41
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 
toxicities2
3-41
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
Events4
41
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.
1
Permanent discontinuation should be considered for any severe or life threatening event. Consult Sponsor before restarting treatment after Grade 4 drug related AE.
2
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.
3
Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion.
4Allow continuous treatment for non clinical significant lab AE, such as low MG, CA, or K, that is asymptomatic and deemed to be safe by the investigator.
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Table 11
Recommended 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
Hematologic3
Neutropenia
31
Neutrophil count
resolves to >1000/mm3
No Reduction
*consider G-CSF
Toxicity does not resolve
within 4-5 weeks of last 
infusion or if >2 DL reductions
exceeded
4
1
Neutrophil count
resolves to >1000/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
1
Toxicity resolves
Reduce by 1 DL
Toxicity does not resolve
within 4-5 weeks of last 
infusion or if >2 DL reductions
exceeded
4
1
N/A
Discontinue
Permanently discontinue 
Thrombocytopenia
3-41
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 
toxicities2
3-41
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 Events4
41
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
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Category
Toxicity
Hold 5-FU Treatment 
for Grade
Timing for Restarting
5-FU Treatment
Dose for Restarting 5-FU
Treatment
Discontinue
5-FU
DL  Dose Level; G CSF
granulocyte colony stimulating factor; N/A not applicable.
1
Permanent discontinuation should be considered for any severe or life threatening event. Consult Sponsor before restarting treatment after Grade 4 drug related AE.
2
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.
3
Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion.
4Allow continuous treatment for non clinical significant lab AE, such as low MG, CA, or K, that is asymptomatic and deemed to be safe by the investigator.
6.6.4.3
SOX Dose Modification (Japan SOX Cohort Only)
Table 12
Recommended Dose Modification Guidelines for SOX Drug-related Adverse Events (Japan SOX Cohort Only)
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
S-1
60 mg/dose
50 mg/dose
40 mg/dose
50 mg/dose
40 mg/dose
Discontinue
40 mg/dose
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
S-1=combination product containing tegafur, a prodrug of 5-FU, and 2 types of enzyme inhibitors, CDHP and Oxo; SOX=S-1 plus oxaliplatin
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Table 13
Recommended 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
Hematologic1
Neutropenia5
2-32
Neutrophil count resolves
to ≥1500/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
42
Neutrophil count resolves
to ≥1500/mm3
Reduce by 1 DL
If >3 DL reductions
exceeded
Febrile neutropenia
3-42
Toxicity resolves
Reduce by 1 DL
If >3 DL reductions
exceeded
Thrombocytopenia
3-42
Platelet count resolves to 
≥75,000/mm3
Reduce by 1 DL3
If >3 DL reductions
exceeded
Non-hematologic
Creatinine 
increased
≥1.5 mg/dL2
<1.5 mg/dL
No reduction
If >3 DL reductions
exceeded
Peripheral sensory 
neuropathy4
3-42
Toxicity resolves to
Grade 0-2
Reduce by 1 DL
If >3 DL reductions
exceeded
All other non-
hematologic 
toxicities1
3-4
2
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
If >3 DL reductions
exceeded
Laboratory
Adverse Events6
4
2
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
If >3 DL reductions
exceeded
DL  Dose Level; G CSF  granulocyte colony stimulating factor.
1 Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion.
2 Permanent discontinuation should be considered for any severe or life threatening event.  Consult Sponsor before restarting treatment after Grade 4 drug related AE.
3 Dose reduction at Grade 3 is at the discretion of the investigator but not required.
4 Administration may be interrupted or reduced at the discretion of the investigator.
5 See the package insert of each G CSF drugs for administration of G CSF for neutropenia.
6Allow continuous treatment for non clinical significant lab AE, such as low MG, CA, or K, that is asymptomatic and deemed to be safe by the investigator.
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Table 14
Recommended Dose Modification Guidelines for S-1 Drug-related Adverse Events
Category
Toxicity
Hold S-1 
Treatment for 
Grade
Timing for 
Restarting S-1 
Treatment
Dose for Restarting S-1 
Treatment
Discontinue S-1
Hematologic1
Neutropenia3
32
Neutrophil count
resolves to
≥1500/mm3
No Reduction
If the criteria for starting the 
course are not met at Day 22, 
reduce by 1 DL.
If >2 DL reductions exceeded
42
Neutrophil count
resolves to
≥1500/mm3
Reduce by 1 DL
If >2 DL reductions exceeded
Febrile neutropenia
3-42
Toxicity resolves
Reduce by 1 DL
If >2 DL reductions exceeded
Thrombocytopenia
3-42
Platelet count
resolves to
≥75,000/mm3
Reduce by 1 DL
If >2 DL reductions exceeded
Non-hematologic
Diarrhea, Mucositis, 
or Hand and foot 
syndrome
2-42
Grade 0-1
Reduce by 1 DL
If >2 DL reductions exceeded
Creatinine increased
≥1.5 mg/dL2
<1.5 mg/dL
No Reduction
If >2 DL reductions exceeded
All other non-
hematologic 
toxicities1
3-4
2
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
If >2 DL reductions exceeded
Laboratory Adverse
Events4
3-4
2
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
If >2 DL reductions exceeded
DL  Dose Level; G CSF  granulocyte colony stimulating factor; S 1
combination product containing tegafur, a prodrug of 5 FU, and 2 types of enzyme inhibitors, CDHP 
and Oxo.
1 Participants with intolerable or persistent Grade 2 drug related AE may hold at physician discretion.
2 Permanent discontinuation should be considered for any severe or life threatening event. Consult Sponsor before restarting treatment after Grade 4 drug related AE.
3 See the package insert of each G CSF drugs for administration of G CSF for neutropenia.
4Allow continuous treatment for non clinical significant lab AE, such as low MG, CA, or K, that is asymptomatic and deemed to be safe by the investigator.
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6.6.5
Dose Modification and Toxicity Management for Trastuzumab
Caution should be exercised when treating participants with clinically significant 
cardiovascular disease such as preexisting coronary artery disease or CHF. Participants with 
symptomatic CHF, unstable angina pectoris, or symptomatic or poorly controlled cardiac 
arrhythmia should not be enrolled in clinical trials with trastuzumab. Trastuzumab should be 
discontinued in the event of any Grade 3 or 4 events consistent with CHF.
There will be no dose modifications of trastuzumab. Trastuzumab dose delays are permitted 
for Grade 3/4 clinical toxicity or at investigator discretion. Dose delays are not required for 
laboratory abnormalities unless associated with clinical symptoms. Omitted doses of 
trastuzumab are not replaced or restored; instead, the participant should resume the planned 
treatment cycles. Participants who develop signs and symptoms of CHF should have 
trastuzumab held and should receive treatment for CHF. Participants with an asymptomatic 
absolute decrease in LVEF of ≥16 percentage points or an absolute decrease in LVEF of 
≥10 percentage points to below the lower limit of normal should have trastuzumab held as 
outlined below.
Congestive Heart Failure and Other Cardiac Dysfunction
All participants must have a baseline evaluation of cardiac function, including a 
measurement of LVEF by ECHO, prior to entry into the study. If an ECHO cannot be 
performed or is technically limited, a MUGA scan can alternatively be performed. Only 
participants with normal LVEF (≥55%) should be entered into this study. All participants 
will undergo regular cardiac monitoring throughout the study, including at baseline and 
repeated at Cycles 3 and 5 and every 4 cycles starting from Cycle 9.
Cycles can be started within 1 week after ECHO/MUGA, without additional test and without 
Sponsor consultation, if the following criteria are met:
1) Baseline LVEF was above 55% 
2) Participant did not have any clinically significant LVEF abnormality based on 
ECHO/MUGA tests
3) Current ECHO/MUGA result is normal and does not require trastuzumab to be held
4) The delay to start treatment is not due to cardiac dysfunction or heart failure 
If the site wants to delay the start of the next cycle for more than 1 week after ECHO, 
consultation with Sponsor is required.
During the course of trastuzumab therapy, participants should be monitored for signs and 
symptoms of CHF (ie, dyspnea, tachycardia, new unexplained cough, neck vein distention, 
cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, 
and rapid unexplained weight gain). Participants who develop signs or symptoms of CHF 
will be further evaluated with a repeat LVEF assessment using the same method selected at 
baseline (either ECHO or MUGA) if possible.
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Management of Symptomatic Cardiac Changes
Participants who develop signs and symptoms of CHF should have trastuzumab held and 
should receive treatment for CHF as recommended by the ACC/AHA (eg, angiotensin 
converting enzyme inhibitors, angiotensin-II receptor blockers, β-blockers, diuretics, and 
cardiac glycosides, as needed) with referral to cardiology for consultation.
If the symptoms of CHF resolve with treatment, and/or cardiac function improves to 
baseline, reinitiating of trastuzumab can be considered at the discretion of the investigator, 
after discussion with the participant concerning the risks and benefits of continued therapy 
and in consultation with a cardiologist. If the participant is benefiting clinically from
trastuzumab, the benefit of continued treatment may outweigh the risk of cardiac dysfunction 
or heart failure. If trastuzumab is restarted, continued surveillance with noninvasive 
measures of LVEF (MUGA or ECHO) will resume as regularly scheduled. Additional LVEF 
assessments prior to the next regularly scheduled LVEF measurement may be performed at 
the investigator’s discretion.
Management of Asymptomatic Decreases in LVEF
Trastuzumab can be continued in participants experiencing an asymptomatic absolute
decrease in LVEF of <16 percentage points from baseline, when the ejection fraction remains 
within the imaging center's range of normal limits. Repeat measures of LVEF should be 
obtained using the methodology selected at baseline if possible. Close follow-up of such 
participants is recommended. Participants with an asymptomatic absolute decrease in LVEF 
of ≥16 percentage points or an absolute decrease in LVEF of ≥10 percentage points to below 
the lower limit of normal should have trastuzumab held. Referral to cardiology should be 
considered for evaluation and management of left ventricular systolic dysfunction with 
adherence to ACC/AHA guidelines. In light of the variability inherent in the assessment of 
ejection fraction, consideration should be given to repeating the study within 4-7 days to 
confirm an observed decline. Repeat measures of LVEF should be obtained using the same 
methodology selected at baseline if possible, but at the discretion of the investigator or 
consulting cardiologist. If trastuzumab has been held for an asymptomatic decline in LVEF, 
a repeat measure of LVEF will be obtained within 1 month to evaluate for recovery of LVEF.
If LVEF does not improve after repeat assessment within 1 month, the participant should be 
monitored with monthly or as clinically indicated ECHOs/MUGAs until LVEF is improved.
If cardiac function improves and LVEF no longer meets “hold” criteria as defined above, 
trastuzumab may be restarted. If trastuzumab is restarted, continued surveillance with 
noninvasive measures of LVEF (MUGA or ECHO), using the optimal methodology as 
determined by the investigator or consulting cardiologist, will resume per the standard 
schedule. Additional LVEF assessments prior to the next regularly scheduled LVEF 
measurement may be performed at the investigator’s discretion. If the participant is 
benefiting clinically from trastuzumab, the benefit of continued treatment may outweigh the 
risk of cardiac dysfunction even in the setting of an asymptomatic LVEF decline and 
reinitiating of trastuzumab can be considered at the discretion of the investigator after 
consultation with a cardiologist and discussion with the participant concerning the risks and 
benefits of continued therapy.
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See the trastuzumab package insert for more details.
6.7
Second Course Phase (Retreatment Period)
All participants who have received pembrolizumab and stop trial treatment 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 trial treatment from the initial treatment phase.  
Participants who elect to continue SOC treatment beyond 35 cycles may still qualify for 
Second Course treatment if they meet criteria below. This retreatment is termed the Second 
Course Phase of this trial and is only available if the trial remains open and the participant 
meets the following conditions:
Condition #1
Either

