Conditions: Gastric Cancer Gastroesophageal Junction Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1007
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of pembrolizumab (MK-3745) in the neoadjuvant (prior to surgery) or adjuvant (after surgery) treatment of previously untreated adults with gastric and gastroesophageal junction (GEJ) adenocarcinoma.

The primary study hypotheses are that:

* Neoadjuvant and adjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab is superior to neoadjuvant and adjuvant placebo plus chemotherapy, followed by adjuvant placebo in terms of Event-free Survival (EFS) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), and
* Neoadjuvant pembrolizumab plus chemotherapy is superior to neoadjuvant placebo plus chemotherapy in terms of rate of Pathological Complete Response (pathCR) at the time of surgery.

With Amendment 10, upon study completion, participants will be discontinued and may be enrolled in an extension study.

Detailed description:

Arms:
arm 1: XP=cisplatin+capecitabine and FP=cisplatin+5-fluorouracil. Neoadjuvant: Prior to surgery, participants receive 3 cycles of pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) PLUS cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m\^2 via oral tablets twice each day (BID) on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m\^2 IV infusion on Day 1 Q3W and 5-fluorouracil (5FU) 800 mg/m\^2 continuous IV infusion on Days 1 to 5 of each 3-week cycle.

Adjuvant: 4 to 10 weeks post-surgery, participants receive 3 cycles of pembrolizumab 200 mg IV infusion on Day 1 Q3W PLUS cisplatin 80 mg/m\^2 IV infusion on Day 1 Q3W and capecitabine 1000 mg/m\^2 via oral tablets BID on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m\^2 IV infusion on Day 1 Q3W and 5FU 800 mg/m\^2 continuous IV infusion on Days 1 to 5 of each 3-week cycle, followed by pembrolizumab monotherapy 200 mg IV infusion on Day 1 Q3W for up to 11 additional cycles. arm 2: Neoadjuvant: Prior to surgery, participants receive 3 cycles of placebo (normal saline solution) via IV infusion on Day 1 Q3W PLUS cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m\^2 via oral tablets BID on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and 5FU 800 mg/m\^2 via continuous IV infusion on Days 1 to 5 of each 3-week cycle.

Adjuvant: 4 to 10 weeks post-surgery, participants receive 3 cycles of placebo via IV infusion on Day 1 Q3W PLUS cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and capecitabine 1000 mg/m\^2 via oral tablets BID on Days 1 to 14 of each 3-week cycle OR cisplatin 80 mg/m\^2 via IV infusion on Day 1 Q3W and 5FU 800 mg/m\^2 via continuous IV infusion on Days 1 to 5 of each 3-week cycle, followed by placebo monotherapy via IV infusion on Day 1 Q3W for up to 11 additional cycles. arm 3: FLOT=docetaxel+oxaliplatin+5FU+leucovorin (calcium folinate). Neoadjuvant: Prior to surgery, participants receive 3 cycles of pembrolizumab 200 mg via IV infusion on Day 1 Q3W PLUS docetaxel 50 mg/m\^2 via IV infusion, oxaliplatin 85 mg/m\^2 via IV infusion, 5FU 2600 mg/m\^2 via IV infusion, and leucovorin (calcium folinate) 200 mg/m\^2 via IV infusion Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3, for 4 administrations).

Adjuvant: 4 to 10 weeks postsurgery, participants receive 3 cycles of pembrolizumab 200 mg via IV infusion Day 1 Q3W PLUS docetaxel 50 mg/m\^2, oxaliplatin 85 mg/m\^2, 5FU 2600 mg/m\^2, and leucovorin 200 mg/m\^2 Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3, for 4 administrations), followed by pembrolizumab monotherapy 200 mg via IV infusion on Day 1 Q3W for up to 11 additional cycles. arm 4: Neoadjuvant: Prior to surgery, participants receive 3 cycles of placebo (normal saline solution) via IV infusion on Day 1 Q3W PLUS docetaxel 50 mg/m\^2 via IV infusion, oxaliplatin 85 mg/m\^2 via IV infusion, 5FU 2600 mg/m\^2 via IV infusion, and leucovorin 200 mg/m\^2 via IV infusion Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3, for 4 administrations).

Adjuvant: 4 to 10 weeks postsurgery, participants receive 3 cycles of placebo via IV infusion on Day 1 Q3W PLUS docetaxel 50 mg/m\^2 via IV infusion, oxaliplatin 85 mg/m\^2 via IV infusion, 5FU 2600 mg/m\^2 via IV infusion, and leucovorin 200 mg/m\^2 via IV infusion Q2W (on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, and Day 1 of Cycle 3, for 4 administrations), followed by placebo monotherapy via IV infusion on Day 1 Q3W for up to 11 additional cycles.

Interventions: intervention 1: Pembrolizumab intervention 2: Placebo intervention 3: Cisplatin intervention 4: Capecitabine intervention 5: 5-fluorouracil intervention 6: Docetaxel intervention 7: Oxaliplatin intervention 8: Leucovorin
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: Oral tablets intervention 5: IV infusion intervention 6: IV infusion intervention 7: IV infusion intervention 8: IV infusion

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase III, Randomized, Double-Blind, Clinical Trial of 
Pembrolizumab (MK-3475) plus Chemotherapy (XP or 
FP) versus Placebo plus Chemotherapy (XP or FP) as 
Neoadjuvant/Adjuvant Treatment for Subjects with 
Gastric and Gastroesophageal Junction (GEJ) 
Adenocarcinoma (KEYNOTE-585)
NCT03221426
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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, Clinical Trial of Pembrolizumab 
(MK-3475) plus Chemotherapy (XP or FP) versus Placebo plus Chemotherapy (XP or FP) as 
Neoadjuvant/Adjuvant Treatment for Subjects with Gastric and Gastroesophageal Junction 
(GEJ) Adenocarcinoma (KEYNOTE-585)
Protocol Number: 585-10
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: 2016-004408-76
Approval Date:  20 November 2023
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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 10
20-NOV-2023
The study was positive for the endpoint of pathCR based on IA1; however, based on IA3, it
did not meet the prespecified criteria for statistical significance of the primary endpoint of 
EFS and the multiplicity strategy will not allow further statistical testing. There were no 
safety concerns; the study will continue to evaluate OS at the time of final analysis. 
Participants on treatment were unblinded to facilitate decision making.
Amendment 9
24-AUG-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
16-APR-2021
Promote OS to primary endpoint for the Main Study.
Amendment 7
11-JAN-2021
Amend statistical analysis plan in preparation for efficacy analyses
Amendment 6
13-DEC-2019

The FLOT Safety Cohort will be expanded to further characterize the safety profile of 
the combination of FLOT with pembrolizumab and will be designated the FLOT 
Cohort.

Adjust the statistical analysis plan to account for an enrollment delay.
Amendment 5
14-MAR-2019
Response to Regulatory Authority input regarding safety monitoring procedures and 
radiation therapy.
Amendment 4
03-AUG-2018
Implement feedback from regulatory authorities and align with current pembrolizumab 
program standards
Amendment 3
22-MAY-2018
Introduce flexibility in electronic patient-reported outcome (ePRO) completion during the 
Survival Follow-up period
Amendment 2
09-JAN-2018
Include the use of the FLOT regimen as one of the options for the SOC chemotherapy 
backbone
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Document
Date of Issue
Overall Rationale
Amendment 1
01-SEP-2017
Revise stratification information; change from central to local laboratory use
Original Protocol
25-APR-2017
Not Applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 10
Overall Rationale for the Amendment:
The study was positive for the endpoint of pathCR based on IA1; however, based on IA3, it
did not meet the prespecified criteria for statistical significance of the primary endpoint of 
EFS and the multiplicity strategy will not allow further statistical testing. There were no 
safety concerns; the study will continue to evaluate OS at the time of final analysis. 
Participants on treatment were unblinded to facilitate decision making.
Summary of Changes Table
Section Number and 
Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 5, Study 
Design
Participants on treatment were
unblinded to study intervention. 
This change was made to address new data. Based 
on IA3, the primary endpoint of EFS did not meet 
statistically significant superiority, although the 
endpoint of pathCR was positive. The multiplicity 
strategy will not allow further statistical testing.
Participants on treatment were unblinded to 
facilitate decision making regarding continued 
treatment in the study. 
Section Number and 
Name
Description of Change
Brief Rationale
Additional Changes
Section 7.8, Treatment 
After the End of the 
Study
Added text indicating that participants 
may be enrolled into an extension study 
using pembrolizumab.
An extension study is available for participants to 
receive continued treatment and/or follow-up after 
completion of the study.
Section 9.1.10, 
Procedures for 
Negative Studies 
Without Safety 
Concerns
Added new subsection to describe 
negative studies. 
To describe actions that may occur for participants 
when data present negative outcomes without 
safety concerns, and aligned with the outcome of 
the interim analysis in this study.
Section 9.1.11, 
Participant 
Blinding/Unblinding
Added text to describe the unblinding of 
participants on treatment in the China 
extension to make treatment decisions. 
Refer to Section 5 rationale.
Section 9.3.1, Time 
Period and Frequency 
for Collecting AE, 
SAE, and Other 
Reportable Safety 
Event Information
Added text to describe collection of 
safety data for participants who may 
enter the extension study. 
To ensure reporting of safety information for 
participants who enter the extension study meets 
guidelines stated in the protocol for such reporting. 
Throughout
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...............................................5
1.
Synopsis.......................................................................................................................16
2.
Schedule of Activities (SoA)......................................................................................22
FLOT Cohort...........................................................................................................22
Neoadjuvant Combination Treatment Group 1: FLOT + 
Pembrolizumab OR Neoadjuvant Combination Treatment Group 2: 
FLOT + Placebo...................................................................................................22
Adjuvant Combination Treatment Group 1: FLOT + Pembrolizumab 
OR Adjuvant Combination Treatment Group 2: FLOT + Placebo......................27
Adjuvant Monotherapy Treatment Group 1: Pembrolizumab OR 
Adjuvant Monotherapy Treatment Group 2: Placebo..........................................29
End of Treatment and Post-treatment Study Period.............................................31
Main Study (XP/FP)................................................................................................33
Neoadjuvant Combination Phase (3 cycles) ........................................................33
Neoadjuvant Combination Treatment Group 1: XP or FP + 
Pembrolizumab OR Neoadjuvant Combination Treatment Group 
2: XP or FP + Placebo ..................................................................................33
Adjuvant Combination Phase (3 cycles)..............................................................37
Adjuvant Combination Treatment Group 1: XP or FP + 
Pembrolizumab OR Adjuvant Combination Treatment Group 2: 
XP or FP + Placebo.......................................................................................37
Adjuvant Monotherapy Phase (11 Cycles) ..........................................................39
Adjuvant Monotherapy Treatment Group 1: Pembrolizumab or 
Adjuvant Monotherapy Treatment Group 2: Placebo...................................39
End of Treatment and Post-treatment Study Period.............................................41
3.
Introduction................................................................................................................43
Study Rationale .......................................................................................................43
Rationale for the Study and Selected Participant Population ..............................43
Rationale for Neoadjuvant Treatment...........................................................43
Rationale for Adjuvant Treatment ................................................................44
Clinical Studies With Pembrolizumab in Gastric Cancer.............................44
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Clinical Studies With Neoadjuvant Pembrolizumab ....................................47
Background..............................................................................................................47
Pharmaceutical and Therapeutic Background .....................................................48
Pre-clinical and Clinical Studies..........................................................................49
Ongoing Clinical Studies of Pembrolizumab in Malignancies............................49
Benefit/Risk Assessment.........................................................................................50
4.
Objectives/Hypotheses and Endpoints.....................................................................51
5.
Study Design...............................................................................................................54
Overall Design .........................................................................................................55
Main Study (XP/FP) ............................................................................................55
Main Study Diagram.....................................................................................58
FLOT Cohort .......................................................................................................58
FLOT Cohort Diagram .................................................................................59
Number of Participants ..........................................................................................59
Beginning and End of Study Definition ................................................................60
Clinical Criteria for Early Study Termination .....................................................60
Scientific Rationale for Study Design....................................................................60
Rationale for Endpoints .......................................................................................60
Efficacy Endpoints........................................................................................60
Safety Endpoints...........................................................................................61
Patient-reported Outcomes............................................................................61
EORTC QLQ-C30 .................................................................................61
EORTC QLQ-STO22 ............................................................................61
EuroQoL EQ-5D-5L..............................................................................62
Planned Exploratory Biomarker Research....................................................62
Future Biomedical Research.........................................................................63
Rationale for the Use of Chemotherapy/Placebo.................................................64
Rationale for the Use of Cisplatin + Capecitabine or 5-FU in 
Gastric Cancer...............................................................................................64
Rationale for Use of FLOT in Gastric Cancer..............................................65
Safety Evaluation of Pembrolizumab + XP in KEYNOTE 059 
Cohort 2 ........................................................................................................66
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Justification for Dose ..............................................................................................66
6.
Study Population........................................................................................................68
Inclusion Criteria....................................................................................................68
Exclusion Criteria ...................................................................................................70
Lifestyle Restrictions...............................................................................................73
Meals and Dietary Restrictions............................................................................73
Photosensitivity....................................................................................................73
Screen Failures ........................................................................................................73
Participant Replacement Strategy.........................................................................73
7.
Treatments..................................................................................................................73
Treatments Administered.......................................................................................73
Dose Modification (Escalation/Titration/Other)..................................................76
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).........................................................................................................77
Dose Modifications for Cisplatin and Capecitabine or 5-FU ..............................86
Dose Modification Guidelines for Docetaxel ......................................................88
Dose Modification Guidelines for Oxaliplatin.....................................................90
Dose Modification for Adjuvant Therapy............................................................92
Method of Treatment Assignment.........................................................................92
Stratification.........................................................................................................92
Blinding....................................................................................................................92
Preparation/Handling/Storage/Accountability ....................................................93
Dose Preparation..................................................................................................93
Handling, Storage and Accountability.................................................................93
Treatment Compliance...........................................................................................93
Concomitant Therapy.............................................................................................94
Acceptable Concomitant Medications/Therapy...................................................94
Prohibited Concomitant Medication/Therapy......................................................95
Rescue Medications and Supportive Care ...........................................................96
Supportive Care Guidelines for Immune-related Adverse Events................96
Supportive Care Guidelines for Cisplatin.....................................................97
Supportive Care Guidelines for Capecitabine...............................................97
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Supportive Care Guidelines for 5-FU...........................................................97
Supportive Care Guidelines for the FLOT Regimen....................................98
Treatment After the End of the Study ..................................................................98
Clinical Supplies Disclosure...................................................................................98
Standard Policies.....................................................................................................99
8.
Discontinuation/Withdrawal Criteria......................................................................99
Discontinuation of Study Treatment.....................................................................99
Withdrawal from the Study .................................................................................100
Lost to Follow Up..................................................................................................100
9.
Study Assessments and Procedures........................................................................101
Administrative and General Procedures ............................................................101
Informed Consent...............................................................................................101
General Informed Consent..........................................................................101
Consent and Collection of Specimens for Future Biomedical 
Research......................................................................................................102
Inclusion/Exclusion Criteria ..............................................................................102
Participant Identification Card...........................................................................102
Medical History .................................................................................................103
Prior and Concomitant Medications Review .....................................................103
Prior Medications........................................................................................103
Concomitant Medications...........................................................................103
Assignment of Screening Number.....................................................................103
Assignment of Treatment/Randomization Number...........................................103
Treatment Administration..................................................................................104
Timing of Dose Administration..................................................................104
Discontinuation and Withdrawal .......................................................................105
Withdrawal From Future Biomedical Research .........................................105
Procedures for Negative Studies Without Safety Concerns...............................106
Participant Blinding/Unblinding........................................................................106
Calibration of Equipment...................................................................................107
Efficacy Assessments.............................................................................................108
Tumor Scans and Assessment of Disease..........................................................108
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Initial Tumor Scans.....................................................................................108
Tumor Scans During the Study...................................................................108
End of Treatment and Follow-up Tumor Scans..........................................109
RECIST 1.1 Assessment of Disease...........................................................109
irRECIST Assessment of Disease...............................................................110
Surgery...............................................................................................................112
Pathological Evaluation of Surgically Resected Tumor Tissue..................113
Pathological Complete Response.......................................................................113
Patient-Reported Outcomes ...............................................................................114
Adverse Events (AE), Serious Adverse Events (SAE) and Other 
Reportable Safety Events .....................................................................................115
Time Period and Frequency for Collecting AE, SAE and Other 
Reportable Safety Event Information ................................................................115
Method of Detecting AE, SAE and Other Reportable Safety Events................117
Follow-up of AE, SAE and Other Reportable Safety Event Information..........118
Regulatory Reporting Requirements for SAE ...................................................118
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs................................................................................118
Pregnancy and Exposure During Breastfeeding ................................................118
Events of Clinical Interest (ECI)........................................................................119
Treatment of Overdose.........................................................................................119
Safety......................................................................................................................120
Physical Examinations.......................................................................................120
Full Physical Exam .....................................................................................120
Directed Physical Exam..............................................................................120
Vital Signs..........................................................................................................120
Electrocardiograms ............................................................................................120
Eastern Cooperative Oncology Group (ECOG) Performance Status ................121
Clinical Safety Laboratory Assessments............................................................121
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)...................................................................................................121
Pregnancy Test...................................................................................................122
Pharmacokinetics..................................................................................................122
Pharmacodynamics...............................................................................................122
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Biomarkers ............................................................................................................122
Planned Genetic Analysis Sample Collection....................................................123
Future Biomedical Research Sample Collection................................................123
Visit Requirements................................................................................................123
Screening............................................................................................................123
Treatment Period Visit.......................................................................................124
Post-treatment Follow-up...................................................................................124
Safety Follow-up Visit................................................................................124
Efficacy Follow-up Visits...........................................................................124
Survival Follow-up Assessments................................................................125
Vital Status.........................................................................................................125
10.
Statistical Analysis Plan ..........................................................................................125
Statistical Analysis Plan Summary......................................................................126
Responsibility for Analyses/In-house Blinding...................................................128
Hypotheses/Estimation .........................................................................................129
Analysis Endpoints................................................................................................130
Efficacy Endpoints.............................................................................................130
Safety Endpoints ................................................................................................131
Patient-Reported Outcome Endpoints................................................................131
Analysis Populations.............................................................................................131
Efficacy Analysis Populations ...........................................................................131
Safety Analysis Populations ..............................................................................132
Patient-reported Outcome Analysis Populations ...............................................132
Statistical Methods................................................................................................132
Statistical Methods for Efficacy Analyses.........................................................132
Event-free Survival (EFS)...........................................................................132
Pathological Complete Response (pathCR) Rate .......................................133
Overall Survival (OS) .................................................................................133
Analysis Strategy for Key Efficacy Variables............................................133
Disease-free Survival (DFS).......................................................................134
Statistical Methods for Safety Analyses ............................................................134
Statistical Methods for Patient-reported Outcome Analyses.............................136
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Summaries of Demographic and Baseline Characteristics ................................136
Interim Analyses ...................................................................................................136
Multiplicity ............................................................................................................137
Event-free Survival ............................................................................................138
Overall Survival.................................................................................................140
Pathological Complete Response.......................................................................142
Sample Size and Power Calculations ..................................................................143
Subgroup Analyses................................................................................................145
Compliance (Medication Adherence)..................................................................146
Extent of Exposure................................................................................................146
11.
References.................................................................................................................147
12.
Appendices................................................................................................................161
Appendix 1: Study Governance Considerations ................................................161
Code of Conduct for Clinical Trials...............................................................................161
Financial Disclosure.......................................................................................................165
Data Protection...............................................................................................................165
Confidentiality of Data ..................................................................................................165
Confidentiality of Participant Records...........................................................................166
Confidentiality of IRB/IEC Information........................................................................166
Committees Structure.....................................................................................................166
Scientific Advisory Committee......................................................................................166
Study Steering Committee.........................................................................................166
Executive Oversight Committee................................................................................167
Data Monitoring Committee......................................................................................167
Publication Policy ..........................................................................................................168
Compliance with Study Registration and Results Posting Requirements .....................168
Compliance with Law, Audit and Debarment ...............................................................168
Data Quality Assurance .................................................................................................169
Source Documents .........................................................................................................170
Study and Site Closure...................................................................................................170
Appendix 2: Collection and Management of Specimens for Future 
Biomedical Research.............................................................................................171
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Appendix 3: Contraceptive Guidance and Pregnancy Testing.........................176
Definitions......................................................................................................................176
Contraception Requirements..........................................................................................176
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................179
Definition of AE ............................................................................................................179
Definition of SAE ..........................................................................................................180
Recording AE and SAE .................................................................................................182
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor................185
Appendix 5: Eastern Cooperative Oncology Group (ECOG) 
Performance Status...............................................................................................187
Appendix 6: Clinical Laboratory Tests...............................................................188
Appendix 7: Technical Note for the Statistical Model.......................................190
Poisson Mixture Model......................................................................................190
Approximated Overall HR for the Main Study (XP/FP) and FLOT 
Cohort Combined...............................................................................................191
Appendix 8: Abbreviations and Trademarks.....................................................193
Appendix 9: Country-specific Requirements .....................................................197
France-specific Requirements............................................................................197
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LIST OF TABLES
Table 1
Main Study: Treatment Dose and Schedule .........................................................56
Table 2
FLOT Cohort: Treatment Dose and Schedule......................................................59
Table 3
Adequate Organ Function Laboratory Values......................................................70
Table 4
Study Treatments..................................................................................................75
Table 5
Dose Modifications for Chemotherapies + Pembrolizumab or Placebo ..............77
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ....................................................................79
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines.............................................................................................................84
Table 8
Dose Modification Guidelines for Cisplatin Drug-related Adverse 
Events ...................................................................................................................87
Table 9
Dose Modification Guidelines for Capecitabine or 5-FU Drug-related 
Adverse Events .....................................................................................................88
Table 10
Dose Modification Guidelines for Docetaxel Drug-related Adverse 
Events ...................................................................................................................89
Table 11
Dose Modification Guidelines for Oxaliplatin Drug-related Adverse 
Events ...................................................................................................................91
Table 12
Antiemetic Therapy ..............................................................................................98
Table 13
Scan and Treatment After First Radiologic Evidence of Progressive 
Disease for Participants Receiving Protocol Treatment.....................................112
Table 14
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events....................................................................................116
Table 15
Analysis Strategy for Key Efficacy Endpoints...................................................134
Table 16
Analysis Strategy for Safety Parameters ............................................................135
Table 17
Summary of Interim and Final Analysis Strategy (Main Study (XP/FP) 
and/or Main Study (XP/FP) and FLOT Combined) ...........................................137
Table 18
Efficacy Boundaries and Properties for Event-free Survival Analyses in 
Main Study (XP/FP) ...........................................................................................139
Table 19
Efficacy Boundaries and Properties for Event-free Survival Analyses in 
Main Study (XP/FP) and FLOT Cohort Combined............................................140
Table 20
Efficacy Boundaries and Properties for Overall Survival Analyses in 
Main Study (XP/FP) ...........................................................................................141
Table 21
Efficacy Boundaries and Properties for Overall Survival Analyses in 
Main Study (XP/FP) and FLOT Cohort Combined............................................142
Table 22
Highly Effective Contraception Methods...........................................................178
Table 23
Protocol-required Safety Laboratory Assessments.............................................189
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LIST OF FIGURES
Figure 1
Main Study Diagram.............................................................................................58
Figure 2
FLOT Cohort Diagram .........................................................................................59
Figure 3
Multiplicity Strategy...........................................................................................138
Figure 4 
Survival Curves of EFS Under Poisson Mixture Model and Exponential 
Distribution Model..............................................................................................190
Figure 5
Survival Curves of OS Under Poisson Mixture Model and Exponential 
Distribution Model..............................................................................................191
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Protocol/Amendment No.: 585-10
MK-3475-585-10 Final Protocol
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1. Synopsis
Protocol Title:  
A Phase III, Randomized, Double-Blind, Clinical Trial of Pembrolizumab (MK 
3475) plus Chemotherapy (XP or FP) versus Placebo plus Chemotherapy (XP or 
FP) as Neoadjuvant/Adjuvant Treatment for Subjects with Gastric and 
Gastroesophageal Junction (GEJ) Adenocarcinoma (KEYNOTE-585).
Short Title: 
Phase III Trial of Pembrolizumab + Chemotherapy in Participants with Gastric or GEJ 
Adenocarcinoma.
Objectives/Hypotheses and Endpoints:
In male and female participants with previously untreated, locally advanced resectable 
gastric or GEJ adenocarcinoma of at least 18 years of age:
Objective/Hypothesis
Endpoint
Primary
Main Study (XP/FP) 