Stopped initial treatment with pembrolizumab after attaining an 
investigator-determined confirmed CR based on RECIST 1.1, and
o
Was treated with at least 8 cycles of pembrolizumab before discontinuing 
treatment, and
o
Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared
Or

Had SD, PR, or CR and stopped trial treatment after completion of 
35 administrations of pembrolizumab for reasons other than disease progression 
or intolerability
AND
Condition #2

Experienced an investigator-determined radiographic disease progression after 
stopping initial treatment, and
o
Completed first course of trial treatment, stopped trial treatment with SD or 
better, and upon disease progression were unblinded and found to have 
received pembrolizumab, and
o
No new anticancer treatment was administered after the last dose of trial 
treatment, and
o
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
o
The trial 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 
trial.
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6.8
Treatment After the End of the Study
There is no study-specified treatment following the end of the study.
6.9
Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment/randomization schedule for the 
study to unblind participants and to unmask study treatment identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.11). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic treatment allocation/randomization system (IRT) should be used in 
order to unblind participants and to unmask study treatment identity. The Sponsor will not 
provide random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
Discontinuation of Study Treatment and Participant Withdrawal
7.1
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment. Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 1.3 and Section 8.10.3.
Participants may discontinue study treatment at any time for any reason or be discontinued
from the study treatment at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study treatment by the investigator 
or the Sponsor if study treatment is inappropriate, the study plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study treatment discontinuation are provided in Section 8.10.3.
A participant must be discontinued from study treatment 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 treatment.
o
The participant interrupts study treatment administration for more than 12 consecutive 
weeks unless Sponsor approval to continue is received.
o
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 treatment.
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.
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o
Confirmed radiographic disease progression outlined in Section 8.2 (exception if the 
Sponsor approves treatment continuation).
o
Noncompliance with study treatment or procedure requirements.
o
Recurrent Grade 2 pneumonitis.
o
Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 24 
weeks), receiving 2 cycles of the combination including 2 doses of 
pembrolizumab/placebo and at least 80% of the planned doses of the other study 
treatments beyond the date when the initial CR was declared. These participants may be 
eligible for Second Course treatment described in Section 6.7.
o
Completion of 35 treatments (approximately 2 years) with pembrolizumab. For 
participants receiving standard of care beyond 35 administrations of pembrolizumab, 
study treatment discontinuation will be on the date of the last dose of standard of care 
treatment received or 1 year after the completion of pembrolizumab administrations, 
whichever comes first.
Note: The number of treatments is calculated starting with the first dose. Standard of care 
treatment refers to trastuzumab + capecitabine or 5-FU or S-1.
o
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.
o
The participant has a confirmed positive serum pregnancy test.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
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 8.1.10. 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 assuring 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, etc.), and thus local 
regulations may require that additional informed consent be obtained from the 
participant. In these cases, such evaluations/testing will be performed in accordance with 
those regulations.
The maximum amount of blood collected from each participant at each treatment cycle/visit 
will be approximately 6.0 mL-51.0 mL.  Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples.
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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
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of their 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.
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.
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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 utilized 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 
treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment 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.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically important by the investigator.  Details regarding the disease 
for which the participant has enrolled in this study will be recorded separately and not listed 
as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study.  Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up visit.  In addition, new medications started 
during the Second Course Phase through the Tumor Safety Follow-up visit should be 
recorded.
8.1.5.3
Disease Status and Prior Cancer Treatment History
The investigator or qualified designee will also review the participant’s current disease 
status.  They will also review all prior anticancer treatments including systemic treatments, 
radiation, and surgeries.
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 one screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
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Specific details on the Screening visit requirements (screening/rescreening) are provided in 
Section 8.10.1. 
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.
The investigator must decide the choice of intervention and provide the rationale prior to 
randomization.
8.1.7.1
Treatment Eligibility Assessment
The treatment eligibility assessment is included in this study to document investigator 
assessment of participant suitability for potential treatment with study interventions other 
than pembrolizumab and the rationale. These data may be required to support reimbursement 
efforts for pembrolizumab. 
The investigator must provide rationale to document the choice of study interventions prior 
to randomization.
8.1.8
Treatment Administration
Administration of study medication will be performed according to the specifications in the 
pharmacy manual.
Study Treatment should begin within 3 days of randomization.
8.1.8.1
Timing of Dose Administration
Trial treatment in all arms will begin on Day 1 of each 3-week dosing cycle after all 
procedures/assessments have been completed as detailed in the SoA (Section 1.3).  Trial 
treatments may be administered up to 3 days before or after the scheduled Day 1 of each
cycle due to administrative reasons.
All trial treatments may be administered on an outpatient basis.
Treatments will be administered in the order presented below:

Pembrolizumab or placebo infusion is administered first, followed by trastuzumab 
infusion, then cisplatin or oxaliplatin infusion, and then 5-FU infusion, capecitabine, or 
S-1 (Japan only).
Treatment may continue until confirmed disease progression, clinical progression, 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 withdraw the 
participant, participant withdraws consent, pregnancy of the participant, noncompliance with 
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trial treatment or procedure requirements, participant receives 35 administrations 
(approximately 2 years) of pembrolizumab/placebo or until the participant has discontinued 
all other standard of care chemotherapy received beyond 35 administrations of 
pembrolizumab/placebo, achievement of a CR, or administrative reasons requiring cessation 
of treatment. Participants have the option to receive up to 1 additional year of trastuzumab 
and capecitabine or 5-FU or S-1 beyond 35 administrations of pembrolizumab/placebo at the 
investigator’s discretion and after Sponsor consultation. Pembrolizumab/placebo treatment is 
not allowed beyond 35 administrations in the initial treatment course. Participants who stop 
pembrolizumab/placebo treatment after 35 administrations, for reasons other than disease 
progression or intolerability, or participants who attain a CR and stop trial treatment, may be 
eligible for up to 17 additional administrations of pembrolizumab upon experiencing disease 
progression if they are randomized to the pembrolizumab arm.
Note: Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons (ie, elective surgery, unrelated medical events, participant vacation, and holidays) not 
related to study therapy. Participants should be placed back on study therapy as soon as 
clinically appropriate per the investigator, and not exceeding 3 weeks from the interrupted 
dosing. Day 1 of subsequent cycles should be adjusted accordingly to adhere to Q3W dosing 
schedule.  Discuss with the Sponsor if participants cannot restart study medication within 3 
weeks. The reason for interruption should be documented in the participant's study record.
8.1.8.2
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 
must 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 of infusion pumps from site to site, 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 a normal saline or dextrose
solution prepared by the unblinded pharmacist. The placebo will be dosed and administered 
by blinded and qualified study site personnel in the same manner as the investigational 
product (pembrolizumab).
8.1.8.3
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 for up to 6 cycles. Cisplatin may be 
administered beyond 6 cycles at the discretion of the investigator.
5-FU 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 Schedule of Assessments. 5-FU may be administered up to 1 additional year 
beyond 35 administrations of pembrolizumab/placebo at the discretion of the investigator and 
after Sponsor consultation.
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Investigators are advised to counsel participants assigned to receive 5-FU about risk of 
photosensitivity and to take sun protection measures accordingly.
8.1.8.4
CAPOX
Oxaliplatin 130 mg/m2 will be administered as a 2-hour IV infusion or per the site’s 
standard practice on Day 1 of each treatment cycle.  
Capecitabine will be administered as a 1000 mg/m2 dose bid Days 1 to 14 Q3W.  The 
evening dose of capecitabine should be taken approximately 12 hours after the morning dose 
and should be taken with food, or within 30 minutes after food/meal, with approximately 
200 mL of water. Capecitabine may be administered up to 1 additional year beyond 
35 administrations of pembrolizumab/placebo at the discretion of the investigator and after 
Sponsor consultation.  
Please refer to the product label for additional guidance on administration procedures for 
capecitabine.
Note: If participant is enrolled later in the day, it is acceptable for only 1 dose taken on Day 1 
and bid dosing can resume on Days 2 to 14 and 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.
8.1.8.5
Trastuzumab
Trastuzumab will be administered as an IV 8 mg/kg loading dose, and then 6 mg/kg 
maintenance thereafter Q3W on Day 1 of every treatment cycle. Trastuzumab may be 
administered up to 1 additional year beyond 35 administrations of pembrolizumab/placebo at 
the discretion of the investigator and after Sponsor consultation.
8.1.8.6
SOX (Japan SOX Cohort Only)
Oxaliplatin 130 mg/m2 will be administered as a 2-hour IV infusion or per the site’s 
standard practice on Day 1 of each treatment cycle.  
S-1 The dose of 40 mg to 60 mg will be administered bid on Days 1 to 14 Q3W.  The Day 1 
dose of S-1 will be administered after completion of pembrolizumab, trastuzumab, and 
oxaliplatin infusion.  An interval of at least 8 hours should be kept between the evening and 
morning doses of S-1.  The participants should have a meal and take the drug within 60 
minutes after the meal.  For additional guidance on the treatment method of S-1, see the 
package insert.
Note: If participant is enrolled later in the day, it is acceptable for only 1 dose to be taken on 
Day 1.  Twice-daily dosing can resume on Days 2 to 14 and the final dose will be taken in 
the morning of Day 15.
S-1 may be administered up to 1 additional year beyond 35 administrations of 
pembrolizumab/placebo at the discretion of the investigator and after Sponsor consultation.
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8.1.9
Second Course of Therapy
See Section 6.7 for details concerning Second Course of Therapy.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study treatment 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
which are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10.1
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.
8.1.11
Participant Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND THE PARTICIPANT. 
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s treatment assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
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intensity/toxicity grade of the AEs observed, the relation to study treatment, 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.
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.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or non-study treating physician must be discontinued from study 
intervention but should continue to be monitored in the study.  
Additionally, the investigator 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.
Treatment identification information is to be unblinded ONLY in following situation:
1.
For the welfare of the participant, if necessary. 
2.
Participants requiring Second Course/re-retreatment who completed 35 cycles of 
pembrolizumab and stop pembrolizumab/placebo trial treatment with SD or better and 
had to discontinue for reason other than disease progression or intolerability or stop 
trial treatment due to CR (per protocol requirement). Such participant must have 
experienced radiographic disease progression while off pembrolizumab treatment 
according to the criteria in Section 6.7.
Every effort should be made to avoid unblinding the participant unless necessary. In the 
event that unblinding has occurred, the circumstances around the unblinding (eg, date and 
reason) must be documented promptly, and the Sponsor Clinical Director notified as soon as 
possible.  Every effort should be made to not unblind the Sponsor.  Only the principal 
investigator or delegate and the respective participant’s code should be unblinded. Note: PD-
L1 status will remain blinded to the participant and the investigator.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.2
Efficacy Assessments 
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the BICR can be found in the Site 
Imaging Manual. Tumor imaging is strongly preferred to be acquired by computed 
tomography (CT). For the abdomen and pelvis, contrast-enhanced magnetic resonance 
imaging (MRI) may be used when CT with iodinated contrast is contraindicated, or when 
mandated by local practice. MRI is the strongly preferred modality for imaging the brain. 
The same imaging 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 imaging. In general, imaging should include 
the chest, abdomen, and pelvis.  
Note: For the purposes of assessing tumor imaging, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer located at the site or at an offsite 
facility.  
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1.  All scheduled images for all study participants from the sites will be 
submitted to the central imaging vendor.  In addition, images (including via other modalities) 
that are obtained at an unscheduled time point to determine disease progression, as well as 
imaging obtained for other reasons, but which demonstrate radiologic progression, should 
also be submitted to the central imaging vendor.
When the investigator identifies radiographic progression per RECIST 1.1, the image must 
be submitted to the central imaging vendor to perform expedited verification of radiologic 
PD and communicate the results to the trial site and Sponsor (see Section 8.2.1.5 and Figure 
3).  Treatment should continue until PD has been verified by BICR (if initial site-assessed PD 
was not verified by BICR, each subsequent scan must be submitted to central imaging vendor 
with verification of PD request until PD has been verified). Regardless of whether PD is 
verified, if the investigator considers the participant has progressed, but elects to implement 
iRECIST, the investigator will assess for confirmation of progression by iRECIST at 
subsequent time points.  Images should continue to be submitted to the central imaging 
vendor.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
randomization. The site study team must review screening images to confirm the participant 
has measurable disease per RECIST 1.1.  Tumor imaging performed as part of routine 
clinical management is acceptable for use as screening tumor imaging if it is of diagnostic 
quality and performed within 28 days prior to the date of randomization and can be assessed 
by the central imaging vendor.
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If brain imaging is performed to document the stability of existing metastases, MRI should 
be used if possible.  If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed 6 weeks (42 days + 7 days) from
the date of randomization. Subsequent tumor imaging should be performed every 6 weeks 
(42 days ± 7 days) or more frequently if clinically indicated. After 1 year, participants who 
remain on treatment will have imaging performed every 6 weeks. Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts.  Imaging should 
continue to be performed until disease progression is identified by the investigator and 
verified by BICR (unless the investigator elects to continue treatment and follow iRECIST), 
the start of new anticancer treatment, withdrawal of consent, or death, or notification by the 
Sponsor, whichever occurs first. All supplemental imaging must be submitted to the central 
imaging vendor for BICR. 
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting 
with the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.
Note:  Response does not typically need to be verified in real time by the BICR.
Per iRECIST (Section 8.2.1.6), disease progression should be confirmed by the site 4 to 
8 weeks after site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants with unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site, provided they have 
met the conditions detailed in Section 8.2.1.6. Participants who receive confirmatory 
imaging do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point, if 
clinically stable. Participants with confirmed disease progression by iRECIST, as assessed 
by the site, will discontinue study treatment. Exceptions are detailed in Section 8.2.1.6.
8.2.1.3
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (± 4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study treatment due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment (see Section 8.2.1.2) until the start of a 
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new anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or 
the end of the study, whichever occurs first.
8.2.1.4
Second Course (Retreatment) Tumor Imaging
Tumor imaging must be performed within 28 days prior to restarting treatment with 
pembrolizumab.  Local reading (investigator assessment with site radiology reading) will be 
used to determine eligibility.  All Second Course imaging should be submitted to the central 
imaging vendor for quality control, storage, and possible retrospective review.
The first on-study imaging assessment should be performed at 6 weeks (42 days + 7 days) 
after the restart of treatment.  Subsequent tumor imaging should be performed every 6 weeks 
(42 days ± 7 days) or more frequently, if clinically indicated.
Per iRECIST (Section 8.2.1.6), if tumor imaging shows initial PD, tumor assessment should 
be repeated 4 to 8 weeks later in order to confirm PD with the option of continuing treatment 
while awaiting radiologic confirmation of progression.  Participants who obtain confirmatory 
imaging do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and 
may wait until the next scheduled imaging time point, if clinically stable.
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, pregnancy, withdrawal of consent, death, or notification by the Sponsor, 
whichever occurs first.  In clinically stable participants, disease progression may be 
confirmed by the investigator using iRECIST 4 to 8 weeks after the first tumor imaging 
indicating PD.
For participants who discontinue Second Course study treatment, tumor imaging should be 
performed at the time of treatment discontinuation (± 4 week window).  If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory.  For participants who discontinue study treatment due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study treatment without documented disease 
progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging every 6 weeks (42 days ± 7 days) until either the start of a new anticancer 
treatment, disease progression, death, withdrawal of consent, or the end of the study, 
whichever occurs first.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used 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 treatment). Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in total 
and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.  Initial 
tumor imaging showing site-assessed PD should be submitted immediately for BICR 
verification of PD. The site will be notified if the BICR verifies PD using RECIST 1.1.  
Figure 3 illustrates the imaging flow involving verification of PD for clinically stable 
participants.
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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 9. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be 
captured in the clinical database.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status 
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
central verification of site-assessed first radiologic evidence of PD and is not required to have 
repeat tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent to the 
central imaging vendor for potential retrospective BICR. 
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has confirmed radiographic progression (iCPD), study treatment should be 
discontinued; however, if the participant is achieving a clinically meaningful benefit, an 
exception to continue study treatment may be considered following consultation with the 
Sponsor. In this case, if study treatment is continued, tumor imaging should continue to be 
performed following the intervals as outlined in Section 1.3 and submitted to the BICR. 
A description of the adaptations and iRECIST process are found 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 15 and illustrated as a flowchart in 
Figure 3.
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Table 15
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 treatment 
at the assessment
of the 
investigator and 
after the 
participant’s 
consent
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 treatment 
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 
treatment at the 
investigator’s 
discretion.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD 
per 
investigator’s 
discretion only.
Discontinue 
treatment
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Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
Repeat tumor 
imaging shows 
iSD, iPR, or 
iCR by 
iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
treatment at the 
investigator’s 
discretion.
Continue 
regularly 
scheduled 
imaging 
assessments.
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion.  Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
BICR blinded independent central review; iCPD iRECIST confirmed progressive 
disease; iCR iRECIST complete response; iPR iRECIST partial response; 
iRECIST modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD iRECIST stable disease; iUPD iRECIST unconfirmed progressive 
disease; PD progressive disease; RECIST 1.1 Response Evaluation Criteria in Solid 
Tumors 1.1; VOP verification of progression.
Note:  If progression has been centrally verified, further management is by the site, based 
on iRECIST.  Any further imaging should still be submitted to the central imaging vendor, 
but no rapid review will occur.  If RECIST 1.1 disease progression has not been centrally 
verified, ideally the site should continue treatment.  Whether or not treatment continues, 
imaging should be collected and submitted to the central imaging vendor with VOP 
request until RECIST 1.1 progression is verified by BICR.
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Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
iCRO imaging contract research organization; iRESIST modified Response Evaluation Criteria in Solid Tumors for 
immune based therapeutics; PD
progressive disease; RECIST 1.1 Response Evaluation Criteria in Solid Tumors version 
1.1;
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
Screening Period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study treatment, new clinically significant abnormal findings should be recorded as 
AEs.
8.3.1.2
Directed Physical Exam
For cycles that do not required a full physical exam as defined in Section 1.3, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to the 
administration of the study treatment.  New clinically significant abnormal findings should 
be recorded as AEs.
8.3.1.3
Ophthalmologic Complications due to Capecitabine
Participants 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.
8.3.1.4
Severe Skin Reactions due to Capecitabine
Capecitabine can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic 
Epidermal Necrolysis.  Capecitabine should be permanently discontinued in participants who 
experience a severe skin reaction during treatment.
8.3.2
Vital Signs
Vital signs include temperature, pulse, respiratory rate, weight, and blood pressure. Height 
will be measured only at Screening.  The investigator or qualified designee will take vital 
signs at Screening, prior to the administration of each dose of study treatment, and at time of 
study discontinuation as specified in the SoA (Section 1.3).
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8.3.3
Electrocardiograms
A standard 12-lead electrocardiogram (ECG) will be performed and reviewed by an 
investigator or medically qualified designee (consistent with local requirements) once at 
Screening.  Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary.
Note: A 6-lead ECG is allowed per institutional standard
France only:  For participants receiving oxaliplatin:

A 12-lead ECG must be performed on the day of administration before and after 
intravenous administration of oxaliplatin.
8.3.4
Echocardiography or Multigated Acquisition Scan
An echocardiography (ECHO) or multigated acquisition (MUGA) scan will be required at 
Screening to determine study eligibility.  The assessment method will be at the investigator’s 
discretion and per the local standard of care.  Additional assessments should be performed 
according to Section 1.3 and may be performed as clinically necessary.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 5 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 5, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).

If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study treatment, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator. 
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8.3.6
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 after cessation of therapy for each study intervention is as follows:
-
Pembrolizumab 120 days
-
Trastuzumab 210 days
-
Chemotherapy 180 days

Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant's participation in the study.
8.3.7
Audiometry
Audiometry testing will be performed at baseline for participants on the FP chemotherapy 
backbone, and is repeated during the trial as clinically indicated per the treating physician or 
designee. Pure tone audiometry is an acceptable method to measure. Other ototoxicity tests 
per local requirement are also acceptable. It is not acceptable to skip audiometry testing at 
baseline. 
8.3.8
Performance Assessments
8.3.8.1
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 8) at 
Screening, prior to the administration of each dose of study treatment and during the
follow-up period as specified in the SoA (Section 1.3).
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 4.
Progression of the cancer under study is not considered an AE as described in Section 8.4.5 
and Appendix 4.
AE, 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). 
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment randomization must be reported by the investigator if the participant is 
receiving placebo run-in or other run-in treatment, if the event causes the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, or a procedure. 

All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator. 

All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier 
must be reported by the investigator. 

All pregnancies and exposure during breastfeeding, from the time of treatment 
randomization through 7 months following cessation of study treatment, or 30 days 
following cessation of study treatment 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 to be 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 treatment 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 16.
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8.4.3
Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECIs, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
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 4.
8.4.4
Regulatory Reporting Requirements for SAE
●
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is 
essential so that legal obligations and ethical responsibilities toward the safety of 
participants and the safety of a study treatment 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 treatment 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 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
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 monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint which upon review 
is not progression of the cancer under study will be forwarded to Global Pharmacovigilance
as an SAE within 24 hours of determination that the event is not progression of the cancer 
under study.
8.4.6
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.
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All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of 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.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and serious adverse events 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 may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Trial 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, or ≥5 times the indicated dose.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
Overdose with other study treatments should follow the prescribed information in their 
relative package inserts.
8.6
Pharmacokinetics
To evaluate the immunogenicity and exposure of pembrolizumab and trastuzumab in this 
indication, sample collections for analysis of PK and ADA are currently planned as shown in 
the SoA (Section 1.3.1). Blood samples for PK and ADA collected will be stored. Analysis 
will be performed only if required. If ongoing PK and/or ADA sampling is deemed to be 
unnecessary by the Sponsor, it may be reduced or discontinued.  Sample collection, storage,
and shipment instructions for samples will be provided in the operations/laboratory manual. 
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8.9
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics data, associated with medical encounters, 
will be collected in the CRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded. 
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The data collected may be used to conduct exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)

Duration of hospitalization (total days or length of stay, including duration by wards 
[eg, intensive care unit])