Objective:  To evaluate 
event-free survival (EFS)
Hypothesis (H1):  Neoadjuvant 
and adjuvant pembrolizumab 
plus chemotherapy, followed by 
adjuvant pembrolizumab is 
superior to neoadjuvant and 
adjuvant placebo plus 
chemotherapy, followed by 
adjuvant placebo in terms of 
EFS based on Response 
Evaluation Criteria in Solid 
Tumors version 1.1 
(RECIST 1.1) as assessed by
investigator.

EFS based on RECIST 1.1 as assessed by 
investigator. EFS is defined as the time from 
randomization to the first of the following 
events:
o
Radiographic disease progression per 
RECIST 1.1
o
Local or distant recurrence as assessed by 
CT scan or biopsy if indicated (for 
participants who are disease free after 
surgery)
o
Clinical progression as evidenced by 
peritoneal carcinomatosis confirmed by 
pre-operative laparoscopy or laparotomy 
(for participants who are confirmed to be 
free of peritoneal involvement by 
laparoscopy at screening)
o
Death due to any cause
A second primary malignancy is not considered an 
EFS event.
Radiographic PD during the neoadjuvant phase 
that does not preclude successful surgery (ie, 
disease free after surgery) is not considered an 
EFS event.  
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Objective/Hypothesis
Endpoint

Objective:  To evaluate the 
rate of pathological complete 
response based on central 
review. 
Hypothesis (H2): Neoadjuvant 
pembrolizumab plus 
chemotherapy is superior to 
neoadjuvant placebo plus 
chemotherapy in terms of rate 
of pathCR at the time of 
surgery. 
The pathCR rate is considered as 
an early endpoint. 

Pathological complete response (pathCR) is 
defined as no invasive disease within an 
entirely submitted and evaluated gross lesion, 
and histologically negative nodes. PathCR rate 
is defined as the proportion of participants 
having pathCR.

Objective:  To evaluate overall 
survival (OS)
Hypothesis (H3): Neoadjuvant 
and adjuvant pembrolizumab 
plus chemotherapy, followed by 
adjuvant pembrolizumab is 
superior to neoadjuvant and 
adjuvant placebo plus 
chemotherapy, followed by 
adjuvant placebo in terms of 
OS.

OS is defined as the time from randomization 
to death due to any cause. Participants without 
documented death at the time of analysis will 
be censored at the date of last known alive.
The study is considered to have met its primary objective if neoadjuvant and adjuvant 
pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab is superior to 
neoadjuvant and adjuvant placebo plus chemotherapy, followed by adjuvant placebo in 
EFS.
FLOT Cohort

Objective:  To evaluate the 
safety and tolerability of 
pembrolizumab in combination 
with docetaxel, oxaliplatin, 5-
FU, and leucovorin (calcium 
folinate) (FLOT)

AEs

Study treatment discontinuations due to AEs
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Protocol/Amendment No.: 585-10
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Objective/Hypothesis
Endpoint
Secondary
Main Study (XP/FP), and Main Study (XP/FP) and FLOT Cohort Combined

Objective:  To evaluate the 
safety and tolerability of 
pembrolizumab in combination 
with chemotherapy.

AEs

Study treatment discontinuations due to AEs
Main Study (XP/FP)

Objective:  To evaluate the 
disease-free survival (DFS) as 
assessed by investigator for 
participants who are disease 
free after surgery.

DFS based on RECIST 1.1 as assessed by 
investigator. DFS is defined as the time from 
post-surgery baseline scan until the first 
occurrence of:
o
Local or distant recurrence
o
Death from any cause
Main Study (XP/FP) and FLOT Cohort Combined

Objective:  To evaluate OS
Hypothesis (H4): Neoadjuvant 
and adjuvant pembrolizumab 
plus chemotherapy, followed 
by adjuvant pembrolizumab is 
superior to neoadjuvant and 
adjuvant placebo plus 
chemotherapy, followed by 
adjuvant placebo in terms of 
OS. 

OS

Objective:  To evaluate EFS
Hypothesis (H5):  
Neoadjuvant and adjuvant 
pembrolizumab plus 
chemotherapy, followed by 
adjuvant pembrolizumab is 
superior to neoadjuvant and 
adjuvant placebo plus 
chemotherapy, followed by 
adjuvant placebo in terms of 
EFS based on RECIST 1.1 as 
assessed by investigator.

EFS based on RECIST 1.1 as assessed by 
investigator
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Overall Design:
Study Phase
Phase III
Clinical Indication
Perioperative treatment of locally advanced resectable gastric 
or GEJ adenocarcinoma
Population
Adult participants with previously untreated, locally advanced 
resectable gastric or GEJ adenocarcinoma
Study Type
Interventional
Type of Design
Randomized, parallel-group, multi-site
Type of Control
Placebo and active control
Study Blinding
Double-blind
Estimated Duration of 
Study
The Sponsor estimates that the study will require 
approximately 7 years from the time the first participant (or 
their legally acceptable representative) provides documented
informed consent until the last participant’s last study-related 
contact.  
Number of Participants:
Approximately 200 participants will be randomized in the FLOT Safety cohort. 
Approximately 800 participants will be randomized in the Main study (XP/FP). In total, 
approximately 1000 participants will be randomized in the entire study.
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Product:  MK-3475 
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Treatment Groups and Duration:
Treatment Groups
FLOT Cohort
A safety cohort will evaluate the combination of 
pembrolizumab with the chemotherapy backbone treatment 
known as FLOT (docetaxel + oxaliplatin + 5-FU + leucovorin
[calcium folinate]).
Treatment Group 1: Neoadjuvant: FLOT + pembrolizumab, 
followed by surgical resection. Adjuvant: FLOT + 
pembrolizumab followed by pembrolizumab alone.
Treatment Group 2: Neoadjuvant: FLOT + placebo, followed 
by surgical resection. 
Adjuvant: FLOT + placebo followed by placebo alone.
Safety analyses will be performed after participants have 
completed surgical resection + 30 days post-surgical 
evaluation. Following a review of the available safety data by
the standing internal Data Monitoring Committee (siDMC),
the FLOT regimen may be incorporated as one of the standard-
of-care chemotherapy backbones in the main study. 
As of Amendment 06, the FLOT Safety Cohort will be 
expanded to 200 participants and will be designated the FLOT 
Cohort. Future interim analyses of the FLOT Cohort will be 
monitored by the external DMC.
Main Study (XP/FP)
Treatment Group 1: Neoadjuvant: [cisplatin + capecitabine 
(XP) or cisplatin + 5-fluorouracil (FP)] + pembrolizumab, 
followed by surgical resection. Adjuvant: [XP or FP] + 
pembrolizumab followed by pembrolizumab alone.
Treatment Group 2: Neoadjuvant: [XP or FP] + placebo, 
followed by surgical resection. Adjuvant: [XP or FP] + 
placebo followed by placebo alone.
The investigator will decide the chemotherapy backbone (XP 
or FP) prior to randomization. Participants will continue on the 
chemotherapy chosen prior to randomization throughout the 
study and will not be allowed to switch between chemotherapy 
treatments (exception may be granted after Sponsor 
consultation, eg, participants who have difficulty swallowing 
oral study treatment).
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Protocol/Amendment No.: 585-10
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Duration of 
Participation
Each participant will participate in the study from the time the 
participant provides documented informed consent through the 
final protocol-specified contact. 
After a screening phase, each eligible participant will be 
randomized into 1 of the 2 treatment groups. The participant 
will receive 3 cycles of neoadjuvant and 14 cycles of adjuvant 
treatment with study medication. Each participant assigned 
will receive study treatment until one of the conditions for 
discontinuation of study treatment is met.
All participants will be followed for EFS and OS. After the 
end of treatment, participants will have a 30-day assessment 
for AE monitoring (serious adverse events will be collected for 
90 days after the end of treatment or 30 days after the end of 
treatment if the participant initiates new anti-cancer therapy, 
whichever occurs first).
After the end of treatment, each participant will be followed 
for the occurrence of AEs and spontaneously reported 
pregnancy.
Participants who discontinue treatment for reasons other than 
disease progression/recurrence will have post-treatment 
follow-up scans for disease status until any of the conditions 
for discontinuation of scans are met.
All participants will be followed by telephone for OS until 
death, withdrawal of consent, or the end of the study.
Study governance considerations are outlined in Appendix 1. A list of abbreviations used in 
this document can be found in Appendix 8.
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2. Schedule of Activities (SoA)
FLOT Cohort
Neoadjuvant Combination Treatment Group 1: FLOT + Pembrolizumab OR Neoadjuvant Combination Treatment 
Group 2: FLOT + Placebo
Study Period:
Screening Phase
Treatment Cycles
Notes
Treatment Cycles:
C1
D1
C1
D15
C2
D1
C2
D8
C3
D1
Surgery
Scheduling Window 
(Days)a:
-42 to -1
-28 to -1
-21 to -1
-10 to -1
± 3
± 3
± 3
± 3
3 to 9 weeks 
after C3D1
Admin Procedures
Informed Consent
X
Written 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 is acceptable in lieu of a screening 
test if performed within the specified time frame. 
Screening number will be assigned when the study 
informed consent is signed.
Informed Consent for 
Future Biomedical 
Research
X
Providing FBR sample(s) is optional. Detailed 
instructions for the collection and management of 
specimens for FBR are provided in the Procedures 
Manual and Appendix 2. The FBR consent does not need 
to be signed during the screening period; it may be signed 
during the study.
Inclusion/Exclusion 
Criteria
X
See Sections 6.1 and 6.2.
Participant 
Identification Card
X
See Section 9.1.3.
Demographics and 
Medical History
X
See Section 9.1.4.
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Study Period:
Screening Phase
Treatment Cycles
Notes
Treatment Cycles:
C1
D1
C1
D15
C2
D1
C2
D8
C3
D1
Surgery
Scheduling Window 
(Days)a:
-42 to -1
-28 to -1
-21 to -1
-10 to -1
± 3
± 3
± 3
± 3
3 to 9 weeks 
after C3D1
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
Prior medications – Record all medications taken within 
30 days of first dose. Concomitant medications – enter 
new medications started during the study through the 
Safety Follow-up visit. Record all medications taken for 
SAEs as defined in Appendix 4.
Pembrolizumab 200 mg 
or placebo
X
X
X
See Sections 7.1 and 9.1.8.1.
FLOT
Docetaxel 50 mg/m2
X
X
X
X
See Sections 7.1 and 9.1.8.1.
Oxaliplatin 85 mg/m2
X
X
X
X
5-FU 2600 mg/m2
X
X
X
X
Leucovorin (calcium 
folinate) 200 mg/m2
X
X
X
X
Efficacy Procedures
Tumor Imaging
X
X
Area to be imaged: chest, abdomen, and pelvis. The first 
on-study scan will be performed after completion of 3 
cycles of preoperative therapy. See Section 9.2.1.
Tumor Staging
X
Tumor staging prior to enrollment must consist of at least 
1 imaging modality: CT or MRI (ie, not limited to 
laparoscopic staging or endoscopic ultrasound). Follow
the current edition of the American Joint Committee on 
Cancer (AJCC) staging guidelines. Lauren histological 
classification required at baseline.
Surgery
X
See Section 9.2.2.
pathCR Assessment
X
See Section 9.2.2.1.
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Study Period:
Screening Phase
Treatment Cycles
Notes
Treatment Cycles:
C1
D1
C1
D15
C2
D1
C2
D8
C3
D1
Surgery
Scheduling Window 
(Days)a:
-42 to -1
-28 to -1
-21 to -1
-10 to -1
± 3
± 3
± 3
± 3
3 to 9 weeks 
after C3D1
ePROs (HRQoL 
Measures)
X
X
Perform within 3 days prior to Day 1 of the cycles 
indicated. It is strongly recommended that ePROs are 
administered prior to administration of study medication, 
AE evaluation, and disease status notification. See 
Section 9.2.4.
Safety Procedures
Review AEs
X
X
X
X
X
X
X
X
X
X*
See Section 9.3. *AEs must be assessed during the 
surgical period however this is not a clinic visit.
Full Physical 
Examination
X
See Section 9.5.1.1. Height will be measured at Visit 1 
only.
Directed Physical 
Examination
X
(X)b
X
(X)b
X
Perform within 3 days prior to administration of study 
treatment on the days and cycles indicated. See Section 
9.5.1.2.
Vital Signs and Weight
X
X
(X)b
X
(X)b
X
During the treatment period, perform within 3 days prior 
to administration of study treatment on the days and 
cycles indicated. See Section 9.5.2. 
12-Lead ECG (Local)
X
See Section 9.5.3.
ECOG Performance 
Status
X
X
(X)b
X
(X)b
X
ECOG status must be performed within 3 days of 
beginning of Cycle 1 and prior to each treatment 
administration. See Section 9.5.4.
Pregnancy Test – Serum 
or Urine
X
X
(X)b
X
(X)b
X
For women of reproductive potential, perform during the 
treatment period within 72 hours prior to administration
of study treatment on the days and cycles indicated, and 
perform 30 days post-treatment discontinuation. See 
Section 9.5.6.
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Study Period:
Screening Phase
Treatment Cycles
Notes
Treatment Cycles:
C1
D1
C1
D15
C2
D1
C2
D8
C3
D1
Surgery
Scheduling Window 
(Days)a:
-42 to -1
-28 to -1
-21 to -1
-10 to -1
± 3
± 3
± 3
± 3
3 to 9 weeks 
after C3D1
PT/INR and aPTT/PTT
X
All laboratory tests will be performed by a local
laboratory. During the treatment period, perform within 
72 hours prior to administration of study treatment on the
days and cycles indicated. See Section 9.5.5.
CBC with Differential
X
(X)b
X
(X)b
X
Chemistry Panel
X
(X)b
X
(X)b
X
Urinalysis
X
T3 or Free T3, FT4, and 
TSH
X
X
During the treatment period, perform within 21 days prior 
to study drug administration on Day 1 of Cycle 2. See 
Section 9.5.5.
Biomarkers/FBR
Blood for Genetic 
Analysis
X
Perform within 72 hours prior to administration of study 
treatment on the days and cycles indicated. See 
Sections 9.8 and 9.9.
Blood for RNA 
Analyses
X
X
X
Blood for Serum 
Biomarker Analyses
X
X
X
Blood for ctDNA
X
X
Archived or Newly 
Obtained Tissue 
Collection for 
Biomarker Testing
X
Tumor tissue for biomarker analysis is required at 
baseline. Tumor tissue may be from newly obtained core 
biopsy, excisional biopsy, biopsy by endoscopy (FNA is 
not adequate) or archival tissue sample (where available). 
Archival tissue sample (FFPE block), may be collected up 
to 1 year before treatment start and submitted during the 
screening period. Consent must be obtained prior to 
tumor tissue submission/collection. Detailed instructions 
for tissue collection, processing and shipment are 
provided in the Procedures Manual. See Sections 9.8 and 
9.9.
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Study Period:
Screening Phase
Treatment Cycles
Notes
Treatment Cycles:
C1
D1
C1
D15
C2
D1
C2
D8
C3
D1
Surgery
Scheduling Window 
(Days)a:
-42 to -1
-28 to -1
-21 to -1
-10 to -1
± 3
± 3
± 3
± 3
3 to 9 weeks 
after C3D1
Newly Obtained Tissue 
Collection for 
Biomarker Testing
X
Representative samples from relevant sections of the 
tumor tissue obtained during the surgery are required for 
biomarker analysis and pathCR.
Admin=administrative; AE=adverse event; aPTT=activated partial thromboplastin time; C=Cycle; CBC=complete blood count; ctDNA=circulating tumor deoxyribonucleic 
acid; CT=computed tomography; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; ePROs=electronic patient-reported outcomes; FBR=future 
biomedical research; FLOT=docetaxel + oxaliplatin + 5-FU + leucovorin (calcium folinate); FNA=fine needle aspirate; FT4=free thyroxine; 5-FU=5-fluorouracil; FP=cisplatin 
+5-FU; HRQoL=Health Related Quality of Life; INR=international normalized ratio; MRI=magnetic resonance imaging; pathCR=pathological complete response; 
PT=prothrombin time; PTT=partial thromboplastin time; RNA=ribonucleic acid; T3=triiodothyronine; TSH=thyroid stimulating hormone; XP=cisplatin + capecitabine.
a.Unless otherwise specified, the window for each visit is ±3 days. Cycle 1 study treatment must begin as close to treatment allocation as possible and must be given within 
3 days of allocation.
b.C1D15 and C2D8 assessments are only required for participants receiving FLOT.
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Adjuvant Combination Treatment Group 1: FLOT + Pembrolizumab OR Adjuvant Combination Treatment Group 2: 
FLOT + Placebo
Study Period:
Treatment Cyclesa
Notes
Treatment Cycles:
C1
D1
C1
D15
C2
D1
C2
D8
C3
D1
Scheduling Window 
(Days)b:
± 3
± 3
± 3
± 3
± 3
Admin Procedures
Prior and Concomitant 
Medication Review
X
X
X
X
X
Concomitant medications – Enter new medications started during the study through the 
Safety Follow-up visit. Record all medications taken for SAEs as defined in 
Appendix 4.
Pembrolizumab 200 mg or 
placebo
X
X
X
See Sections 7.1 and 9.1.8.1.
FLOT
Docetaxel 50 mg/m2
X
X
X
X
See Sections 7.1 and 9.1.8.1.
Oxaliplatin 85 mg/m2
X
X
X
X
5-FU 2600 mg/m2
X
X
X
X
Leucovorin (calcium 
folinate) 200 mg/m2
X
X
X
X
Efficacy Procedures
Tumor Imaging
X
See Section 9.2.1.
ePROs (HRQoL 
Measures)
X
X
Perform within 3 days prior to Day 1 of the cycles indicated. It is strongly 
recommended that ePROs are administered prior to administration of study medication, 
AE evaluation, and disease status notification. See Section 9.2.4.
Safety Procedures
Review AEs
X
X
X
X
X
See Section 9.3.
Directed Physical 
Examination
X
X
X
X
X
Perform within 3 days prior to administration of study treatment on the days and cycles 
indicated. See Section 9.5.1.2.
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Study Period:
Treatment Cyclesa
Notes
Treatment Cycles:
C1
D1
C1
D15
C2
D1
C2
D8
C3
D1
Scheduling Window 
(Days)b:
± 3
± 3
± 3
± 3
± 3
Vital Signs and Weight
X
X
X
X
X
Perform within 3 days prior to administration of study treatment on the days and cycles 
indicated. See Section 9.5.2.
ECOG Performance Status
X
X
X
X
X
Perform within 3 days prior to administration of study treatment on the days and cycles 
indicated. See Section 9.5.4.
Pregnancy Test – Serum or 
Urine
X
X
X
X
X
For women of reproductive potential, perform within 72 hours prior to administration 
of study treatment on the days and cycles indicated, and perform 30 days post-treatment 
discontinuation. See Section 9.5.6.2.
CBC with Differential
X
X
X
X
X
All laboratory tests will be performed by a local laboratory. Perform within 72 hours 
prior to administration of study treatment on the days and cycles indicated. See Section 
9.5.5.
Chemistry Panel
X
X
X
X
X
T3 or Free T3, FT4, and 
TSH
X
Perform within 21 days prior to study drug administration on Day 1 of Cycle 2. See 
Section 9.5.5.
Biomarkers/FBR
Blood for RNA Analyses
X
Perform within 72 hours prior to administration of study treatment on Day 1 of Cycle 1. 
See Sections 9.8 and 9.9.
Blood for Serum 
Biomarker Analyses
X
Blood for ctDNA
X
Admin=administrative; AE=adverse event; C=Cycle; CBC=complete blood count; ctDNA=circulating tumor deoxyribonucleic acid; D=Day; ECOG=Eastern Cooperative 
Oncology Group; ePROs=electronic patient-reported outcomes; FBR=future biomedical research; FT4=free thyroxine; 5-FU=5-fluorouracil; FLOT=docetaxel + oxaliplatin + 
5-FU + leucovorin (calcium folinate); HRQoL=Health Related Quality of Life; IV=intravenous; PD=progressive disease; RNA=ribonucleic acid; T3=triiodothyronine; 
TSH=thyroid stimulating hormone.
a.Adjuvant combination therapy should be started 4 to 10 weeks post-surgery. 
b.Unless otherwise specified, the window for each visit is ± 3 days. 
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Adjuvant Monotherapy Treatment Group 1: Pembrolizumab OR Adjuvant Monotherapy Treatment Group 2: Placebo
Study Period:
Treatment Cycles
Notes
Treatment Cycles:
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
C9
D1
C10
D1
C11
D1
C12
D1
C13
D1
C14b
D1
Scheduling Window 
(Days)a:
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Admin Procedures
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications – Enter new medications started during the study
through the Safety Follow-up visit. Record all medications taken for SAEs
as defined in Appendix 4.
Pembrolizumab 200 mg or 
placebo
X
X
X
X
X
X
X
X
X
X
X
See Sections 7.1 and 9.1.8.1.
Efficacy Procedures
Tumor Imaging
X
X
X
See Section 9.2.1.
ePROs (HRQoL Measures)
X
X
X
X
Perform within 3 days prior to Day 1 of the cycles indicated. It is strongly 
recommended that ePROs are administered prior to administration of study 
medication, AE evaluation, and disease status notification. See 
Section 9.2.4.
Safety Procedures
Review AEs
X
X
X
X
X
X
X
X
X
X
X
See Section 9.3. 
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
Perform within 3 days prior to administration of study treatment on Day 1 
of each cycle. See Section 9.5.1.2.
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
Perform within 3 days prior to administration of study treatment on Day 1 
of each cycle. See Section 9.5.2.
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
Perform within 3 days prior to administration of study treatment on Day 
1of each cycle. See Section 9.5.4.
Pregnancy Test – Serum or 
Urine
X
X
X
X
X
X
X
X
X
X
X
For women of reproductive potential, perform within 72 hours prior to 
administration of study treatment on Day 1of each cycle, and perform 
30 days post-treatment discontinuation. See Section 9.5.6.
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Study Period:
Treatment Cycles
Notes
Treatment Cycles:
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
C9
D1
C10
D1
C11
D1
C12
D1
C13
D1
C14b
D1
Scheduling Window 
(Days)a:
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
CBC with Differential
X
X
X
X
X
X
All laboratory tests will be performed by a local laboratory. Perform 
within 72 hours prior to administration of study treatment on Day 1 of the 
cycles indicated. See Section 9.5.5.
Chemistry Panel
X
X
X
X
X
X
T3 or Free T3, FT4, and TSH
X
X
X
X
X
X
Perform within 21 days prior administration of study treatment on Day 1 
of the cycles indicated. See Section 9.5.5.
Admin=administrative; AE=adverse event; CBC=complete blood count; ECOG=Eastern Cooperative Oncology Group; ePROs=electronic patient-reported outcomes; FT4=free 
thyroxine; HRQoL=Health Related Quality of Life; IV=intravenous; PD=progressive disease; T3=triiodothyronine; TSH=thyroid stimulating hormone.
a. Unless otherwise specified, the window for each visit is ± 3 days.
b. Participants completing all 14 cycles of adjuvant treatment will not have an end of treatment visit and their next visit will be the safety follow-up visit.
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End of Treatment and Post-treatment Study Period
Study Period:
End of 
Treatment
Post-treatment Follow-up
Notes
Safety Follow-
up
Efficacy Follow-
upa
Survival 
Follow-upb
Timepoints:
At Time of 
Treatment 
Discontinuation
30 Days after 
last dose of 
treatment 
Every 12 Weeks
Every 
12 Weeks
Scheduling Window (Days)
± 3
± 3
± 7
± 7
Admin Procedures
Prior and Concomitant 
Medication Review
X
X
Concomitant medications – Enter new medications started during 
the study through the Safety Follow-up visit. Record all 
medications taken for SAEs as defined in Appendix 4.
Post-study Anti-cancer Therapy 
Status
X
X
X
Survival Statusb
-------------------------------------------------------------
X
See Section 9.10.4.
Efficacy Procedures
Tumor Imaging
X
X
See Section 9.2.1.3.
ePROs (HRQoL Measures)
X
X
X
See Section 9.2.4. 
Safety Procedures
Review AEs
X
X
X
See Section 9.3. Record all AEs occurring within 30 days after the 
last dose of study treatment. Report all SAEs (related and unrelated 
to study treatment) occurring up until 90 days after the last dose of 
study treatment or 30 days after the end of treatment if the 
participant initiates new anti-cancer therapy, whichever occurs 
first. Afterwards, report only SAEs that are related to study
treatment.
Full Physical Examination
X
See Section 9.5.1.1.
Vital Signs and Weight
See Section 9.5.2.
ECOG Performance Status
X
See Section 9.5.4.
Pregnancy Test – Serum or Urine
X
For women of reproductive potential, perform 30 days post-
treatment discontinuation. See Section 9.5.6.
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Study Period:
End of 
Treatment
Post-treatment Follow-up
Notes
Safety Follow-
up
Efficacy Follow-
upa
Survival 
Follow-upb
Timepoints:
At Time of 
Treatment 
Discontinuation
30 Days after 
last dose of 
treatment 
Every 12 Weeks
Every 
12 Weeks
Scheduling Window (Days)
± 3
± 3
± 7
± 7
CBC with Differential
X
X
See Section 9.5.5. Labs do not need to be repeated after the end of 
treatment if labs are within normal range.
Chemistry Panel
X
X
T3 or Free T3, FT4, and TSH
X
Biomarkers/FBR
Blood for RNA Analyses
X
See Sections 9.8 and 9.9.
Blood for Serum Biomarker 
Analyses
X
Blood for ctDNA
X
Newly Obtained Tissue 
Collection
X (optional if 
recurrence)
An optional newly obtained core or excisional biopsy (FNA not 
adequate) can be collected at treatment discontinuation if tumor 
has recurred. This biopsy is requested but not required. Endoscopic 
biopsies are permitted. See Sections 9.8 and 9.9.
Admin=administrative; AE=adverse event; CBC=complete blood count; ctDNA=circulating tumor deoxyribonucleic acid; ECOG=Eastern Cooperative Oncology Group; 
ePROs=electronic patient-reported outcomes; FBR=future biomedical research; FNA=fine needle aspirate; FT4=free thyroxine; HRQoL=Health Related Quality of Life; 
PD=progressive disease; RNA=ribonucleic acid; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid stimulating hormone.
a The Efficacy Follow-up visits should be scheduled to coincide with the scan schedule the participant is on at the time of treatment discontinuation.
b After the start of new anti-cancer treatment or documented PD, the participant should be contacted by telephone approximately every 12 weeks to assess for survival status. In 
addition, upon Sponsor request, participants may be contacted for survival status at any time during the course of the study.
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Main Study (XP/FP)
Neoadjuvant Combination Phase (3 cycles)
Neoadjuvant Combination Treatment Group 1: XP or FP + Pembrolizumab OR Neoadjuvant Combination 
Treatment Group 2: XP or FP + Placebo
Study Period:
Screening Phase
Treatment Cycles
Notes
Treatment Cycles:
C1
D1
C2
D1
C3
D1
Surgery
Scheduling Window 
(Days)a:
-42 to 
-1
-28 
to -1
-21 
to -1
-10 to -1
± 3
± 3
3 to 9 weeks 
after C3D1
Admin Procedures
Informed Consent
X
Written 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 is 
acceptable in lieu of a screening test if performed within the specified 
time frame. Screening number will be assigned when the study 
informed consent is signed.
Informed Consent for 
Future Biomedical 
Research
X
Providing FBR sample(s) is optional. Detailed instructions for the 
collection and management of specimens for FBR are provided in the 
Procedures Manual and Appendix 2. The FBR consent does not need 
to be signed during the screening period; it may be signed during the 
study.
Inclusion/Exclusion 
Criteria
X
See Sections 6.1 and 6.2.
Participant Identification 
Card
X
See Section 9.1.3.
Demographics and 
Medical History
X
See Section 9.1.4.
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
Prior medications – Record all medications taken within 30 days of 
first dose. Concomitant medications – Enter new medications started 
during the study through the Safety Follow-up visit. Record all 
medications taken for SAEs as defined in Appendix 4.
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Study Period:
Screening Phase
Treatment Cycles
Notes
Treatment Cycles:
C1
D1
C2
D1
C3
D1
Surgery
Scheduling Window 
(Days)a:
-42 to 
-1
-28 
to -1
-21 
to -1
-10 to -1
± 3
± 3
3 to 9 weeks 
after C3D1
Pembrolizumab 200 mg or 
placebo
X
X
X
See Sections 7.1 and 9.1.8.1.
XP/FP
Cisplatin 80 mg/m2
X
X
X
See Sections 7.1 and 9.1.8.1.
Capecitabine 1000 mg/m2
or 5-FU 800 mg/m2/day
X
X
X
See Sections 7.1 and 9.1.8.1.
Efficacy Procedures
Tumor Imaging
X
X
Area to be imaged: chest, abdomen, and pelvis. The first on-study 
scan will be performed after completion of 3 cycles of preoperative 
therapy. See Section 9.2.1.
Tumor Staging
X
Tumor staging prior to enrollment must consist of at least 1 imaging 
modality: CT or MRI (ie, not limited to laparoscopic staging or 
endoscopic ultrasound). Follow the current edition of the American 
Joint Committee on Cancer (AJCC) staging guidelines. Lauren 
histological classification required at baseline.
Surgery
X
See Section 9.2.2.
pathCR Assessment
X
See Section 9.2.2.1.
ePROs (HRQoL 
Measures)
X
X
Perform within 3 days prior to Day 1 of the cycles indicated. It is 
strongly recommended that ePROs are administered prior to 
administration of study medication, AE evaluation, and disease status 
notification. See Section 9.2.4.
Safety Procedures
Review AEs
X
X
X
X
X
X
X
X*
See Section 9.3. *AEs must be assessed during the surgical period, 
however this is not a clinic visit.
Full Physical Examination
X
See Section 9.5.1.1. Height will be measured at Visit 1 only.
Directed Physical 
Examination
X
X
X
Perform within 3 days prior to administration of study treatment on 
Day 1 of each cycle. See Section 9.5.1.2.
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Study Period:
Screening Phase
Treatment Cycles
Notes
Treatment Cycles:
C1
D1
C2
D1
C3
D1
Surgery
Scheduling Window 
(Days)a:
-42 to 
-1
-28 
to -1
-21 
to -1
-10 to -1
± 3
± 3
3 to 9 weeks 
after C3D1
Vital Signs and Weight
X
X
X
X
Perform within 3 days prior to administration of study treatment on 
Day 1 of each cycle. See Section 9.5.2. 
12-Lead ECG (Local)
X
See Section 9.5.3.
ECOG Performance 
Status
X
X
X
X
ECOG status must be performed within 3 days of beginning of 
Cycle 1 and prior to each treatment administration. See Section 9.5.4.
Pregnancy Test – Serum 
or Urine
X
X
X
X
For women of reproductive potential, during the treatment period, 
perform within 72 hours prior to administration of study treatment on 
Day 1 of each cycle, and perform 30 days post-treatment 
discontinuation. See Section 9.5.6.
PT/INR and aPTT/PTT
X
All laboratory tests will be performed by a local laboratory. During 
the treatment period, laboratory tests are performed within 72 hours 
prior to administration of study treatment on Day 1 of the cycles 
indicated. See Section 9.5.5.
CBC with Differential
X
X
X
Chemistry Panel
X
X
X
Urinalysis
X
T3 or Free T3, FT4, and 
TSH
X
X
During the treatment period, perform within 21 days prior to study 