Number and type of diagnostic and therapeutic tests and procedures

Outpatient medical encounters and treatments (including physician or emergency room 
visits, tests and procedures, and medications).
All hospitalization and emergency room visits must be reported in the eCRF from the time of 
treatment randomization through 90 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new anticancer therapy, 
whichever is earlier.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
8.10.1
Screening
8.10.1.1
Pre-screening Period
The Pre-screening period may be utilized by participants to determine biomarker eligibility
based on HER2 and PD-L1 status using an archival tumor sample. After signing an 
authorization for release of tumor tissue form, participants will be assigned a screening 
number. Characterization of HER2 and PD-L1 status will be performed at a Pre-screening 
visit for participants with an available archival tumor biopsy sample. If the participants are 
HER2 positive, 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 
pre-screening period as eligibility based on HER2 expression will be determined in the main 
study screening period.
8.10.1.2
Screening Period
Approximately 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. 
Screening procedures may be repeated after consultation with the Sponsor.
8.10.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8. Unless otherwise specified, assessments/procedures are to be 
performed prior to administration of study treatment. Unless otherwise specified, the 
window for each visit is ± 3 days.
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8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
8.10.3.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. 
8.10.3.2
Follow-up
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-up Phase and should be assessed every 6 weeks (± 7 days) by imaging 
until PD to monitor disease status. Every effort should be made to collect information 
regarding disease status until disease progression, the start of new anti-cancer therapy, 
withdrawal of consent, pregnancy, or end of study, whichever occurs first. Information 
regarding post-study anticancer treatment will be collected if new treatment is initiated. The 
Sponsor may request survival status to be assessed at additional time points during the course 
of the study (not to exceed approximately 12 weeks). 
8.10.3.3
Survival Follow-up Assessments
Participant survival follow-up status will be assessed approximately every 12 weeks until 
death, withdrawal of consent, or the end of the study, whichever occurs first.  
The first survival follow-up assessment should be scheduled as described below: 
For participants who discontinue treatment intervention and who will not enter the Follow-up 
Phase, the first survival follow-up assessment will be scheduled 12 weeks after the 
discontinuation visit and/or Safety Follow-up visit (whichever is last).  
For participants who completed assessments in the efficacy Follow-up Phase, the first 
survival follow-up assessment will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
8.10.4
Survival Status 
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to: an external 
DMC review, interim analysis (IA), and/or final analysis. Upon Sponsor notification, all 
participants who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding participants 
that have a previously recorded death event in the collection tool).
8.10.5
Post-study
Participants will be required to return to clinic approximately 30 days after the last dose of 
study treatment for the post-study visit. If the post-study visit occurs less than 30 days after 
the last dose of study treatment, a subsequent follow-up telephone call should be made at 
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30 days post the last dose of study treatment to determine if any AEs have occurred since the 
post-study clinic visit.
9
Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the Global Cohort.  
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 non-confirmatory analyses made after the protocol has been finalized will be 
documented in a supplemental Statistical Analysis Plan (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.
The Japan-specific SOX cohort will be analyzed separately.  The detailed analyses will be 
specified in sSAP.  
9.1
Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan are summarized below; the comprehensive plan 
is provided in Section 9.2 through Section 9.11.
Study Design Overview
This is a Phase III, randomized, double-blind trial comparing pembrolizumab 
and placebo, both in combination with trastuzumab plus chemotherapy as first-
line treatment in participants with HER2 positive advanced gastric or GEJ 
adenocarcinoma
Treatment Assignment
Participants will be randomized in a 1:1 ratio to the experimental arm and the 
control arm. Stratification factors are in Section 6.3.1.1.
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoints
1) Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR
2) Overall survival (OS)
Key Secondary Endpoint
Objective response (OR) per RECIST 1.1 assessed by BICR
Statistical Methods for
Key Efficacy Analyses
The dual primary hypotheses on PFS and OS will be evaluated by comparing 
the experimental arm to the control arm using a stratified log-rank test. The 
hazard ratio will be estimated using a stratified Cox regression model. Event 
rates over time will be estimated within each treatment group using the 
Kaplan-Meier method. The stratified Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985]with sample size weights will be used 
for analysis of ORR.
Statistical Methods for
Key Safety Analyses
For analyses in which 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events, these analyses will be 
performed using the Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985].
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Interim Analyses
Three interim analyses (IA) may be performed in this study based on current 
projection of enrollment and event accrual rates. Results will be reviewed by
an external Data Monitoring Committee. Details are provided in Section 9.7.

IA1: 
o
Timing: to be performed when ~ 260 participants have been followed 
up for ~ 8.5 months.
o
Primary purpose: efficacy analysis for ORR (hypothesis testing).

IA2a: 
o
Timing: to be performed after ~ 542 PFS events have occurred AND
~ 9 months after last participant randomized.
o
Primary purpose: efficacy analysis for PFS and OS.

IA3a: 
o
Timing: to be performed when ~ 18 months after the last participant 
has been randomized AND approximately 606 PFS events have been 
observed. This is the final PFS analysis.
o
Primary purpose: efficacy analysis for PFS and OS.

Final analysisa: 
o
Timing: to be performed when ~ 28 months after the last participant 
has been randomized AND ~ 551 deaths have occurred. 
o
Primary purpose: efficacy analysis for OS.
Multiplicity
The overall type I error over the primary endpoints (PFS and OS) and the key 
secondary endpoint (ORR) is strongly controlled at 2.5% (1-sided), with 
initially 0.2% allocated to ORR, 0.3% to PFS and 2% to OS.
By using the graphical approach of Maurer and Bretz, if 1 hypothesis is 
rejected, the alpha will be shifted to other hypotheses [Maurer, W. and Bretz, 
F. 2013].
Sample Size and Power
The planned sample size is ~ 692 participants. 
For ORR, with sample size of ~ 260 at IA1, the study has ~ 90% power for 
detecting a 25% difference in ORR (73% vs 48%) at an initially assigned 
0.002 (1-sided) significance level. 
For PFS, there will be ~ 606 events at the PFS final analysis. With 606 PFS 
events, the study has ~ 95% power for detecting a hazard ratio (HR) of 0.7 at 
an initially assigned 0.003 (1-sided) significance level. 
For OS, there will be ~ 551 deaths at the OS final analysis. With 551 deaths, 
the study has ~ 90% power for detecting a HR of 0.75 at an initially assigned 
0.020 (1-sided) significance level.
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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. 
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.
Blinding issues related to the planned interim analyses are described in Section 9.7. 
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoint
Dual Primary

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. 

Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause.
Secondary

Objective Response Rate (ORR) per RECIST 1.1 by BICR
Objective Response is defined as a CR or PR (note: only CR or PR prior to a curative 
surgical resection will be used among participants with curative surgical resection).