drug administration on Day 1 of Cycle 2. See Section 9.5.5.
Biomarkers/FBR
Blood for Genetic 
Analysis
X
Perform within 72 hours prior to administration of study treatment on 
the days and cycles indicated. See Sections 9.8 and 9.9.
Blood for RNA Analyses
X
X
X
Blood for Serum 
Biomarker Analyses
X
X
X
Blood for ctDNA
X
X
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Study Period:
Screening Phase
Treatment Cycles
Notes
Treatment Cycles:
C1
D1
C2
D1
C3
D1
Surgery
Scheduling Window 
(Days)a:
-42 to 
-1
-28 
to -1
-21 
to -1
-10 to -1
± 3
± 3
3 to 9 weeks 
after C3D1
Archived or Newly 
Obtained Tissue 
Collection for Biomarker 
Testing
X
Tumor tissue for biomarker analysis is required at baseline. Tumor 
tissue may be from newly obtained core biopsy, excisional biopsy, 
biopsy by endoscopy (FNA is not adequate) or archival tissue sample 
(where available). Archival tissue sample (FFPE block), may be 
collected up to 1 year before treatment start and submitted during the 
screening period. Consent must be obtained prior to tumor tissue 
submission/collection. Detailed instructions for tissue collection, 
processing and shipment are provided in the Procedures Manual. See 
Sections 9.8 and 9.9.  
Newly Obtained Tissue 
Collection for Biomarker 
Testing
X
Representative samples from relevant sections of the tumor tissue 
obtained during the surgery are required for biomarker analysis and 
pathCR.
Admin=administrative; AE=adverse event; aPTT=activated partial thromboplastin time; CBC=complete blood count; ctDNA=circulating tumor deoxyribonucleic acid; 
CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; ePROs=electronic patient-reported outcomes; FBR=future biomedical 
research; FNA=fine needle aspirate; FP=cisplatin + 5-FU; FT4=free thyroxine; 5-FU=5-fluorouracil; HRQoL=Health Related Quality of Life; INR=international normalized 
ratio; MRI=magnetic resonance imaging; pathCR=pathological complete response; PT=prothrombin time; PTT=partial thromboplastin time; RNA=ribonucleic acid; 
T3=triiodothyronine; TSH=thyroid stimulating hormone; XP=cisplatin + capecitabine.
a.Unless otherwise specified, the window for each visit is ±3 days. Cycle 1 study treatment must begin as close to treatment allocation as possible and must be given within 
3 days of allocation.
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Adjuvant Combination Phase (3 cycles)
Adjuvant Combination Treatment Group 1: XP or FP + Pembrolizumab OR Adjuvant Combination Treatment 
Group 2: XP or FP + Placebo
Study Period:
Treatment Cyclesa
Notes
Treatment Cycles:
C1
D1
C2
D1
C3
D1
Scheduling Window 
(Days)b:
± 3
± 3
± 3
Admin Procedures
Prior and Concomitant 
Medication Review
X
X
X
Concomitant medications – Enter new medications started during the study through the Safety 
Follow-up visit. Record all medications taken for SAEs as defined in Appendix 4.
Pembrolizumab 200 mg or 
placebo
X
X
X
See Sections 7.1 and 9.1.8.1.
XP/FP
Cisplatin 80 mg/m2
X
X
X
See Sections 7.1 and 9.1.8.1. 
Capecitabine 1000 mg/m2 or 
5-FU 800 mg/m2/day
X
X
X
See Sections 7.1 and 9.1.8.1.
Efficacy Procedures
Tumor Imaging
X
See Section 9.2.1.
ePROs (HRQoL Measures)
X
X
Perform within 3 days prior to Day 1 of the cycles indicated. It is strongly recommended that ePROs are 
administered prior to administration of study medication, AE evaluation, and disease status notification. 
See Section 9.2.4.
Safety Procedures
Review AEs
X
X
X
See Section 9.3.
Directed Physical 
Examination
X
X
X
Perform within 3 days prior to administration of study treatment on Day 1 of each cycle. See Section 
9.5.1.2.
Vital Signs and Weight
X
X
X
Perform within 3 days prior to administration of study treatment on Day 1 of each cycle. See Section 
9.5.2.
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Study Period:
Treatment Cyclesa
Notes
Treatment Cycles:
C1
D1
C2
D1
C3
D1
Scheduling Window 
(Days)b:
± 3
± 3
± 3
ECOG Performance Status
X
X
X
Perform within 3 days prior to administration of study treatment on Day 1 of each cycle. See Section 
9.5.4.
Pregnancy Test – Serum or 
Urine
X
X
X
For women of reproductive potential, perform within 72 hours prior to administration of study treatment
on Day 1 of each cycle, and perform 30 days post-treatment discontinuation. See Section 9.5.6.
CBC with Differential
X
X
X
All laboratory tests will be performed by a local laboratory. Perform within 72 hours prior to 
administration of study treatment on Day 1 of each cycle.  See Section 9.5.5. 
Chemistry Panel
X
X
X
T3 or Free T3, FT4, and TSH
X
Perform within 21 days prior to administration of study treatment on Day 1 of Cycle 2. See Section 
9.5.5.
Biomarkers/FBR
Blood for RNA Analyses
X
Perform within 3 days prior to administration of study treatment on Day 1 of Cycle 1. See Sections 9.8
and 9.9.
Blood for Serum Biomarker 
Analyses
X
Blood for ctDNA
X
Admin=administrative; AE=adverse event; C=Cycle; CBC=complete blood count; ctDNA=circulating tumor deoxyribonucleic acid; D=Day; ECOG=Eastern Cooperative 
Oncology Group; ePROs=electronic patient-reported outcomes; FBR=future biomedical research; FP=cisplatin + 5-fluorouracil; FT4=free thyroxine; 5-FU=5-fluorouracil; 
HRQoL=Health Related Quality of Life; IV=intravenous; PD=progressive disease; RNA=ribonucleic acid; T3=triiodothyronine; TSH=thyroid stimulating hormone; 
XP=cisplatin + capecitabine.
a. Adjuvant combination therapy should be started 4-10 weeks post-surgery. 
b. Unless otherwise specified, the window for each visit is ± 3 days.
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Adjuvant Monotherapy Phase (11 Cycles)
Adjuvant Monotherapy Treatment Group 1: Pembrolizumab or Adjuvant Monotherapy Treatment Group 2: Placebo
Study Period:
Treatment Cycles
Notes
Treatment Cycles:
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
C9
D1
C10
D1
C11
D1
C12
D1
C13
D1
C14b
D1
Scheduling Window 
(Days)a:
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Admin Procedures
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications – Enter new medications started during the study
through the Safety Follow-up visit. Record all medications taken for SAEs
as defined in Appendix 4.
Pembrolizumab 200 mg or 
placebo
X
X
X
X
X
X
X
X
X
X
X
See Sections 7.1 and 9.1.8.1.
Efficacy Procedures
Tumor Imaging
X
X
X
See Section 9.2.1.
ePROs (HRQoL Measures)
X
X
X
X
Perform within 3 days prior to Day 1 of the cycles indicated. It is strongly 
recommended that ePROs are administered prior to administration of study 
medication, AE evaluation, and disease status notification. See 
Section 9.2.4.
Safety Procedures
Review AEs
X
X
X
X
X
X
X
X
X
X
X
See Section 9.3. 
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
Perform within 3 days prior to administration of study treatment on Day 1 
of each cycle. See Section 9.5.1.2.
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
Perform within 3 days prior to administration of study treatment on Day 1 
of each cycle. See Section 9.5.2.
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
Perform within 3 days prior to administration of study treatment on Day 1 
of each cycle. See Section 9.5.4.
Pregnancy Test – Serum or 
Urine
X
X
X
X
X
X
X
X
X
X
X
For women of reproductive potential, perform within 72 hours prior to 
administration of study treatment on Day 1 of each cycle, and perform 
30 days post-treatment discontinuation. See Section 9.5.6.
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Study Period:
Treatment Cycles
Notes
Treatment Cycles:
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
C9
D1
C10
D1
C11
D1
C12
D1
C13
D1
C14b
D1
Scheduling Window 
(Days)a:
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
CBC with Differential
X
X
X
X
X
X
All laboratory tests will be performed by a local laboratory. Perform within 
72 hours prior to administration of study treatment on Day 1 of the cycles 
indicated.  See Section 9.5.5.
Chemistry Panel
X
X
X
X
X
X
T3 or Free T3, FT4, and TSH
X
X
X
X
X
X
Perform within 21 days prior to administration of study treatment on Day 1 
of the cycles indicated. See Section 9.5.5.
Admin=administrative; AE=adverse event; C=Cycle; CBC=complete blood count; D=Day; ECOG=Eastern Cooperative Oncology Group; ePROs=electronic patient-reported 
outcomes; FT4=free thyroxine; HRQoL=Health Related Quality of Life; IV=intravenous; PD=progressive disease; T3=triiodothyronine; TSH=thyroid stimulating hormone.
a. Unless otherwise specified, the window for each visit is ± 3 days.
b. Participants completing all 14 cycles of adjuvant treatment will not have an end of treatment visit and their next visit will be the safety follow-up visit.
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End of Treatment and Post-treatment Study Period
Study Period:
End of 
Treatment
Post-Treatment Follow-Up
Notes
Safety 
Follow-up
Follow-up
Visitsa
Survival 
Follow-upb
Timepoints:
At Time of 
Treatment 
Discontinuation
30 Days After 
Last Dose of 
Treatment 
Every 12 Weeks
Every 
12 Weeks
Scheduling Window (Days):
± 3
± 3
± 7
± 7
Admin Procedures
Prior and Concomitant 
Medication Review
X
X
Concomitant medications – Enter new medications started during the 
study through the Safety Follow-up visit. Record all medications 
taken for SAEs as defined in Appendix 4.
Post-study Anti-cancer Therapy 
Status
X
X
X
Survival Statusb
-------------------------------------------------------------
X
See Section 9.10.4.
Efficacy Procedures
Tumor Imaging
X
X
See Section 9.2.1.3.
ePROs (HRQoL Measures)
X
X
X
See Section 9.2.4. 
Safety Procedures
Review AEs
X
X
X
See Section 9.3. Record all AEs occurring within 30 days after the 
last dose of study treatment. Report all SAEs (related and unrelated 
to study treatment) occurring up until 90 days after the last dose of 
study treatment or 30 days after the end of treatment if the 
participant initiates new anti-cancer therapy, whichever occurs first. 
Afterwards, report only SAEs that are related to study treatment.
Full Physical Examination
X
See Section 9.5.1.1.
Vital Signs and Weight
See Section 9.5.2.
ECOG Performance Status
X
See Section 9.5.4.
Pregnancy Test – Serum or Urine
X
For women of reproductive potential, perform 30 days post-treatment 
discontinuation. See Section 9.5.6.
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Study Period:
End of 
Treatment
Post-Treatment Follow-Up
Notes
Safety 
Follow-up
Follow-up
Visitsa
Survival 
Follow-upb
Timepoints:
At Time of 
Treatment 
Discontinuation
30 Days After 
Last Dose of 
Treatment 
Every 12 Weeks
Every 
12 Weeks
Scheduling Window (Days):
± 3
± 3
± 7
± 7
CBC with Differential
X
X
See Section 9.5.5. Labs do not need to be repeated after the end of 
treatment if labs are within normal range.
Chemistry Panel
X
X
T3 or Free T3, FT4, and TSH
X
Biomarkers/FBR
Blood for RNA Analyses
X
See Sections 9.8 and 9.9.
Blood for Serum Biomarker 
Analyses
X
Blood for ctDNA
X
Newly Obtained Tissue 
Collection
X (optional if 
recurrence)
An optional newly obtained core or excisional biopsy (FNA not 
adequate) can be collected at treatment discontinuation if tumor has 
recurred. This biopsy is requested but not required. Endoscopic 
biopsies are permitted. See Sections 9.8 and 9.9.
Admin=administrative; AE=adverse event; CBC=complete blood count; ctDNA=circulating tumor deoxyribonucleic acid; ECOG=Eastern Cooperative Oncology Group; 
ePROs=electronic patient-reported outcomes; FBR=future biomedical research; FNA=fine needle aspirate; FT4=free thyroxine; HRQoL=Health Related Quality of Life; 
PD=progressive disease; RNA=ribonucleic acid; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid stimulating hormone.
a The Follow-up visits should be scheduled to coincide with the scan schedule the participant is on at the time of treatment discontinuation.
b After the start of new anti-cancer treatment or documented PD, the participant should be contacted by telephone approximately every 12 weeks to assess for survival status. In 
addition, upon Sponsor request, participants may be contacted for survival status at any time during the course of the study, whichever occurs first.
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3. Introduction
Study Rationale
Rationale for the Study and Selected Participant Population
Cancers of the upper gastrointestinal (GI) tract are a group of highly aggressive malignancies 
and a major public health problem globally. Approximately 951,600 new cases of gastric 
cancer are diagnosed annually. These cancers are responsible for 723,100 annual deaths 
worldwide [Torre, L. A., et al 2015]. In the United States alone, 28,000 new cases of stomach 
cancer are estimated to be diagnosed in 2017, with approximately 10,960 deaths attributed to 
this disease. Despite the evolution in the management of locoregional disease with 
multimodality treatment strategies, gastric cancer continues to remain as one of the most 
lethal malignancies with 5-year survival rates reaching only 22% [Siegel, R. L., et al 2017]. 
These results are far too short of our goal to achieve a cure for these patients, particularly for 
those diagnosed with non-metastatic disease.
There is no uniformly accepted standard of practice for the management of these patients at 
this time. Therefore, a wide range of treatment approaches are encountered in clinical 
practice depending on the institution, geographical region, and personal preferences of the 
treating oncologist. It is an urgent unmet need to identify effective novel strategies for the 
treatment of these patients that are aimed at improving the clinical outcomes beyond the 
activity of the existing approaches. Targeting the immune checkpoint pathways to activate 
the host immune system against cancer cells is one such novel approach that is rapidly 
evolving in the recent years. 
Rationale for Neoadjuvant Treatment
The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) study 
(ISRCTN 93793971), sponsored by the United Kingdom Medical Research Council, 
provided evidence that perioperative chemotherapy confers longer overall survival (OS) to 
participants with gastric or gastroesophageal cancer [Cunningham, D., et al 2006]. The study 
included approximately 500 participants from the United Kingdom, Netherlands, Germany, 
Brazil, Singapore, and New Zealand who had an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1 and were diagnosed with potentially resectable gastric, 
gastroesophageal junction (GEJ), or distal esophageal cancer with a grade of T2 or higher; 
74% of participants enrolled had gastric tumors, 15% had GEJ tumors, and 11% had distal 
esophageal tumors. Participants were randomized to receive surgery alone or surgery along 
with both neoadjuvant and adjuvant chemotherapy. Chemotherapy consisted of 3 cycles each 
of preoperative and postoperative treatment consisting of every 3-week infusions of 
epirubicin, cisplatin, and continuous fluorouracil. Participants receiving radical surgery and 
chemotherapy had a higher rate of curative resection (79%) than participants receiving 
radical surgery alone (70%; p=0.03) as assessed by the surgeons. Importantly, participants 
receiving chemotherapy also had significantly higher 5-year survival rates (36%) compared 
with patients receiving surgery only (23%). This study provided the first evidence from a 
large randomized controlled study that perioperative chemotherapy improves OS in this 
population.
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The Fédération Francophone de Cancérologie Digestive (FFCD) 9703 study was a 
multi-center randomized controlled study performed in France [Ychou, M., et al 2011]. The 
study enrolled 224 participants with gastric, GEJ, or distal esophageal cancer judged to be 
amenable to curative resection, and performance status of ECOG 0 or 1. Most of the 
participants (64%) had GEJ tumors, while smaller numbers had gastric (25%) or esophageal 
(11%) tumors. Participants were randomized to receive surgery alone or surgery plus 
neoadjuvant chemotherapy (2 or 3 cycles of cisplatin + 5-fluorouracil [FP]); the protocol 
recommended that participants receiving neoadjuvant therapy also receive FP adjuvant 
therapy, though only about half of the participants in that group received adjuvant therapy. 
Overall, participants receiving perioperative chemotherapy had a higher curative (R0) 
resection rate compared with participants receiving surgery only (84% versus 73%, p=0.04), 
with no evident difference in postoperative complications. Participants receiving 
chemotherapy also had a higher 5-year OS rate (38% versus 24%). 
Together with results from the MAGIC study, the results from the FFCD study show that 
perioperative chemotherapy can improve the rate of potentially curative resection and extend 
OS of patients in this population. 
Rationale for Adjuvant Treatment
Postoperative adjuvant chemotherapy in gastric cancer is primarily supported by the 
Adjuvant Chemotherapy Trial of TS1 for Gastric Cancer (ACTS-GC) [Sasako, M., et al 
2011] and the Capecitabine and Oxaliplatin Adjuvant Trial in Stomach Cancer (CLASSIC) 
[Bang, Y. J., et al 2012] studies, both of which investigated the role of chemotherapy after 
gastrectomy with D2 dissection. The Japanese ACTS-GC study randomly assigned 1,059 
participants with Stage II or III gastric cancer to surgery alone or surgery followed by 1 year 
of S-1 (an orally bioavailable prodrug of fluorouracil) chemotherapy. S-1–treated participants 
had a 5-year OS of 71.7% versus 61.1% for those who received surgery alone (hazard ratio 
[HR], 0.67; 95% confidence interval (CI), 0.54 to 0.83). The Asian CLASSIC study 
randomly assigned 1,035 participants with Stage II or III gastric cancer after curative D2 
gastrectomy to treatment with 6 months of capecitabine plus oxaliplatin or surgery alone. The 
results online at www.clinicaltrials.gov (Identifier NCT02339324) demonstrated an improved 
3-year disease-free survival (DFS) in the chemotherapy group compared with surgery alone 
(74% versus 59%; HR, 0.56; 95% CI, 0.44 to 0.72).
Two recent meta-analyses including studies from around the world support the use of 
adjuvant postoperative chemotherapy for patients and demonstrate a 15% to 18% decreased 
risk of death with the addition of chemotherapy postoperatively [GASTRIC Group, et al 
2010] [Diaz-Nieto, R., et al 2013].
Clinical Studies With Pembrolizumab in Gastric Cancer
The KEYNOTE 012 study [Muro, K., et al 2014] is a Phase IB, multi-cohort study of 
participants with recurrent or metastatic gastric or GEJ adenocarcinoma who expressed 
programmed cell death-ligand 1 (PD-L1) (≥1% by immunohistochemistry). This cohort 
enrolled 39 participants (19 from Asia and 20 outside of Asia). The primary endpoint was 
overall response rate (ORR). Although 69% of participants received 2 or more prior lines of 
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chemotherapy, pembrolizumab monotherapy demonstrated an ORR of 20.5% by Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) per central radiology 
assessment (95% CI: 9.3%, 36.5%; 7 partial responses [PRs], 1 complete response [CR]), and 
was similar in participants from Asia and outside of Asia. Responses were observed across 
all lines of treatment. Forty-four percent of the participants with measurable disease 
displayed some degree of tumor shrinkage from baseline. As of the data cutoff date of 
26-Apr-2016, the median duration of response was 9.5 months. The 6-month PFS and OS
were 24% and 67%, respectively, in this heavily pretreated group. Based on these data, there 
appears to be a correlation between response and degree of PD-L1 positivity.
Single-agent pembrolizumab at a dose and frequency of 10 mg/kg every 2 weeks [Q2W] was 
generally well tolerated, with the type, severity, and frequency of adverse events (AEs)
similar to that observed in other indications.
The overall safety results of pembrolizumab in participants treated with single agent 
pembrolizumab at a dose and frequency of 10 mg/kg Q2W with gastric cancer reported in 
this study were consistent with the previously established pembrolizumab safety profile 
based on data in melanoma, non-small cell lung cancer (NSCLC), and head and neck cancer 
(see the Investigator’s Brochure (IB) for information about AEs in other indications). There 
were 3 deaths reported in the gastric cancer cohort, with none of these fatal serious adverse 
events (SAEs) attributed to study treatment.
The KEYNOTE 028 is a Phase Ib, non-randomized, multi-cohort study that treated 
23 participants with PD-L1 positive esophageal cancer; 17 with squamous cell cancer and 
5 with adenocarcinoma [Semrad, T. J. 2015]. Seven out of 23 participants (30%) had PR and 
of the 5 participants with adenocarcinoma, 2 participants had PR and 2 participants had 
stable disease.
KEYNOTE 059 is a Phase II, non-randomized, multi-site, open-label study of 
pembrolizumab in participants with gastric or GEJ adenocarcinoma. A total of 
315 participants were enrolled across 3 cohorts to examine the safety and efficacy of 
pembrolizumab. Cohort 1 participants who had progressed on at least 2 prior systemic 
treatments for advanced disease (third-line [3L]+participants) that received pembrolizumab 
as monotherapy; (Cohort 2) participants who had not previously received systemic therapy 
for advanced disease (first-line [1L] participants) received pembrolizumab in combination 
with cisplatin and 5-fluorouracil (5-FU). Sites in Japan also administered pembrolizumab in 
combination with cisplatin and capecitabine; and (Cohort 3) PD-L1-positive participants who 
had not previously received systemic therapy for advanced disease (1L participants) who 
received pembrolizumab as monotherapy. The primary objectives of the study were to 
determine the safety, tolerability, and ORR of pembrolizumab (200 mg fixed dose every 
3 weeks [Q3W]) given as first and third-line monotherapy to participants with gastric or GEJ 
adenocarcinoma whose tumors expressed PD-L1, and to determine the safety and tolerability 
of pembrolizumab administered in combination with cisplatin and 5-FU as first-line therapy 
in participants with gastric or GEJ adenocarcinoma. The primary endpoint was overall 
response rate (ORR). As of the data cutoff date of 16-Jan-2017:
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In Cohort 1 (3L+ participants receiving pembrolizumab monotherapy), ORR (CR + PR) was 
11.6%, of which 2.3% (6 participants) had a CR, and 42.4% of participants experienced a 
reduction in measurable tumor size. The median PFS was 2.0 months. The PFS rates at 3 and 
6 months were 29.0% and 14.1%, respectively. The median OS was 5.6 months. The OS 
rates were 46.5% and 23.4% at 6 and 12 months, respectively. As of the data cutoff date, 
87 participants continued to survive beyond 8 months with 27 participants surviving longer 
than 12 months.
In Cohort 2 (1L participants receiving pembrolizumab in combination with cisplatin + 5-FU 
or capecitabine), ORR was 60.0%. Of the responders, 1 participant (4.0%) had a CR. The 
median PFS was 6.6 months. The PFS rates at 3 and 6 months were 88.0% and 68.0%, 
respectively. The median OS was 20.8 months. The OS rates were 76.0% and 54.9% at 6 and 
12 months, respectively.
In Cohort 3 (1L participants receiving pembrolizumab monotherapy), ORR was 25.8%. Of 
the responders, 1 participant (3.2%) had a CR. The median PFS was 3.3 months. The PFS 
rates at 3 and 6 months were 51.6% and 34.9%, respectively. The median OS was not 
reached as of the data cutoff date. The OS rates were 72.6% and 61.7% at 6 months and 
12 months, respectively.
The safety results from KEYNOTE 059 were generally consistent with the established safety 
profile of pembrolizumab in the target populations. This study also established the safety and 
efficacy of pembrolizumab in combination with cisplatin and fluoropyrimidine-based 
chemotherapy in patients with gastric and GEJ adenocarcinoma.
KEYNOTE 061 is a randomized, multi-center, open-label study of pembrolizumab versus 
paclitaxel as 2L treatment in participants with advanced gastric or GEJ adenocarcinoma who 
had progressed after failure of any combination chemotherapy containing a platinum and a 
fluoropyrimidine agent. Enrollment in this study has completed and 592 participants were 
randomized. The enrollment included all participants without regard for PD-L1 expression 
status. The overall study enrollment was driven by the number of participants with PD-L1 
positive expression on their tumor (n=360). That is, enrollment was stopped when 
approximately 360 participants with PD-L1 positive expression on their tumor had been 
randomized. Additionally, there was a cap on enrollment (30% of the total) for participants 
residing in the Asia-Pacific region for this study. The primary efficacy endpoints are PFS and 
OS. The study is currently ongoing and following participants for OS.
KEYNOTE 062 is a Phase III randomized, active-controlled, multi-site, partially blinded, 
study of pembrolizumab, or pembrolizumab + cisplatin + 5-FU versus placebo + cisplatin + 
5-FU, as first-line treatment in PD-L1 positive, human epidermal growth factor receptor 
2 negative participants with advanced gastric or GEJ adenocarcinoma. The study has 
completed enrollment and approximately 750 participants have been randomized in a 1:1:1 
ratio among the 3 treatment groups, to compare the efficacy and safety of pembrolizumab or 
pembrolizumab + cisplatin +5-FU versus placebo + cisplatin + 5-FU as a first-line treatment. 
Participants were, stratified by geographic region, disease status, and fluoropyrimidine 
treatment. The study has dual primary endpoints of OS and progression-free survival (PFS), 
and patients will be monitored for safety every 6 months.
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KEYNOTE 063 is a Phase III, randomized, multi-center, open-label study of pembrolizumab 
versus paclitaxel in Asian participants with advanced gastric or GEJ adenocarcinoma who 
have progressed after failure of any combination chemotherapy containing a platinum and a 
fluoropyrimidine agent. This planned study will enroll approximately 360 PD-L1 positive 
participants (approximately 70% to 80% of the total will be from China). The primary 
efficacy endpoints are PFS and OS. 
Clinical Studies With Neoadjuvant Pembrolizumab
In addition, neoadjuvant pembrolizumab with or without chemotherapy is currently being 
studied in multiple solid tumors, including:

Phase Ib/II Study of Neoadjuvant Pembrolizumab With Gemcitabine-Cisplatin 
(Cisplatin-Eligible) or Gemcitabine (Cisplatin-Ineligible) in Subjects With 
T2-4aN0M0 Urothelial Cancer: HCRN GU14-188 (study start May 2015, end 
March 2018; available at www.clinicaltrials.gov: NCT02365766)

Neoadjuvant Pembrolizumab for Unresectable Stage III and Unresectable Stage IV 
Melanoma (study start January 2015; end February 2017; available at 
www.clinicaltrials.gov: NCT02306850)

A Clinical Trial to Evaluate the Effect of Neoadjuvant MK-3475 (Pembrolizumab) 
Therapy on Intratumoral Immune Infiltrates in Renal Cell Cancer (RCC) Patients 
Undergoing Surgical Resection (study start December 2014, end February 2016; 
available at www.clinicaltrials.gov: NCT02212730)

Immunotherapy With MK-3475 in Locoregionally Advanced, Surgically Resectable 
Head and Neck Squamous Cell Carcinoma (study start March 2015, end March 2022; 
available at www.clinicaltrials.gov: NCT02296684)

Neoadjuvant Combination Biotherapy with Pembrolizumab (MK-3475) and High 
Dose IFN-α2b in Patients with Locally/Regionally Advanced/Recurrent Melanoma: 
Safety, Efficacy and Biomarker Study (study start December 2014; available at 
www.clinicaltrials.gov: NCT02339324)

A Randomized Multicenter Phase Ib/II study to assess the safety and the 
immunological effect of chemoradiation therapy (CRT) in combination with 
Pembrolizumab (MK-3475) compared to CRT alone in patients with resectable or 
borderline resectable pancreatic cancer (study start March 2015, end 2019; available 
at www.clinicaltrials.gov: NCT02305186)
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody with 
high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-1) and programmed cell death ligand 2 
(PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
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receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety 
profile and is in clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies. KEYTRUDA® (pembrolizumab) is indicated for the treatment of patients 
across a number of indications including patients with recurrent locally advanced or 
metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-
L1 (Combined Positive Score (CPS) ≥1) as determined by an FDA-approved test, with 
disease progression on or after ≥2 prior lines of therapy including fluoropyrimidine- and 
platinum-containing chemotherapy and if appropriate, HER2/neu targeted therapy. For more 
details on specific indications refer to the IB.
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation 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 [Dong, H., et al 2002] [Sharpe, A. H. and Freeman, G. J. 
2002] [Brown, J. A., et al 2003] [Francisco, L. M., et al 2010] [Thompson, R. H., et al 2007]. 
In particular, the presence of cluster of differentiation CD8+ T-cells and the ratio of CD8+ 
effector T-cells/FoxP3+ regulatory T-cells correlates with improved prognosis and long-term 
survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4) which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [Talmadge, J. E., et al 2007] [Usubütün, A., 
et al 1998]. 
The structure of murine PD-1 has been resolved [Al-Shibli, K. I., et al 2008]. PD-1 and 
family members are type I transmembrane glycoproteins containing an Ig Variable-type 
(IgV-type) domain responsible for ligand binding and a cytoplasmic tail responsible for the 
binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases, SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ, and ZAP70, which are involved in the CD3 T-cell signaling cascade [Talmadge, J. E., 
et al 2007] [Deschoolmeester, V., et al 2010] [Diez, M., et al 1998] [Galon, J., et al 2006].
The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins 
[Hiraoka, N. 2010] [Nobili, C., et al 2008]. PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, Tregs and natural killer 
cells [Hodi, F. S. and Dranoff, G. 2010] [Kloor, M. 2009]. Expression has also been shown 
during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of 
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macrophages and dendritic cells [Hillen, F., et al 2008]. The ligands for PD-1 (PD-L1 and 
PD-L2) are constitutively expressed or can be induced in a variety of cell types, including 
non-hematopoietic tissues as well as in various tumors [Lee, H. E., et al 2008] [Leffers, N., et 
al 2009] [Nishimura, H., et al 2000] [Hiraoka, N. 2010]. Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signaling motifs. Binding of 
either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. 
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. 
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues [Hiraoka, N. 2010]. 
Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in participants with melanoma [Liotta, F., et al 
2011].
In gastric cancer, PD-L1 and PD-L2 overexpression have recently been associated with 
Epstein-Barr virus-positive tumors [Cancer Genome Atlas Research Network 2014]. This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and can 
be an attractive target for therapeutic intervention.
Pre-clinical and Clinical Studies
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma, and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted 
CD8+ T-cell infiltration into the tumor and the presence of interferon gamma (IFNγ), 
granzyme B and perforin, indicating that the mechanism of action involved local infiltration 
and activation of effector T-cell function in vivo [Ropponen, K. M., et al 1997] [Dudley, M. 
E., et al 2005] [Hunder, N. N., et al 2008] [Pölcher, M., et al 2010] [Okazaki, T., et al 2001] 
[Greenwald, R. J., et al 2005]. Experiments have confirmed the in vivo efficacy of PD-1 
blockade as a monotherapy as well as in combination with chemotherapy in syngeneic mouse 
tumor models (see the IB).
Clinical studies have demonstrated efficacy in participants with advanced melanoma, 
NSCLC, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-negative breast 
cancer, and gastric adenocarcinoma.
Ongoing Clinical Studies 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 (detailed in 
Section 3.1.1.3), and hematologic malignancies. For study details, please refer to the IB.
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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.
Beneficial effects of pembrolizumab have been seen in several studies to date. Publications of 
a significantly positive benefit:risk ratio have been reported for melanoma in a single arm study 
encompassing nearly 1,000 participants (KEYNOTE 001), which led to FDA approval in 
September 2014, and in a randomized comparison to chemotherapy (KEYNOTE 002 is further 
detailed in the IB). Additional potential benefits are addressed in Section 3.1.1.3, which details 
responses of the KEYNOTE 012 study; a multi-cohort Phase Ib study of which one cohort 
enrolled participants with recurrent or metastatic gastric or GEJ adenocarcinoma that expressed 
PD-L1 (≥1% by immunohistochemistry). Although two-thirds of participants received at least 
2 prior therapies for advanced disease, pembrolizumab monotherapy achieved an ORR of 
20.5% by RECIST v.1.1 central radiology assessment (95% CI [9.3%, 36.5%]; 7 partial 
responses, 1 complete response). The median duration of response was 9.5 months (range 5.6 
to 22.1 months).
In KEYNOTE 012, the most common AEs included abdominal pain (35.9%), decreased 
appetite (30.8%), fatigue (30.8%), nausea (28.2%), and vomiting (25.6%). Fatigue (10.3%) 
was the only Grade 3 to 5 AE that was reported in >10% of participants. There were 12.8% 
of participants who experienced drug-related Grade 3 to 4 AEs. There were no drug-related 
Grade 5 (fatal) AEs reported.
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).
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4. Objectives/Hypotheses and Endpoints
In male and female participants with previously untreated, locally advanced resectable gastric 
or GEJ adenocarcinoma of at least 18 years of age:
Objective/Hypothesis
Endpoint
Primary
Main Study (XP/FP) 

Objective:  To evaluate event-free 
survival (EFS)
Hypothesis (H1):  Neoadjuvant and 
adjuvant pembrolizumab plus 
chemotherapy, followed by adjuvant 
pembrolizumab, is superior to 
neoadjuvant and adjuvant placebo 
plus chemotherapy, followed by 
adjuvant placebo in terms of EFS 
based on Response Evaluation 
Criteria in Solid Tumors version 1.1 
(RECIST 1.1) as assessed by 
investigator.

EFS based on RECIST 1.1 as assessed by 
investigator. EFS is defined as the time 
from randomization to the first of the 
following events:
o
Radiographic disease progression per 
RECIST 1.1 
o
Local or distant recurrence as assessed 
by CT scan or biopsy if indicated (for 
participants who are disease free after 
surgery)
o
Clinical progression as evidenced by 
peritoneal carcinomatosis confirmed by 
pre-operative laparoscopy or 
laparotomy (for participants who are 
confirmed to be free of peritoneal 
involvement by laparoscopy at 
screening)
o
Death due to any cause
A second primary malignancy is not 
considered an EFS event.
Radiographic PD during the neoadjuvant phase 
that does not preclude successful surgery (i.e., 
disease free after surgery) is not considered an 
EFS event.  

Objective: To evaluate the rate of 
pathological complete response 
based on central review. 
Hypothesis (H2): Neoadjuvant 
pembrolizumab plus chemotherapy is 
superior to neoadjuvant placebo plus 
chemotherapy in terms of rate of 
pathCR at the time of surgery.
The pathCR rate is considered an early
endpoint. 

Pathological complete response (pathCR) is 
defined as no invasive disease within an 
entirely submitted and evaluated gross 
lesion, and histologically negative nodes. 
PathCR rate is defined as the proportion of 
participants having pathCR.
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Objective/Hypothesis
Endpoint

Objective:  To evaluate overall 
survival (OS)
Hypothesis (H3):  Neoadjuvant and 
adjuvant pembrolizumab plus 
chemotherapy, followed by adjuvant 
pembrolizumab is superior to 
neoadjuvant and adjuvant placebo 
plus chemotherapy, followed by 
adjuvant placebo in terms of OS.

OS is defined as the time from 
randomization to death due to any cause. 
Participants without documented death at 
the time of analysis will be censored at the 
date of last known alive.
The study is considered to have met its primary objective if neoadjuvant and adjuvant 
pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab is superior to 
neoadjuvant and adjuvant placebo plus chemotherapy, followed by adjuvant placebo in 
EFS.
FLOT Cohort

Objective: To evaluate the safety and 
tolerability of pembrolizumab in 
combination with docetaxel, 
oxaliplatin, 5-FU, and leucovorin 
(calcium folinate) (FLOT).

AEs

Study treatment discontinuations due to 
AEs 
Secondary
Main Study (XP/FP), and Main Study (XP/FP) and FLOT Cohort Combined

Objective:  To evaluate the safety 
and tolerability of pembrolizumab in 
combination with chemotherapy.

AEs

Study treatment discontinuations due to 
AEs
Main Study (XP/FP)

Objective: To evaluate the 
disease-free survival (DFS) as 
assessed by investigator for 
participants who are disease free 
after surgery.

DFS based on RECIST 1.1 as assessed by 
investigator. DFS is defined as the time 
from post-surgery baseline scan until the 
first occurrence of:
o
Local or distant recurrence
o
Death from any cause
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Objective/Hypothesis
Endpoint
Main Study (XP/FP) and FLOT Cohort Combined

Objective:  To evaluate OS
Hypothesis (H4): Neoadjuvant and 
adjuvant pembrolizumab plus 
chemotherapy, followed by adjuvant 
pembrolizumab is superior to 
neoadjuvant and adjuvant placebo 
plus chemotherapy, followed by 
adjuvant placebo in terms of OS.

OS

Objective:  To evaluate EFS
Hypothesis (H5): Neoadjuvant and 
adjuvant pembrolizumab plus 
chemotherapy, followed by adjuvant 
pembrolizumab is superior to 
neoadjuvant and adjuvant placebo 
plus chemotherapy, followed by 
adjuvant placebo in terms of EFS 
based on RECIST 1.1 as assessed by 
investigator.

EFS based on RECIST 1.1 as assessed by 
investigator
Tertiary/Exploratory
Main Study (XP/FP) and FLOT Cohort Combined

Objective:  To evaluate the rate of 
pathological complete response 
based on central review. 

PathCR rate

Objective:  To evaluate the DFS as 
assessed by investigator for 
participants who are disease free 
after surgery.

DFS based on RECIST 1.1 as assessed by 
investigator
Main Study (XP/FP), and Main Study (XP/FP) and FLOT Cohort Combined

Objective:  To evaluate efficacy by 
participant’s programmed cell death 
ligand 1 (PD-L1) status.

OS, EFS, pathCR rate as appropriate

Objective:  To evaluate the R0 
resection rate

R0 resection rate
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Objective/Hypothesis
Endpoint

Objective:  To evaluate changes in 
health-related quality of life 
(HRQoL) assessments from baseline 
in neoadjuvant and adjuvant phases 
using the European Organization for 
Research and Treatment of Cancer 
(EORTC) Quality of Life 
Questionnaire Core 30 (EORTC 
QLQ-C30) and EORTC Gastric 
Cancer–Specific Quality of Life 
Questionnaire (EORTC 
QLQ-STO22).

EORTC QLQ-C30 and EORTC 
QLQ-STO22 change from baseline

Objective:  To characterize utilities 
in participants with gastric cancer in 
neoadjuvant and adjuvant phases 
using EuroQoL-5 Dimension 
Questionnaire (EQ-5D-5L).

EQ-5D-5L

Objective:  To identify molecular 
(genomic, metabolic and/or 
proteomic) biomarkers that may be 
indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or 
the mechanism of action of 
pembrolizumab in combination with 
chemotherapy and other treatments.

Biomarker analyses may include germline 
genetic variation, genetic (DNA) mutations 
from tumor, tumor and blood RNA 
variation, proteomics and 
immunohistochemistry, and other blood-
derived biomarkers.
5. Study Design
NOTE: Based on IA3, there was a trend towards improvement in EFS; however, the study 
was not able to show statistically significant superiority of EFS in the main cohort of 
pembrolizumab plus chemotherapy compared to placebo plus chemotherapy. The study was 
positive for the endpoint of pathCR based on IA1. No new safety concerns were identified. 
After review of these results by the external DMC, the recommendation was to continue the 
study to final analysis; no additional statistical testing is possible per the multiplicity strategy 
of the statistical plan (see Sections 10.2, 10.7, and 10.8). Refer to Section 9.1.10 for details 
regarding negative studies without safety concerns.
Participants on treatment after IA3 was conducted have been unblinded to study intervention 
to facilitate shared decision-making between the investigator and participant regarding
continued treatment in the study. The investigator may consider continuing study 
intervention for a participant, in consultation with the Sponsor, if the participant is 
benefitting from the study intervention and it is in the participant’s best interest to continue. 
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If study intervention is continued, administration will follow the description in Section 7.1 
and all protocol-specified procedures will be performed as in the SoA (see Section 2).
Participants discontinuing study intervention, should complete a Discontinuation Visit. A 
Safety Follow-up Visit will be performed 30 days after treatment discontinuation. All 
remaining study procedures will be performed as described in the SoA (Section 2), including 
Efficacy and Survival follow-up. Reporting of safety information will occur as described in 
Section 9.3.3 and Section 9.3.4. 
Participants may be eligible to enroll in an extension study as described in Section 7.8.
Overall Design
This is a Phase III, randomized, placebo-controlled, multi-site, double-blinded study in 
participants diagnosed with previously untreated, locally advanced resectable gastric or GEJ
adenocarcinoma. In the main study, participants will be randomized to receive 
pembrolizumab (Treatment Group 1) or placebo (Treatment Group 2), administered in 
addition to the standard of care chemotherapy backbone treatments XP or FP. Concurrently, 
a FLOT Safety Cohort will be opened at selected sites to evaluate the safety of the FLOT 
regimen and pembrolizumab. The FLOT regimen will only be added as an additional 
chemotherapy backbone in the main study if the data from the FLOT Safety Cohort 
establishes safety of the regimen in combination with pembrolizumab.  As of Amendment 
06, the FLOT Safety Cohort will be expanded to enroll 200 participants and will be 
designated the FLOT Cohort. After enrollment of the global portion of the study is complete, 
the study may remain open to enrollment in China alone until the target number of 
participants from China have been enrolled to meet local regulatory requirements.
Main Study (XP/FP)
Approximately 800 participants will be randomized in a 1:1 ratio to receive pembrolizumab 
(Treatment Group 1) or placebo (Treatment Group 2), administered in addition to standard of 
care chemotherapy backbone treatments (Table 1). The protocol is open to enrollment and 
sites may enroll participants in the study and choose either the XP or FP chemotherapy 
backbone. 
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Table 1
Main Study: Treatment Dose and Schedule
Neoadjuvant Combination Phase (3 cycles) and Adjuvant Combination Phase (3 
cycles)
Group 1: XP or FP + pembrolizumab 200 mg
Group 2: XP or FP + placebo
Adjuvant Monotherapy Phase (11 cycles)
Group 1: pembrolizumab 200 mg
Group 2: placebo
Abbreviations: FP=cisplatin + 5-FU; XP=cisplatin + capecitabine.
1 treatment cycle=3 weeks duration (treatment cycles are based on pembrolizumab/placebo administration)
Pembrolizumab or placebo: administered on Day 1 of each treatment cycle every 3 weeks (Q3W).
Standard of Care Chemotherapy backbones:

XP: cisplatin (80 mg/m2 administered on Day 1 of each treatment cycle, Q3W) + capecitabine (1000 
mg/m2 administered 2 times a day from Day 1 to Day 14 of each treatment cycle, Q3W), for 3 cycles in 
the neoadjuvant phase and 3 cycles in the adjuvant phase