Duration of Response (DOR) per RECIST 1.1 by BICR
For participants who demonstrated CR or PR, duration of response (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 measurements are described in Section 4.2.1.2.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The intention-to-treat (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. 
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 
treatment. Participants will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population. 
For most participants this will be the treatment group to which they are randomized. 
Participants who take incorrect study treatment for the entire treatment period will be 
included in the treatment group corresponding to the study treatment actually received. Any 
participant who receives the incorrect study medication for 1 or more cycles but receives the 
correct treatment 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 treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
In this section, for the stratified analyses, small strata may be collapsed. Please see details in 
the footnotes of Table 19. Response or progression in the Second Course Phase will not 
count toward the PFS of the primary endpoint in this trial.
9.6.1.1
Progression-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, HR) between the treatment arms. 
The HR and its 95% CI from the stratified Cox model with Efron’s method of tie handling 
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and with a single treatment covariate will be reported. The stratification factors used for 
randomization (see Section 6.3.1.1) will be applied to both the stratified log-rank test and the 
stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the date of the 
first assessment at which PD is objectively documented per RECIST 1.1 by BICR. Death is 
always considered as a confirmed PD event. Sensitivity analyses will be performed for 
comparison of PFS based on investigator's assessment. 
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 1 primary 
and 2 sensitivity analyses with a different set of censoring rules will be performed. For the 
primary analysis, if the events (PD or death) are immediately after more than 1 missed 
disease assessment, the data are censored at the last disease assessment prior to missing 
visits. Also, data after new anti-cancer therapy are censored at the last disease assessment 
prior to the initiation of new anti-cancer therapy. The first sensitivity analysis follows the 
intention-to-treat principle. That is, PDs/deaths are counted as events regardless of missed 
study visits or initiation of new anti-cancer therapy. The second sensitivity analysis
considers discontinuation of treatment due to reasons other than complete response or 
initiation of new anticancer treatment, whichever occurs later, to be a PD event for 
participants without documented PD or death. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied. The censoring rules for 
primary and sensitivity analyses are summarized in Table 17.
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Table 17
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anti-cancer therapya, 
if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
PD or death documented 
immediately after ≥2 
consecutive missed 
disease assessments or 
after new anti-cancer 
therapy, if any
Censored at last disease 
assessment prior to 
the earlier date of ≥2 
consecutive missed 
disease assessment and 
new anti-cancer therapy, 
if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
No PD and no death; and 
new anticancer treatment 
is not initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment 
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at last 
disease assessment if still 
on study treatment or 
completed study 
treatment.
No PD and no death; new 
anticancer treatment is 
initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last disease 
assessment
Progressed at date of new 
anticancer treatment
PD = Progressive Disease; PFS = Progression-free Survival
a New anti-cancer therapy: excluding curative surgical resections (the detailed definition in Section 6.5.3).
As imaging will continue, participants who have curative surgical resection during the study 
(per protocol Section 6.5.3) will be followed for PFS events after surgery until local
recurrence, distant metastasis, or death for the primary analysis of PFS. An additional
sensitivity analysis will be conducted for PFS in which these participants will be censored at
last disease assessment prior to the time of the curative surgical resections.
9.6.1.2
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess the
magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from the Cox 
model with a single treatment covariate will be reported. The stratification factors used for 
randomization (see Section 6.3.1.1) will be applied to both the stratified log-rank test and the 
stratified Cox model.
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Participants without documented death at the time of analysis will be censored at the date of 
last contact.
9.6.1.3
Objective Response Rate
The stratified Miettinen and Nurminen method will be used for the comparison of the ORR 
between the 2 treatment groups. The difference in ORR and its 95% confidence interval 
from the stratified Miettinen and Nurminen method with strata weighting by sample size will 
be reported [Miettinen, O. and Nurminen, M. 1985]. The stratification factors used for 
randomization (Section 6.3.1.1) will be applied to the analysis.
9.6.1.4
Duration of Response
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a complete response or partial 
response will be included in this analysis. 
For each DOR analysis, a corresponding summary of the reasons responding subjects are 
censored will also be provided.  Responding subjects who are alive, have not progressed, 
have not initiated new anti-cancer treatment, have not been determined to be lost to follow-
up, and have had a disease assessment within ~ 5 months of the data cutoff date are 
considered ongoing responders at the time of analysis.  If a subject meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied. The censoring rules are 
summarized in Table 18.
Table 18
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new anti-
cancer therapyainitiated
Last adequate disease assessment before 
new anti-cancer therapy initiated
Censor
(non-event)
Death or progression after ≥2 
consecutive missed disease assessments 
or after new anticancer therapy if any
Last adequate disease assessment prior 
to ≥2 missed adequate disease 
assessments
Censor
(non-event)
Death or progression after ≤1 missed 
disease assessments and before new 
anticancer therapy if any
PD or death
End of response
(Event)
PD = Progressive Disease
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
a New anti-cancer therapy: excluding curative surgical resections (the detailed definition in Section 6.5.3).
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9.6.1.5
Analysis Strategy for Key Efficacy Endpoints
Table 19 summarizes the primary analysis approach for key efficacy endpoints.
Table 19
Analysis Strategy for Key Efficacy Endpoints
Endpoint 
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary Endpoints
PFS per RECIST 1.1 by 
BICR 
Test: Stratified log-rank 
test 
Estimation: Stratified Cox 
model with Efron’s tie 
handling method 
ITT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2
(More details are provided 
in Table 17, Censoring 
Rules for Primary and 
Sensitivity Analyses of 
PFS)
OS
Test: Stratified log-rank 
test 
Estimation: Stratified Cox 
model with Efron’s tie 
handling method 
ITT
Censored at the last known 
alive date 
Key Secondary Endpoint
ORR per RECIST 1.1 by
BICR
Test and Estimation: 
Stratified M&N method 
with sample size weights
ITT
Participants without 
assessments are considered 
non-responders and 
conservatively included in 
the denominator
BICR  blinded independent central review; ITT  intention to treat; ORR  objective response rate; OS  overall 
survival; PFS  progression free survival; RECIST 1.1  Response Evaluation Criteria in Solid Tumors version 1.1; 
M&N  Miettinen and Nurminen
a Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization (Section 6.3.1.1) will be applied to the analysis. Small strata will be combined in a way specified by a 
blinded statistician prior to the analysis.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests and vital signs.
The analysis of safety results will follow a tiered approach as shown in Table 20. The tiers 
differ with respect to the analyses that will be performed. Adverse events (specific terms as 
well as system organ class terms) are either prespecified as “Tier 1” endpoints or will be 
classified as belonging to “Tier 2” or “Tier 3” based on the observed proportions of 
participants with an event.  
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Safety parameters or AEs of interest that are identified a priori constitute “Tier 1” safety 
endpoints that will be subject to inferential testing for statistical significance.  There are no 
Tier 1 events for this protocol.  Based on a review of historic chemotherapy data and data 
from ongoing pembrolizumab clinical studies in gastric cancer, there are no AEs of interest 
that warrant inferential testing for comparison between treatment arms in this study.
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for between-
group comparisons.
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other adverse experiences and predefined limits of change will belong to Tier 3.  
The threshold of at least 10% of participants was chosen for Tier 2 event because the
population enrolled in this study are in critical conditions and usually experience various 
adverse events of similar types regardless of treatment, events reported less frequent than 
10% of participants would obscure the assessment of overall safety profile and add little to 
the interpretation of potentially meaningful treatment differences.  In addition, Grade 3 to 5 
AEs (≥5% of participants in 1 of the treatment groups) and SAEs (≥5% of participants in 1 of 
the treatment groups) will be considered Tier 2 endpoints. Because many 95% confidence 
intervals may be provided without adjustment for multiplicity, the confidence intervals 
should be regarded as a helpful descriptive measure to be used in review, not a formal 
method for assessing the statistical significance of the between-group differences.  These 
analyses will be performed using the Miettinen and Nurminen method, an unconditional, 
asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates are provided for Tier 3 safety parameters. For continuous measures such as vital 
signs, summary statistics for baseline and on-treatment will be provided by treatment group 
in tabular format.
Table 20
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
AEs (≥10% of participants in 1 of the treatment 
groups)
X
X
Grade 3-5 AEs (≥5% of participants in 1 of the 
treatment groups)
X
X
SAEs (5% of participants in 1 of the treatment 
groups)
X
X
AEs (<10% of participants in 1 of the treatment 
groups)
X
Tier 3
Discontinuation due to AE
X
Change from Baseline Results (laboratory test 
toxicity grade)
X
AE adverse event; CI confidence interval; SAE serious adverse event; X results will be provided.
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9.6.3
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these
characteristics. The number and percentage of participants screened, randomized, the 
primary reasons for screening failure, and the primary reason for discontinuation will be 
displayed.
Demographic variables (eg, age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
9.7
Interim Analyses
An external Data Monitoring Committee (DMC) will serve as the primary reviewer of the 
results of the interim analysis (analyses) of the study and will make recommendations for 
discontinuation of the study or protocol modifications to an executive committee of the 
Sponsor.  If the DMC recommends modifications to the design of the protocol or 
discontinuation of the study, this executive committee (and potentially other limited Sponsor
personnel) may be unblinded to results at the treatment level in order to act on these 
recommendations. The extent to which individuals are unblinded with respect to results of 
interim analyses will be documented. Additional logistical details will be provided in the 
DMC charter.  
Treatment-level results from the interim analysis will be provided to the DMC by the 
unblinded statistician. Prior to final study unblinding, the unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
9.7.1
Efficacy Interim Analysis
Three interim analyses may be performed in this study based on current projection of 
enrollment and event accrual rates. The timing and the purpose of each analysis are 
summarized in Table 21. Type I error control for the efficacy analyses as well as efficacy 
bounds are described in Section 9.8 Multiplicity.
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Table 21
Summary of Interim and Final Analyses Strategy
Analyses 
Timing
Estimated Time after 
First Participant 
Randomized 
Primary Purpose of Analysis
IA1
The first 260 participants with 
approximately 8.5 months 
follow-up.
~ 22.5 months  
Efficacy analysis of ORR
(hypothesis testing)
IA2a
Approximately 542 PFS 
events have occurred and ~ 
9 months after the last 
participant has been 
randomized.
~ 37 months 
Efficacy analysis for PFS 
and OS
IA3a
Approximately 18 months 
after the last participant has 
been randomized AND ~ 606 
PFS events have been 
observed. This is final PFS 
analysis.
~ 46 months
Efficacy analysis for PFS 
and OS
Final 
Analysesa
Final OS analysis to be 
performed until approximately
28 months after the last 
participant has been 
randomized AND ~ 551 
deaths have occurred.
~ 56 months