FP: cisplatin (80 mg/m2 administered on Day 1 of each treatment cycle, Q3W) + 5-FU (800 mg/m2/day 
administered from Day 1 to Day 5 of each treatment cycle Q3W), for 3 cycles in the neoadjuvant phase 
and 3 cycles in the adjuvant phase
The investigator will decide the chemotherapy backbone (XP or FP) prior to randomization. Participants will 
continue on the chemotherapy chosen prior to randomization throughout the study and will not be allowed to 
switch between chemotherapy treatments (exception may be granted after Sponsor consultation eg, 
participants who have difficulty swallowing oral study treatment).
Schedule of Assessments
Regardless of chemotherapy regimen, study treatment must begin on the day of 
randomization or within 3 days of allocation/randomization. 
Neoadjuvant study treatment will be administered pre-operatively for 3 cycles.
After neoadjuvant (pre-operative) treatment, all participants will have a scan prior to surgery 
and will be re-evaluated for surgical resectability. If there is no evidence of metastatic 
disease, and the tumor is assessed to be surgically resectable, the participants will undergo a 
potentially curative surgical resection within 3 to 9 weeks after Cycle 3 Day 1 of 
pre-operative treatment.
Participants who undergo surgery and have a complete surgical resection (R0 resection) will 
continue to receive the planned post-operative therapy as specified in the protocol adjuvant 
treatment plan. Participants will have a post-surgery baseline scan that must be completed 
within 2 weeks prior to starting the first dose of the adjuvant treatment. 
Adjuvant study treatment will start within 4 to 10 weeks after surgery and will consist of a 
total of 14 cycles (3 cycles of combination phase treatment, followed by 11 cycles of 
monotherapy phase treatment). 
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Participants with microscopic evidence of disease at surgical margins (R1) or macroscopic 
residual disease (R2) following surgical resection may continue protocol planned adjuvant 
treatment if the planned treatment for the participant is perioperative chemotherapy and 
resection. Alternatively, the participants will be permitted to have radiation therapy (RT) 
based on published standards in this disease, in addition to the protocol planned adjuvant 
treatment after surgery.
Participants will be followed by scans every 12 weeks (±7 days) from the post-surgery 
baseline scan. Two years (24 months) after the date of the post-surgery baseline scan, the 
scan schedule will be reduced to every 24 weeks (±7 days). Participants will be followed 
until disease progression/recurrence. 
Participants who are not able to undergo surgery may continue protocol-planned adjuvant 
treatment as prolonged neoadjuvant therapy or palliative therapy or will be permitted to have 
radiation therapy (in addition to the protocol planned treatment) if such therapy is the 
planned medical treatment for the participant. The next cycle of treatment may begin after 
21 days ±3 days) from the last cycle of neo-adjuvant therapy, or per local guidelines. These 
participants will be followed by scans every 12 weeks (±7 days) from the post-neoadjuvant 
scan. The schedule will be reduced to every 24 weeks (±7 days), 2 years after the 
post-neoadjuvant scan. 
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 secondary objectives of the study are described in Section 4.
Details about interim analyses are in Section 10.7. An independent, external DMC will 
monitor the safety and efficacy of this study.
This study will be conducted in conformance with Good Clinical Practices (GCP).
After enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in a possible China extension until the target number of participants in China have
been enrolled to meet local regulatory requirements. A possible extension portion of the 
study will be identical to the global study, (eg, inclusion and exclusion criteria, study 
endpoints, primary and secondary objectives, and study procedures) and details pertaining to 
the statistical analyses for participants enrolled in China will be provided in a separate sSAP.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Study SoA - Section 2. Details of each 
procedure are provided in Section 9 – Study Assessments and Procedures.
NOTE: Country-specific protocol operational items are described in Appendix 9.
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Main Study Diagram
The main study design is depicted in Figure 1.
Figure 1 Main Study Diagram
FLOT Cohort
The FLOT Safety Cohort will be a double-blinded cohort, stratified by tumor staging, in 
which approximately 60 participants will be randomized to evaluate the combination of 
pembrolizumab with the chemotherapy backbone treatment known as FLOT (Table 2).
The safety cohort will open in a limited number of sites. Participants will be randomized in a 
1:1 ratio to receive pembrolizumab + FLOT or placebo + FLOT. The safety cohort data will 
be evaluated after participants have completed surgical resection + 30 days post-surgical 
evaluation. Following review of the available safety data by the standing internal Data 
Monitoring Committee (siDMC), the FLOT regimen may be incorporated as one of the 
standard-of-care chemotherapy backbones in the main study.  
As of Amendment 06, the FLOT Safety Cohort will be expanded to enroll 200 participants 
and will be designated the FLOT Cohort.  Participants will be stratified using the same 
factors as the Main Study (XP/FP), see Section 7.3.1. Future interim analyses of the FLOT 
Cohort will be monitored by the external DMC.  
The schedule of assessments is the same as described for the main study in Section 5.1.1.
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Table 2
FLOT Cohort: Treatment Dose and Schedule
Neoadjuvant Combination Phase (3 cycles) and Adjuvant Combination Phase (3 
cycles)
Group 1: FLOT + pembrolizumab 200 mg
Group 2: FLOT + placebo
Adjuvant Monotherapy Phase (11 cycles)
Group 1: pembrolizumab 200 mg
Group 2: placebo
Abbreviations: FLOT=docetaxel + oxaliplatin + 5-FU + leucovorin (calcium folinate).
1 treatment cycle=3 weeks duration (treatment cycles are based on pembrolizumab/placebo administration).
Pembrolizumab or placebo: administered on Day 1 of each treatment cycle every 3 weeks.
FLOT: Docetaxel 50 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2600 mg/m2, and leucovorin (calcium folinate) 200 
mg/m2. The FLOT regimen will be administered every 2 weeks, for a total of 4 administrations in the 
neoadjuvant combination phase and 4 administrations in the adjuvant combination phase. 
FLOT Cohort Diagram
The FLOT Cohort design is depicted in Figure 2.
Figure 2 FLOT Cohort Diagram
Number of Participants
Approximately 1000 participants will be randomized in the entire study. Approximately 200
participants will be randomized in the FLOT cohort. Approximately 800 participants will be 
randomized in the Main Study (XP/FP). After enrollment of the global portion of the study is 
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complete, the study may remain open to enrollment in China alone until the target number of 
participants from China have been enrolled to meet local regulatory requirements.
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).  
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable.  In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Scientific Rationale for Study Design
Rationale for Endpoints
Efficacy Endpoints
This study will use event-free survival (EFS), pathological complete response (pathCR), and 
overall survival (OS) as primary endpoints. Although OS is the standard endpoint for clinical 
studies, EFS and DFS are common surrogate endpoints for OS that are used to evaluate the 
efficacy of neoadjuvant and adjuvant cancer therapy and are sometimes used as primary 
endpoints [Martin, M., et al 2008] [Morschhauser, F., et al 2008] [Motzer, R. J., et al 2008] 
[Paridaens, R. J., et al 2008] [Sargent, D. J., et al 2005]. See Section 10.4, Analysis 
Endpoints for the primary and secondary endpoint definitions.
It is well established that pathCR following preoperative therapy is associated with improved 
survival in several malignancies, including breast adenocarcinoma after preoperative 
chemotherapy ± RT [Wolmark, N., et al 2001] [Symmans, W. F., et al 2007] [Adams, S., et 
al 2010] [Chavez-Macgregor, M., et al 2010], esophageal cancer after preoperative 
chemoradiotherapy [Berger, A. C., et al 2005] [Rohatgi, P. R., et al 2005] [Chao, Y. K., et al 
2009] [Donahue, J. M., et al 2009] [Park, J. W., et al 2011], lung cancer after preoperative 
chemoradiotherapy [Mamon, H. J., et al 2005] [Chen, A. M., et al 2007]; and rectal cancer 
after preoperative chemoradiotherapy [Maas, M., et al 2010] [Pucciarelli, S., et al 2004]. 
Notably, the 15% to 27% rate of pathCR after chemoradiotherapy in rectal cancer [Maas, M., 
et al 2010] has led some groups to omit surgery and undertake intensive follow-up in select 
participants who achieve a clinical complete response with no detectable residual tumor after 
chemoradiotherapy [Habr-Gama, A., et al 2004].
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The biology of tumors that completely regress with preoperative therapy is likely to be 
distinct from tumors that did not achieve a pathCR [Ajani, J. A. 2005] [Berger, A. C., et al 
2005] and is reflected in EFS and OS. As demonstrated in other malignancies [Wolmark, N., 
et al 2001] [Adams, S., et al 2010] [Berger, A. C., et al 2005] [Rohatgi, P. R., et al 2005] 
[Chao, Y. K., et al 2009] [Donahue, J. M., et al 2009] [Park, J. W., et al 2011] [Maas, M., et 
al 2010] [Pucciarelli, S., et al 2004], patients with gastric/GEJ adenocarcinoma who achieve 
a pathCR following preoperative therapy have significant improvements in OS and 
recurrence-free survival [Fields, R.C., et al 2011], and DSS [Mansour, J. C., et al 2007].
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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Rationale for the Use of Chemotherapy/Placebo
Rationale for the Use of Cisplatin + Capecitabine or 5-FU in Gastric Cancer
Systemic chemotherapy is the mainstay of treatment for advanced and metastatic gastric 
cancer with standard combination chemotherapy regimens containing cisplatin and 
capecitabine or 5-FU.
The V325 study [Van Cutsem, E., et al 2006] was a randomized Phase III study to compare 
docetaxel/cisplatin/5-FU with cisplatin + 5-FU (FP), and it showed statistically significant 
OS time (median 9.2 months and 8.6 months, respectively, p=0.02), PFS time (median 
5.6 months and 3.7 months, respectively; p=0.001), response rate (37% and 25%, 
respectively; p=0.01) associated with docetaxel/cisplatin/5 FU. In terms of safety, the 
addition of docetaxel was associated with increased Grades 3 to 4 neutropenia (82% versus 
57% with 5-FU/cisplatin alone), complicated neutropenia (29% versus 12%), Grades 3 to 4 
diarrhea (19% versus 8%), and Grades 3 to 4 lethargy (19% versus 14%). The result of V325 
supported the registration of docetaxel and docetaxel/cisplatin/5-FU as one of the standard 
regimens for the first-line treatment of gastric cancer. However, due in part to increased 
toxicity; incorporation of docetaxel into first-line gastric cancer regimens has been limited.
The Randomized ECF for Advanced and Locally Advanced Esophagogastric Cancer 2 
(REAL-2) study [Cunningham, D., et al 2006a] was a Phase III study to compare epirubicin 
+ oxaliplatin + 5-FU [EOF], epirubicin + cisplatin + capecitabine [ECX], epirubicin + 
cisplatin + 5-FU [ECF], and epirubicin + oxaliplatin + capecitabine [EOX] in advanced 
esophagogastric cancer. Overall survival was significantly longer among participants 
receiving EOX versus ECF (9.9 months, 9.3 months, 9.9 months, and 11.2 months for ECF, 
EOF, ECX, and EOX, respectively). No significant differences were observed in terms of 
response rate or PFS. As an outcome of the REAL-2 study, ECF became one of the popular 
regimens for first-line treatment of gastric cancer in the European Union. However, 
according to the European Society for Medical Oncology guideline (2013), the use of the 
triplet regimen should be limited because of increased toxicity. There are no Phase III studies
directly comparing FP and ECF.
The ML17032 study [Ryu, M. H. and Kang, Y. K. 2009] compared XP with FP. The primary 
objective was to show noninferiority in terms of PFS time. Median PFS was 5.6 months 
among participants receiving XP and 5.0 months among participants receiving FP; median 
OS times were 10.5 months and 9.3 months, and ORR were 46% and 32%, in these groups,
respectively. Based on this study, capecitabine has been approved in combination with a 
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platinum-based regimen for the first-line therapy of advanced gastric cancer in the United 
States and Japan.
The S-1 Plus cisplatin versus S-1 in RCT in the Treatment for Stomach cancer (SPIRITS) 
study [Koizumi, W., et al 2008] was a Phase III study to compare the oral fluoropyrimidine 
S-1 plus cisplatin versus S-1 in Japanese participants. Median OS was 13 months versus 
11 months, respectively. Progression-free survival was 6 months versus 4 months, 
respectively; p<0.001). Based on these data, S-1 plus cisplatin became the most popular 
regimen for the first-line therapy of advanced gastric cancer in Japan.
The FLAGS study [Ajani, J. A., et al 2010] was a Phase III study to compare the oral 
fluoropyrimidine S-1 plus cisplatin versus 5-FU plus cisplatin in Western populations. The 
study failed to show superiority for S-1 plus cisplatin over FP; median OS was 8.6 months 
and 7.9 months for S-1/cisplatin and FP, respectively. More toxicity of S-1 and dose 
reduction due to AE was observed in Western populations.
In summary, platinum/fluoropyrimidine doublet regimens are the most broadly used for 
first-line chemotherapy regimen for advanced gastric cancer. The comparable efficacy of 
regimens substituting capecitabine for infused 5-FU has been directly studied in 2 Phase III 
studies: the REAL-2 study and the ML17032 study. The combination of infused or oral 5-FU
is therefore recognized worldwide as one of the standard first-line chemotherapy regimens 
for participants with metastatic disease.
Rationale for Use of FLOT in Gastric Cancer
Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-esophageal 
junction adenocarcinoma but had not previously been evaluated in the context of resectable 
patients [Van Cutsem, E., et al 2006].
FLOT4-AIO [Al-Batran, S. E., et al 2016] [Al-Batran, S. E., et al 2017] was a randomized, 
open-label, Phase II/III study in patients with resectable gastric or GEJ adenocarcinoma. 
Patients were assigned (1:1) to either 4 preoperative and 4 postoperative 2-week cycles of 
docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, 
and fluorouracil 2600 mg/m2 as a 24-hour infusion, all on Day 1 (FLOT group), or 
3 preoperative and 3 postoperative 3-week cycles of intravenous epirubicin 50 mg/m2 on 
Day 1, intravenous cisplatin 60 mg/m2 on Day 1, and either 5-FU 200 mg/m2 as continuous 
intravenous infusion or capecitabine 1250 mg/m2 orally (2 doses of 625 mg/m² per day) on 
Days 1 to 21 (ECF/ECX group).
Results are available online at www.clinicaltrials.gov (Identifier NCT01216644).
In the Phase II part of the study, FLOT was associated with significantly higher proportions 
of patients achieving pathological complete regression compared with ECF/ECX (16% [95% 
CI: 10–23] versus 6% [95% CI: 3–11]; p=0·02) [Al-Batran, S. E., et al 2016]. At least one 
SAE involving a perioperative medical or surgical complication was experienced by 25% of 
patients in the FLOT group versus 40% in the ECF/ECX group. The most common non-
surgical Grade 3–4 AEs in the FLOT and ECF/ECX groups, respectively were neutropenia 
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(52% of patients versus 38%), leucopenia (28% versus 20%), infection (12% in both groups), 
fatigue (9% versus 14%), and vomiting (3% versus 10%).
In the Phase III part of the study, FLOT improved OS, with a median OS of 50 months 
versus 35 months for ECF/ECX; HR 0.77 [0.63-0.94]; p=0.012) [Al-Batran, S. E., et al 
2017]. FLOT also improved PFS, with a median PFS of 30 months versus 18 months for
ECF/ECX (HR: 0.75; 95% CI: 0.62-0.91; p=0.004). In the FLOT and ECF/ECX groups, 
respectively, perioperative complications were experienced by 51% of patients versus 50%,
and the 30- and 90-day mortality rates were 2% and 5% versus 3% and 8%. There was more 
Grade 3/4 neutropenia with FLOT and more Grade 3/4 nausea and vomiting with ECF/ECX.
In the FLOT and ECF/ECX groups, respectively, nonsurgical SAEs were experienced by
61% of patients versus 62%; dose modifications were performed for 40% versus 49% (pre-op
dose modifications for 19% versus 31% and post-op dose modifications for 46% versus
56%); and discontinuations due to drug-related AEs for 10% versus 16% (provided by Al-
Batran S, Institute of Clinical Cancer Research; data on file).
Safety Evaluation of Pembrolizumab + XP in KEYNOTE 059 Cohort 2
The safety and tolerability of pembrolizumab in combination with cisplatin and 
fluoropyrimidine (capecitabine or 5-FU) was evaluated in KEYNOTE 059 Cohort 2. Of the 
18 participants treated, 67% were men, and the median age was 58 years old. As of the 
09 OCT 2015 data cutoff date, median follow-up duration was 5.5 months (range 4.0 to 7.3). 
There were no treatment-related deaths and only 1 participant (6%) discontinued treatment 
because of an AE (stomatitis), which was considered by the investigator to be unrelated to 
pembrolizumab or chemotherapy. Seventeen participants (94%) experienced 
treatment-related AEs of any grade, most commonly stomatitis (n=7, 39%), decreased 
appetite (n=6, 33%), nausea (n=5, 28%), and neutropenia/decreased neutrophils (n=11, 61%) 
without neutropenic fever and unrelated to pembrolizumab. Twelve participants (67%) 
experienced Grades 3 to 4 treatment-related AEs; none were attributed to pembrolizumab. 
AEs attributed to pembrolizumab occurred in 7 participants (39%); the most common were 
diarrhea, dysgeusia, hyperthyroidism, and nausea (n=2 each); all were Grades 1 to 2. Eight 
participants (44%) experienced AEs of special interest, regardless of attribution by 
investigator, including hyperthyroidism, hypothyroidism, infusion-related reaction, pruritus, 
and vasculitis and all were Grades 1 to 2.
Based on these data, the combination of pembrolizumab, cisplatin, and fluoropyrimidine 
(capecitabine or 5-FU) has a manageable safety profile.
Justification for Dose
The dose recently approved in the United States for multiple indications is 200 mg Q3W. The 
pembrolizumab dose studied in KEYNOTE 012 that established efficacy in gastric cancer 
participants is 10 mg/kg Q2W, and recent studies in other tumor types have indicated that 
both 10 mg/kg Q2W and 200 mg Q3W are likely to be similar with regard to efficacy and 
tolerability.
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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 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 every 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 OS at 
200 mg Q3W across multiple indications, and;

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from 
physiologically-based pharmacokinetic [PBPK] analysis) at 200 mg Q3W.
Among the eight randomized dose-comparison studies, a total of 2262 participants were 
enrolled with melanoma and non-small cell lung cancer (NSCLC), covering different disease 
settings (treatment naïve, previously treated, PD-L1 enriched and all-comers) and different 
treatment settings (monotherapy and in combination with chemotherapy). Five studies 
compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B2, KN001 D, KN002, KN010 and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B3, KN001 
F2 and KN006). All of these studies demonstrated flat dose- and exposure-response 
relationships across the doses studied representing an approximate 5- to 7.5-fold difference in 
exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the 
highest doses studied. Subsequently, flat dose-/exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer 
and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose 
independent of the tumor type. These findings are consistent with the mechanism of action of 
pembrolizumab, which acts by interaction with immune cells, and not via direct binding to 
cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
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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.
6. Study Population
Male and female participants with previously untreated, locally advanced resectable gastric
or GEJ adenocarcinoma of at least 18 years will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Have previously untreated localized gastric or GEJ adenocarcinoma as defined by T3 
or greater primary lesion or the presence of any positive nodes - N+ (clinical nodes) 
without evidence of metastatic disease. Siewert type 2 or 3 tumors are eligible. 
Enrollment of participants with Siewert type 1 tumors will be limited to those for 
whom the planned treatment is perioperative chemotherapy and resection. Tumor 
staging prior to enrollment must consist of at least 1 imaging modality: computed 
tomography (CT) or magnetic resonance imaging (MRI).
Demographics
2. Be at least 18 years of age on the day of signing informed consent
3. Have an ECOG performance status of 0 to 1, to be performed within 3 days prior to 
the first dose of study treatment
4. Have a life expectancy of greater than 6 months
Male participants:
5. Male participants of childbearing potential must agree to use an adequate method of 
contraception as outlined in Appendix 3, for the course of the study through 180 days 
after the last dose of chemotherapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the participant
Female participants:
6. Female participants of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
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the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
7. Female participants of childbearing potential must be willing to use an adequate 
method of contraception as outlined in Appendix 3, for the course of the study
through 180 days after the last dose of chemotherapy or through 120 days after the 
last dose of pembrolizumab, whichever is greater.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the participant.
Informed Consent
8. The participant provides written informed consent for the study. The participant may 
also provide consent for Future Biomedical Research. However, the participant may 
participate in the main study without participating in Future Biomedical Research.
Other Inclusions
9. Plan to proceed to surgery following pre-operative chemotherapy based on standard 
staging studies per local practice.
10. Be willing to provide tissue from a tumor lesion at baseline and at time of surgery
11. Have adequate organ function as defined in the following table (Table 3). Specimens 
must be collected within 10 days prior to the start of study treatment.
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Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
ANC
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine 
and/or measured or calculatedb creatinine 
clearance
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 × ULN and creatinine clearance ≥30 mL/min
OR
Creatinine clearance ≥60 mL/min for participant 
with creatinine levels >1.5 × institutional ULN
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 
Coagulation
INR OR PT
aPTT/PTT
≤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); ANC=absolute neutrophil 
count; aPTT; activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase (serum 
glutamic oxaloacetic transaminase); CrCl=creatinine clearance; GFR=glomerular filtration rate; 
INR=international normalized ratio; PT=prothrombin time; PTT=partial thromboplastin time; ULN=upper 
limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
b 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.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
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2. Has an active infection requiring systemic therapy.
3. Has a diagnosis of immunodeficiency.
4. Has a known additional malignancy that is progressing or has required active 
treatment within the past 5 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
5. Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active 
substance and/or any of its excipients. (Refer to the respective IB for a list of 
excipients.)
6. Has a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy 
agents and/or to any of their excipients.
7. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment and is allowed.
8. Has a known history of human immunodeficiency virus (HIV) infection. No HIV 
testing is required unless mandated by local health authority.
9. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. 