Efficacy analysis for OS
IA = interim analysis; ORR = Objective Response Rate; OS= Overall Survival; PFS = Progression-free 
Survival
9.7.2
Safety Interim Analysis
The DMC will be responsible for periodic interim safety reviews as specified in the DMC 
charter.  Interim safety analyses will also be performed at the time of interim efficacy 
analyses.
9.8
Multiplicity
The trial uses an extension of the graphical method of Maurer and Bretz [Maurer, W. and 
Bretz, F. 2013] to provide strong multiplicity control for multiple hypotheses while making 
the interim and final analysis timing be more flexible [Anderson, K. M. 2018]. According to 
the Maurer and Bretz approach, study hypotheses may be tested in a group sequential 
fashion, and when a particular null hypothesis is rejected, the alpha allocated to that 
hypothesis can be reallocated to other hypothesis tests.
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Figure 4 shows the initial 1-sided alpha allocation for each hypothesis in the ellipse 
representing the hypothesis. The weights for reallocation from each hypothesis to the others 
are represented in the boxes on the lines connecting hypotheses.
Figure 4
Type I Error Reallocation Strategy
IA1 interim analysis 1; ORR objective response rate; OS overall survival; PFS progression free survival.
Note: If both PFS and OS null hypotheses are rejected, the reallocation strategy allows re testing of ORR at alpha 0.025 based on the 
p value at IA1.
The extended graphical method spends alpha as a function of the minimum of the actual 
event information fraction and the expected event information fraction.  This ensures that the 
actual spending will be no more aggressive than the planned, while at the same time ensuring 
that not all alpha is spent prior to final planned event counts.
9.8.1
Objective Response Rate
The study allocates alpha 0.002, 1-sided, to test ORR, and ORR is tested only at the first 
interim analysis (IA1). However, if the test does not reach statistical significance at IA1, the 
p-value from IA1 can be compared to an updated alpha-level if the null hypotheses for both 
PFS and OS are rejected at a later time. Power at the possible alpha-levels as well as the 
approximate treatment difference required to reach the bound (ORR difference) are shown in
Table 22. 
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Table 22
Possible Alpha-levels and Approximate ORR Difference Required to 
Demonstrate Efficacy for ORR at Interim Analysis 1
Alpha
ORR difference
Power
0.002
~ 0.17
0.90
0.025
~ 0.11
0.99
ORR = objective response rate
9.8.2
Progression-free Survival
The initial alpha-level for testing PFS is 0.003. If the null hypothesis for ORR is rejected, 
Figure 4 shows that half of its alpha, ie, 0.001, is reallocated to PFS hypothesis testing. If the 
null hypothesis for OS is rejected, then alpha 0.02 is essentially fully reallocated to PFS 
hypothesis testing. Thus, the PFS null hypothesis may be tested at alpha 0.003, alpha 0.004
(if the ORR null hypothesis is rejected but not the OS null hypothesis), alpha 0.023 (if the 
OS null hypothesis is rejected but not the ORR null hypothesis), or alpha 0.025 (if both the 
ORR and OS null hypotheses are rejected). Table 23 shows the boundary properties for each 
of these alpha-levels for the interim analyses, which were derived using a Lan-DeMets 
O'Brien-Fleming spending function based on predicted number of events at the planned time 
of interim analysis. Note that the final row indicates the total power to reject the null 
hypothesis for PFS at each alpha-level.
Also note that if the OS or ORR null hypothesis is rejected at an interim or final analysis, 
each PFS interim and final analysis test may be compared to its updated bounds considering 
the alpha reallocation from the OS or ORR hypothesis.
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Table 23
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
=0.003
=0.004
=0.023
=0.025
IA 2: 90%a
Z
2.927
2.826
2.137
2.1
N: 692
p (1-sided)b
0.0017
0.0024
0.0163
0.0179
Events: 542
HR at boundc
0.7777
0.7849
0.8326
0.8353
Month: 37
P(Cross) if HR=1d
0.0017
0.0024
0.0163
0.0179
P(Cross) if HR=0.7e
0.8915
0.9091
0.9785
0.9804
IA 3: 100%a
Z
2.807
2.714
2.086
2.052
N: 692
p (1-sided)b
0.0025
0.0033
0.0185
0.0201
Events: 606
HR at boundc
0.796
0.8024
0.8444
0.8467
Month: 46
P(Cross) if HR=1d
0.003
0.004
0.023
0.025
P(Cross) if HR=0.7e
0.9475
0.9569
0.9909
0.9917
HR  Hazard Ratio; IA  interim analysis
a Percentage of expected number of events at final analysis
b p (1 sided) is the nominal alpha for testing.
c HR at bound is the approximate HR required to reach an efficacy bound
d P(Cross if HR 1) is the cumulative probability of crossing a bound under the null hypothesis
e P(Cross if HR 0.7) is the cumulative probability of crossing a bound under the alternative hypothesis
9.8.3
Overall Survival
The OS hypothesis may be tested at alpha 0.02 (initially allocated alpha), alpha 0.023 (if 
the PFS but not the ORR null hypothesis is rejected), alpha 0.021(if the ORR but not the 
PFS null hypothesis is rejected), or alpha 0.025 (if both the ORR and PFS null hypotheses 
are rejected). Table 24 shows the bounds and boundary properties for OS hypothesis testing 
derived using a Lan-DeMets O'Brien-Fleming spending function based on the predicted 
number of events at the planned time of interim analysis.
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Also note that if the PFS or ORR null hypothesis is rejected at an interim or final analysis, 
each OS interim and final analysis test may be compared to its updated bounds considering 
the alpha reallocation from the PFS or ORR hypothesis.
Table 24
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
=0.02
=0.021
=0.023
=0.025
IA 2: 73%a
N: 692 
Events: 401
Month: 37
Z 
2.493
         2.47
2.426
2.385
p (1-sided)b
0.0063
0.0068
0.0076
0.0085
HR at boundc
0.7794
0.7815
0.7849
0.7881
P(Cross) if HR=1d
0.0063
0.0068
0.0076
0.0085
P(Cross) if HR=0.75e  
0.6513
0.6598
0.6757
0.6902
IA 3: 89%a
N: 692 
Events: 488
Month: 46
Z 
2.272
2.252
2.213
2.178
p (1-sided)b
0.0115
0.0122
0.0134
0.0147
HR at boundc
0.814
0.8158
0.8186
0.8212
P(Cross) if HR=1d
0.0134
0.0142
0.0157
0.0172
P(Cross) if HR=0.75e  
0.8263
0.8316
0.8413
0.85
Final 
N: 692
Events: 551
Month: 56
Z 
2.152
2.133
2.097
2.064
p (1-sided)b
0.0157
0.0165
0.018
0.0195
HR at boundc
0.8325
0.834
0.8366
0.8389
P(Cross) if HR=1d
          0.02
0.021
0.023
0.025
P(Cross) if HR=0.75e
0.9001
0.9035
0.9097
0.9151
HR  Hazard Ratio; IA  interim analysis
a Percentage of expected number of events at final analysis
b p (1 sided) is the nominal α for testing.
c HR at bound is the approximate HR required to reach an efficacy bound.
d P(Cross if HR 1) is the cumulative probability of crossing a bound under the null hypothesis.
e P(Cross if HR 0.75) is the cumulative probability of crossing a bound under the alternative hypothesis.
9.8.4
Safety Analyses
The external DMC has responsibility for assessment of overall risk: benefit. When prompted 
by safety concerns, the external DMC can request corresponding efficacy data. External 
DMC review of efficacy data to assess the overall risk benefit ratio to trial participants will 
not require a multiplicity adjustment typically associated with a planned efficacy IA; 
however, to account for any multiplicity concerns raised by the external DMC review of 
unplanned efficacy data prompted by safety concerns, a sensitivity analysis for efficacy 
endpoints adopting a conservative multiplicity adjustment will be prespecified in the sSAP. 
This analysis will be performed if requested by the external DMC.
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9.9
Sample Size and Power Calculations
In the Global Cohort, ~ 692 participants will be randomized in a 1:1 ratio between the 2 
arms. 
9.9.1
Objective Response Rate
With sample size of ~ 260 at IA1, the study has ~ 90% power for detecting a 25 percent 
difference in ORR (73% versus 48%) at an initially assigned 0.002 (1-sided) significance 
level. 
9.9.2
Progression-free Survival
There will be ~ 606 events at the PFS final analysis. With 606 PFS events, the study has ~ 
95% power for detecting a HR of 0.7 at an initially assigned 0.003 (1-sided) significance 
level. 
9.9.3
Overall Survival
There will be ~ 551 deaths at the OS final analysis. With 551 deaths, the study has ~ 90% 
power for detecting an HR of 0.75 at an initially assigned 0.020 (1-sided) significance level. 
The sample size (number of participants) calculations are based on the following 
assumptions: (1) the enrollment period is 28 months and the ramp-up period of enrollment is 
6 months; (2) the duration of PFS and OS follow exponential distribution; (3) median PFS is 
6.7 months in the control group and the true HR is 0.7; (4) median OS is 13.8 months in the 
control group and the true HR ratio is 0.75 [Bang, Y. J., et al 2010]. Power and interim 
analysis calculations were performed using the gsDesign R package.
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of each subgroup.  The 
following are examples of classification variables:

Age category: (<65 versus ≥65 years)

Sex: (female, male)

Race: (Asian versus non-Asian)

Region: Europe/Israel/North America/Australia versus Asia versus Rest of World 
(including South America)

PD-L1: Positive versus Negative

MSI status

Primary location: Stomach versus GEJ

Histological subtype: Diffuse versus intestinal versus indeterminate
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
Tumor Burden: ≥median versus <median

Number of Metastases: ≤2 versus ≥3

Prior Gastrectomy: yes versus no
9.11
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
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, conducts clinical trials worldwide 
to evaluate the safety and effectiveness of our products. As such, we are committed to designing, planning, 
conducting, analyzing, and reporting these trials in compliance with the highest ethical and scientific standards. 
Protection of participants in clinical trials is the overriding concern in the design and conduct of clinical trials. In all 
cases, MSD clinical trials will be conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and International Council for 
Harmonisation Good Clinical Practice (ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, 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 (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or which 
are retrospective. Further, this Code does not apply to investigator initiated trials, which are not under the full control 
of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc. 
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial and shall respect the data protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including patient advocacy groups/patients 
representing the trial population, caregivers, and healthcare providers to ensure operational feasibility. Trial design 
also includes proactive identification of critical to quality factors utilizing a risk based approach.  Plans are then 
developed to assess and mitigate risks to those factors as appropriate during the trial. All trial protocols are and 
will be assessed for the need and capability to enroll underrepresented groups. Participants must meet protocol 
entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities and 
staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.  Individuals involved in trial conduct receive training commensurate with their role prior to their 
becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts to 
raise awareness of clinical trial opportunities in various communities. MSD will seek to engage underrepresented 
groups and those disproportionately impacted by the disease under study. MSD will support clinical trial 
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investigators to enroll underrepresented groups and expand access to those who will ultimately use the products 
under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and procedures, if potential fraud, 
scientific/research misconduct, privacy incidents/breaches or Clinical Trial related Significant Quality Issues are 
reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority acceptance/authorization 
prior to implementation of the trial or amendment, in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations and ICH Guidelines. Changes to the protocol that are required urgently to 
eliminate an immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee 
approval. MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance 
with local and/or national regulations.
B. Safety
The guiding principle in decision making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care. 
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Trial designs include procedures and systems for the identification, monitoring and reporting of safety 
concerns.  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.
During trial planning, the need for an independent Data Monitoring Committee (DMC) is assessed. DMC review of 
data accumulated during the conduct of the trial is integral to the well being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all applicable 
data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on behalf of 
MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records that might 
identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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E. Trial Results
At the time of providing informed consent and in accordance with local laws and regulations, participants should be 
informed about the plans for availability of trial results.
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 
medical record review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (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 their 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 US 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 which would make the participant identifiable will not be transferred. 
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The participant must be informed that their 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 their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.4
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.
10.1.5
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 in 
order to verify worksheet/CRF data. By signing the consent form, the participant agrees to 
this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked 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.
10.1.6
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.
10.1.7
Committees Structure
10.1.7.1
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (SAC). The 
SAC is comprised of both Sponsor and non-Sponsor scientific experts who provide input 
with respect to study design, interpretation of study results and subsequent peer-reviewed 
scientific publications.
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10.1.7.2
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 Committee regarding the study.
10.1.7.3
Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study. 
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (see 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.
10.1.8
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.
10.1.9
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
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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 site contact information. 
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.9.1
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other 
generally accepted standards of GCP); and all applicable federal, state and local laws, rules 
and regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the study
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.10
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.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
10.1.11
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.
10.1.12
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: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
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signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons. 
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube. 
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research and consent. Future 
biomedical research specimens remaining with the third party after specific analysis is 
performed will be reported to the Sponsor.
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6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
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9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid 45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.3
Appendix 3:  Contraceptive Guidance and Pregnancy Testing
10.3.1
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
10.3.2
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 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.
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o
The following are not acceptable methods of contraception:
▪
Periodic abstinence (calendar, symptothermal, and postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
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 use a 
highly effective method of contraception consistently and correctly as described in Table 25
during the protocol-defined time frame in Section 5.1. 
Table 25
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.d
Non-hormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is ~ 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those which 
inhibit ovulation.
c
Male condoms must be used in addition to female participant hormonal contraception.
d
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
Male condom with cap, diaphragm, or sponge with spermicide.
Male and female condom should not be used together (due to risk of failure with friction).
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●
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 one 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. 
●
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 one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, OR IF 
RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER 
DOSE MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, 
THE INIRB/IEC.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the CRFs/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).
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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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10.6
Appendix 6:  Country-specific Requirements
10.6.1
UK-specific Information
1. Section 5.1
Inclusion Criteria - Demographics 
Males are to be advised to seek counseling on sperm storage before starting treatment 
with pemetrexed, etoposide, and/or platinum-based therapy as per respective SmPCs.
2. Section 5.2
Exclusion Criteria

Exclusion Criterion 9: TB testing is mandatory.

Exclusion Criterion 19: HIV testing is mandatory.

Exclusion Criterion 20: Hepatitis B and C testing is mandatory.
3. Section 6.5.1 Specific Restrictions (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 6.5.1 for information on COVID-19 vaccines.
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.
4. Section 8.3.6 Pregnancy Testing
Monthly urine pregnancy testing is required during treatment as well as at the end of 
study treatment.
10.6.2
Germany-specific Information:

Exclusion Criterion 9: TB testing is mandatory.

Exclusion Criterion 19: HIV testing is mandatory.

Exclusion Criterion 20: Hepatitis B and C testing is mandatory.
10.6.3
Japan-specific Information:
1. Approximately 692 participants will be randomized in the Global Cohort.  A separate 
cohort of approximately 40 participants who will receive SOX (S-1 plus oxaliplatin) will 
be enrolled in Japan for a total of ~ 732 participants.  This is in addition to Japan 
participants enrolled in the Global Cohort.  These 40 participants will have their data 
analyzed separately from the Global Cohort.
2. In Japan, document agreement is necessary for both the participant and their substitute 
when participants are under 20 years of age.
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3. Recommended dose modifications for SOX, oxaliplatin, and S-1 are found in 
Section 6.6.4.3.
4. Section 6.1
Treatments Administered 
Table 3 Study Treatments
5-FU and S-1 used in this study are categorized as “test product(s)” in Japan.
Intravenous solution, not provided by the Sponsor, as placebo for pembrolizumab (MK-
3475) in this protocol is not categorized as “product(s) used in the clinical trial” in Japan.
10.6.4
France-specific Information: 
For participants receiving oxaliplatin:

A 12-lead ECG must be performed on the day of administration before and after 
intravenous administration of oxaliplatin.
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10.7
Appendix 7:  Abbreviations
Abbreviation/Term
Definition
1L
first line
3L
third line
5-FU
5-fluorouracil
ACC
American College of Cardiology
ADA
anti-drug antibodies
ADCC
antibody-dependent cell-mediated cytotoxicity
ADL
activities of daily living
AE
adverse event
AHA
American Heart Association
ALT
alanine aminotransferase
APaT
all participants as treated (population)
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AxMP
auxiliary medicinal product
BICR
blinded independent central review
bid
twice daily
BSA
body surface area
C1D1
Cycle 1 Day 1
CAPOX
capecitabine/oxaliplatin
CBC
complete blood count
CD
cluster of differentiation
CDHP
5-chloro-2,4-dihydroxypyridine
CHF
congestive heart failure
CI
confidence interval
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CPS
combined positive score
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Abbreviation/Term
Definition
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DCR
disease control rate
DILI
drug-induced liver injury
DL
dose level
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECHO
echocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection 
EG
esophagogastric
EMA
European Medicines Agency
EOC
executive oversight committee
EORTC
European Organization 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)
ESMO
European Society for Medical Oncology
EU
European Union
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Abbreviation/Term
Definition
EQ-5D-5L
EuroQoL-5 Dimension Questionnaire
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FISH
fluorescent in-situ hybridization
FP
cisplatin plus 5-fluorouracil
FT4
free thyroxine
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GEJ
gastroesophageal junction
GI
gastrointestinal
G-SOX
S-1 plus cisplatin versus S-1 plus oxaliplatin study
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HR
hazard ratio
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
iCRO
imaging contract research organization
iCPD
iRECIST confirmed progressive disease
IEC
independent ethics committee
iCR
iRECIST confirmed response
Ig
immunoglobulin 
IHC
immunohistochemistry
IL-10
interleukin 10
IMP
investigational medicinal product
INR
international normalized ratio
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Abbreviation/Term
Definition
iPD
iRECIST progressive disease
irAE
immune-related adverse event
IRB
Institutional Review Board
iRECIST
modified Response Evaluation Criteria in Solid Tumors for 
immune-based therapeutics
IRT
interactive response technology
iSD
iRECIST stable disease
ISH
in situ hybridization
ITT
intention to treat
IUD
intrauterine device
iUPD
iRECIST unconfirmed progressive disease
IUS
intrauterine system
IV
intravenous
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MUGA
multiple-gated acquisition
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIMP
non-investigational medicinal product
NK
natural killer
NR
not reached
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
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Abbreviation/Term
Definition
Oxo
potassium oxonate
PBPK
physiologically based pharmacokinetic(s)
PD
progressive disease
PD-1
programmed cell death-1
PD-L1
programmed cell death-ligand 1
PD-L2
programmed cell death-ligand 2
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Device Agency
PR
partial response
PRO
patient-reported outcome(s)
PT
prothrombin time
Q3W
every 3 weeks
QLQ
Quality of Life Questionnaire
QoL
quality of life
REAL-2
Randomized epirubicin, cisplatin, and infused fluorouracil (ECF)
for Advanced and Locally Advanced Esophagogastric Cancer
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RNA
ribonucleic acid
S-1
combination product containing tegafur, a prodrug of 5-FU, and 
2 types of enzyme inhibitors, CDHP and Oxo
SAC
scientific advisory committee
SAE
serious adverse event
SLAB
supplemental lab tests (CRF)
SNP
single nucleotide polymorphism
SoA
Schedule of Activities
SOP
standard operating procedure
SOX
S-1 plus oxaliplatin
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Abbreviation/Term
Definition
SPIRITS
S-1 plus cisplatin versus S-1 In randomized control trial In the 
Treatment for Stomach cancer study
sSAP
supplemental statistical analysis plan
T1DM
type 1 diabetes mellitus
T3
triiodothyronine
TB
tuberculosis
ToGA
Trastuzumab for Gastric Cancer
TSH
thyroid-stimulating hormone
UA
urinalysis
UK
United Kingdom
ULN
upper limit of normal
US
United States
WBC
white blood cells
WOCBP 
woman of childbearing potential
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10.9
Appendix 9: 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 treatment 
until repeat imaging 4 to 8 weeks later is obtained (using iRECIST for participant 
management).  The decision by the investigator should be based on the participant’s overall 
clinical condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of 
disease
•
No decline in ECOG performance status 
•
No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
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.
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
o
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 non-target lesion(s) identified at baseline
•
Development of new lesion(s)
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 non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
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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 initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o
For non-target 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
o
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 non-target lesions 
•
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
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
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•
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 treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 1.3 and 
submitted to the BICR.
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
o
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 trial, 
either before or after an instance of pseudo-progression.
•
Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so 
for the first-time results in iUPD.
o
If non-target 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
o
New lesions appear for the first time
o
Additional new lesions appear
o
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
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o
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 1 
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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11
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