Note: No testing for Hepatitis B and Hepatitis C is required unless mandated 
by local health authority.
10. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
11. Female participants: Is pregnant or breastfeeding or expecting to conceive children 
within the projected duration of the study, starting with the screening visit through180 
days after the last dose of chemotherapy or through 120 days after the last dose of 
pembrolizumab, whichever is greater.
Male participants: Is expecting to father children within the projected duration of the 
study, starting with the screening visit through 180 days after the last dose of 
chemotherapy.
12. Has a history or current evidence of any condition (eg, known deficiency of the 
enzyme dihydropyrimidine dehydrogenase [DPD]), therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the 
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participant’s participation for the full duration of the study, or is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
13. Has had an allogeneic tissue/solid organ transplant.
14. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
15. A woman of child-bearing potential (WOCBP) who has a positive urine pregnancy 
test within 72 hours prior to receiving first dose of study treatment (see Appendix 6). 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
Prior/Concomitant Therapy
16. 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 (ie, 
CTLA-4, OX-40, CD137) or has previously participated in a MSD pembrolizumab 
(MK-3475) clinical study.
17. Has received prior systemic anti-cancer therapy including investigational agents for 
the current malignancy. 
18. Is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of 
prednisone equivalent) or any other form of immunosuppressive therapy within 
14 days prior to the first dose of study treatment.
19. Has received a live vaccine within 30 days prior to the first dose of study treatment. 
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
20. 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.
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Lifestyle Restrictions
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
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.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized.  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 or serious adverse events (SAE) meeting reporting 
requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the study will not be 
replaced.
7. 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. All supplies will be provided open label. Pembrolizumab (MK-3475) will be 
provided as non-kitted single vials or multiple vials in a kit box. Cisplatin, docetaxel, 
oxaliplatin, leucovorin (calcium folinate) and 5-FU will be provided as a kit with a single 
vial. Capecitabine will be provided as a kit with tablets in blister packs or bottles.  Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
Treatments Administered
The treatments to be used in this study are outlined in Table 4. A cycle of treatment is 3 
weeks (21 days) long and is set relative to pembrolizumab/placebo.
Regardless of clinical benefit, participants may only receive 17 administrations 
(approximately 1 year) of pembrolizumab.
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Pembrolizumab and Placebo 
Pembrolizumab or placebo will be administered on Day 1 of each 3-week cycle after all 
procedures/assessments have been completed. Pembrolizumab or placebo will be 
administered as a 30-minute IV infusion Q3W. Sites must make every effort to target 
infusion timing to be as close to 30 minutes as possible. However, given the variability 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 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).
XP/FP
Cisplatin 80 mg/m2 will be administered as a 60- or 120-minute IV infusion or per site’s 
standard practice on Day 1 of each treatment cycle, Q3W for 3 cycles in the neoadjuvant
combination and 3 cycles in the adjuvant combination phases.
Capecitabine 1000 mg/m2 will be administered orally 2 times a day (bid) from Day 1 to 
Day 14 of each treatment cycle, Q3W for 3 cycles in the neoadjuvant combination and 3 
cycles in the adjuvant combination phases.
5-FU 800 mg/m2/day will be administered as a continuous IV infusion from Day 1 to Day 5, 
for a total dose of 4000 mg/m2 (120 hours, or per local standard) of each treatment cycle, 
Q3W for 3 cycles in the neoadjuvant combination and 3 cycles in the adjuvant combination 
phases.
FLOT
FLOT chemotherapy will be administered on Days 1 and 15 of Cycle 1; Day 8 of Cycle 2, 
and Day 1 of Cycle 3 in the neoadjuvant and adjuvant phases.
Docetaxel 50 mg/m2 will be administered as a 60-minute IV infusion, or per site’s standard 
practice.
Oxaliplatin 85 mg/m2 will be administered as a 2-hour IV infusion, or per site’s standard 
practice.
Leucovorin (calcium folinate) 200 mg/m2 will be administered as a 2-hour IV infusion, or per 
site’s standard practice.
5-FU 2600 mg/m2 will be administered as a 24-hour infusion.
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See Section 9.1.8.1 for timing of dose administration.
Table 4
Study Treatments
Study Treatment 
Name
Dosage 
Formulation
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Adminis-
tration
Sourcing
Pembrolizumab/Placebo
Pembrolizumab 
(MK-3475)
Solution for 
infusion
25 mg/mL
200 mg on Day 1 of each 
cycle (Q3W)
IV infusion
Provided centrally 
by the Sponsor
Placebo 
(normal saline)
Solution for 
infusion
N/A
On Day 1 of each cycle 
(Q3W)
IV infusion
Provided locally by 
the study site, 
subsidiary, or 
designee
XP/FP
Cisplatin
Solution for 
infusion
1 mg/mL
80 mg/m2 on Day 1 of each 
cycle (Q3W)
IV infusion
Provided centrally 
by the Sponsor or 
locally by the study 
site, subsidiary, or 
designee
Capecitabine
Tablet
150 mg & 
500 mg
1000 mg/m2 bid on 
Days 1-14 of each cycle 
(Q3W)
Oral
5-FU
Solution for 
infusion
25 mg/mL & 
50 mg/mL
800 mg/m2/day continuous 
on Days 1-5 of each cycle 
(Q3W) (120 hours, or per 
local standard)
IV infusion
FLOT
Docetaxel
Solution for 
infusion
20 mg/mL
50 mg/m2 on Days 1 and 15 
of Cycle 1, Day 8 of 
Cycle 2, and Day 1 of 
Cycle 3 (Q2W)
IV infusion
Provided centrally 
by the Sponsor or 
locally by the study 
site, subsidiary, or 
designee
Oxaliplatin
Solution for 
infusion
5 mg/mL
85 mg/m2 on Days 1 and 15 
of Cycle 1, Day 8 of 
Cycle 2, and Day 1 of 
Cycle 3 (Q2W)
IV infusion
5-FU
Solution for 
infusion
50 mg/mL
2600 mg/m2 on Days 1and 
15 of Cycle 1, Day 8 of 
Cycle 2, and Day 1 of 
Cycle 3 (Q2W)
IV infusion
Leucovorin
(calcium folinate)
Solution for 
infusion
10 mg/mL
200 mg/m2 on Days 1 and 
15 of Cycle 1, Day 8 of 
Cycle 2, and Day 1 of 
Cycle 3 (Q2W)
IV infusion
5-FU=5-fluorouracil; bid=2 times a day; IV=intravenous; N/A=not applicable; Q2W=every 2 weeks; Q3W=every 3 weeks.
The body surface area (BSA) in m2 should be calculated per local guidance.
Chemotherapy backbones include XP (cisplatin + capecitabine), FP (cisplatin + 5 FU), or FLOT (docetaxel + oxaliplatin
+ 5-FU + leucovorin [calcium folinate]).
The investigator will decide the chemotherapy backbone (XP or FP or FLOT) prior to randomization. Participants will 
continue on the chemotherapy chosen prior to randomization throughout the study and will not be allowed to switch 
between chemotherapy treatments (exception may be granted after Sponsor consultation, e.g., participants who have 
difficulty swallowing oral study treatment).
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All supplies indicated in Table 4 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. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to Section 9.1.8 for details regarding administration of the study treatment.
Dose Modification (Escalation/Titration/Other)
If appropriate, the investigator may attribute each toxicity event to any of the components in 
the neoadjuvant and/or adjuvant combination treatment groups.
Pembrolizumab and placebo dose reductions are not permitted. Pembrolizumab and placebo 
treatment may only be interrupted or discontinued due to toxicity. For participants requiring a 
dose modification of standard of care chemotherapy, the next cycle may be delayed if the 
scheduled off-drug periods are not adequate to allow for recovery to ≤ Grade 1 or to the 
baseline status of the participant.
If a dose reduction for toxicity occurs with any chemotherapy agent, the dose may not be 
re-escalated. Participants may have a maximum of 2 dose reductions (if applicable) for 
chemotherapy agents throughout the course of combination neoadjuvant and/or adjuvant 
treatment phases for toxicities. Participants who require a third dose reduction will have that 
chemotherapy agent discontinued. If a participant experiences several toxicities and there are 
conflicting recommendations, please follow the most conservative dose adjustment 
recommended (dose reduction appropriate to the most severe toxicity).
During the neoadjuvant and/or adjuvant phases, the reduction of the dose of 1 chemotherapy 
agent and not the other agent is appropriate if, in the opinion of the investigator, the toxicity 
is clearly related to one of the treatments.  If 1 chemotherapy agent must be held, it is 
recommended to hold all study treatments and delay the entire cycle until the toxicity 
resolves according to the guidelines in Sections 7.2.2, 7.2.3, 7.2.4.  If a cycle is delayed, all 
subsequent cycles must be adjusted/delayed accordingly, to account for the initial delay.
If, in the opinion of the investigator, the toxicity is related to the combination of 
chemotherapy agents, all drugs should be reduced according to the recommended dose 
modifications. If the toxicity is related to the combination of all agents, chemotherapy should 
be reduced, interrupted, or discontinued; pembrolizumab or placebo should be interrupted or 
discontinued according to the recommended dose modifications.
If participants have severe AEs requiring discontinuation of any agents in the standard of 
care chemotherapy treatment(s), the Sponsor must be consulted prior to the discontinuation. 
Neoadjuvant and adjuvant treatment may be altered according to the dose modification
guidelines (Table 5 to Table 11). If toxicity is not otherwise specified, investigators should 
refer to the label or local guidelines for standard of care chemotherapy dose adjustments. If, 
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in the opinion of the investigator, a dose modification for a non-specified toxicity would 
benefit the participant, this may be done.
The CTCAE v4.0 must be used to grade the severity of AEs. All dose modifications will be 
based on the AE requiring the greatest dose modification. Exceptional circumstances to 
following the dose modification tables below may be considered after consultation with the 
Sponsor.
In addition, participants should receive appropriate supportive care measures as deemed 
necessary by the treating investigator. Suggested supportive care measures are included in
Table 6 (pembrolizumab) and Section 7.7.3.
Table 5
Dose Modifications for Chemotherapies + Pembrolizumab or Placebo
Dose level 0
Dose level -1
Dose level -2
Dose level -3
pembrolizumab 
or placebo
200 mg fixed 
dose
Dose reductions 
are not permitted.
Dose reductions 
are not permitted.
Dose reductions 
are not permitted.
XP/FP
cisplatin
80 mg/m2
60 mg/m2
40 mg/m2
Discontinue
capecitabine
1000 mg/ m2 bid
750 mg/m2 bid
500 mg/m2 bid
Discontinue
5-FU
800 mg/m2/day
600 mg/m2/day
400 mg/m2/day
Discontinue
FLOT*
oxaliplatin
85 mg/m2
Reduce to 75%
Reduce to 50%
Discontinue
docetaxel
50 mg/ m2
Reduce to 75%
Reduce to 50%
Discontinue
5-FU
2600 mg/m2
Reduce to 75%
Reduce to 50%
Discontinue
The body surface area (BSA) in m2 should be calculated per local guidance.
*Dose reduction is not needed for leucovorin (calcium folinate).
Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue)
Refer to Appendix 9, Section 12.9.1 for country-specific requirements.
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
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included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 6. 
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to 
≤Grade 1 after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for signs and symptoms 
of pneumonitis
•
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
•
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Diarrhea / Colitis 
Grade 2 or 3
Withhold
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) and of bowel perforation (ie, peritoneal 
signs and ileus)
•
Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis
•
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
•
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
•
Initiate insulin replacement 
therapy for participants with 
T1DM
•
Administer anti-hyperglycemic 
in participants with 
hyperglycemia
•
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypophysitis
Grade 2
Withhold
•
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
•
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
•
Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
•
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
Hypothyroidism
Grade 2-4
Continue
•
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of 
care
•
Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
•
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
•
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 2
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs
(eg, vasculitis and sclerosing cholangitis).
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Dose modification and toxicity management of infusion reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab-associated 
infusion reactions are provided in Table 7. 
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Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (eg, from 100 mL/hr to 
50 mL/hr). Otherwise, dosing will be held until symptoms resolve and the 
participant should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug treatment.
Participant may be premedicated 1.5 h 
(±30 minutes) prior to infusion of 
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 drug 
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.
Dose Modifications for Cisplatin and Capecitabine or 5-FU
Please refer to criteria for cisplatin and capecitabine or 5-FU dose modification included in 
Table 8 and Table 9.
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Table 8
Dose Modification Guidelines for Cisplatin Drug-related Adverse Events
Category
Toxicity
Hold 
Cisplatin
Treatment 
for Grades
Timing for
Restarting
Cisplatin
Treatment
Dose for
Restarting
Cisplatin
Treatment
Discontinue Cisplatin
Hematologic
Neutropenia1
31
Neutrophil
count resolves
to >1,000/mm3
No reduction
(consider
G-CSF)
Toxicity does not resolve
within 4 weeks of last 
infusion or if >2 DL
reductions exceeded
41
Neutrophil
count resolves
to >1,000/mm3
Reduce by 1 DL
(consider
G-CSF)
Toxicity does not resolve
within 4 weeks of last 
infusion or if >2 DL 
reductions exceeded
Febrile 
neutropenia
31
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
41
N/A
Discontinue
Permanently discontinue 
cisplatin
Thrombo-
cytopenia
3-41
Platelet count
resolves to 
>75,000/mm3 or
baseline
Reduce by 1 DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if >2 DL 
reductions exceeded
Non-
hematologic
Creatinine
increased
2
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if >2 DL 
reductions exceeded
3-41
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 or 
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 by1 DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if >2 DL 
reductions exceeded
Laboratory
Adverse Events
41
Toxicity
resolves to
Grade 0-1
Reduce by1 DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if >2 DL 
reductions exceeded
DL=dose level; G-CSF=granulocyte colony-stimulating factor.
1 Permanent discontinuation should be considered for any severe or life-threatening event. 
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 
Grades 0-1 within 12 weeks of the last dose.
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Table 9
Dose Modification Guidelines for Capecitabine or 5-FU Drug-related 
Adverse Events
Category
Toxicity
Hold 
Capecitabine
or 5-FU 
Treatment for
Grade
Timing for
Restarting
Capecitabine
or 5-FU 
Treatment
Dose for
Restarting 
Capecitabine 
or 5-FU
Treatment
Discontinue
Capecitabine or 5-FU
Hematologic
Neutropenia
3
1
Neutrophil
count resolves
to >1,000/mm3
No reduction
(consider
G-CSF)
Toxicity does not resolve
within 4-5 weeks of last 
infusion or if >2 DL
reductions exceeded
4
1
Neutrophil
count resolves
to >1,000/mm3
Reduce by
1 DL
(consider
G-CSF)
Toxicity does not resolve
within 4-5 weeks of last 
infusion or if >2 DL
reductions exceeded
Febrile
neutropenia
3
1
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
1
N/A
Discontinue
Permanently discontinue 
Thrombocytopenia
3-4
1
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 events
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
DL=dose level; 5-FU=5-fluorouracil; G-CSF=granulocyte colony-stimulating factor; N/A=not applicable.
1 Permanent discontinuation should be considered for any severe or life-threatening event. 
2 Participants with intolerable or persistent Grade 2 drug-related adverse event 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 
Grades 0-1 within 12 weeks of the last dose.
Dose Modification Guidelines for Docetaxel
Please refer to criteria for docetaxel dose modification included in Table 10.
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Table 10 Dose Modification Guidelines for Docetaxel Drug-related Adverse Events
Category
Toxicity
Hold Docetaxel 
Treatment for
Grade
Timing for
Restarting
Docetaxel
Treatment
Dose for
Restarting 
Docetaxel 
Treatment
Discontinue
Docetaxel
Hematologic
Neutropenia
1-4 lasting 
≤7 days
ANC resolves
to ≥1500/mm3
N/A
N/A
4 lasting 
>7 days, 1st
occurrence
ANC resolves
to ≥1500/mm3
Reduce by 1 DL N/A
4 lasting 
>7 days, 2nd
occurrence
ANC resolves
to ≥1500/mm3
Reduce by 2 DL N/A
4 lasting 
>7 days, 3rd
occurrence
N/A
N/A
Yes
Febrile neutropenia 
(defined as T 
≥100.5°F and ANC 
≤ 1,000/mm3)
1st occurrence
ANC resolves
to ≥1500/mm3
Reduce by 1 DL
*Consider 
G-CSF for 
subsequent 
cycles
N/A
2nd occurrence
ANC resolves
to ≥1500/mm3
Reduce by 2 DL
*G-CSF highly 
recommended
N/A
3rd occurrence
N/A
N/A
Yes
Thrombocytopenia
1-3
Platelet count 
resolves to 
>100,000/mm3
N/A
N/A
4, 1st
occurrence
Platelet count 
resolves to 
>100,000/mm3
Reduce by 1 DL N/A
4, 2nd
occurrence
Platelet count 
resolves to 
>100,000/mm3
Reduce by 2 DL N/A
4, 3rd
occurrence
N/A
N/A
Yes
Anemia
1-3
Until anemia 
resolves to Grade 
1 or baseline
N/A
N/A
4, 1st
occurrence
Until anemia 
resolves to Grade 
1 or baseline
Reduce by 1 DL N/A
4, 2nd
occurrence
Until anemia 
resolves to 
Grade 1 or 
baseline
Reduce by 2 DL N/A
4, 3rd
occurrence
N/A
N/A
Yes
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Category
Toxicity
Hold Docetaxel 
Treatment for
Grade
Timing for
Restarting
Docetaxel
Treatment
Dose for
Restarting 
Docetaxel 
Treatment
Discontinue
Docetaxel
Non-
hematological 
toxicity and 
other 
hematological 
toxicity not 
described 
above**
All
1-2
No
None
N/A
3-4, 1st
occurrence
Yes, until 
toxicity resolves 
to Grade 0-1
Reduce by 1 DL N/A
3-4, 2nd
occurrence
Yes, until 
toxicity resolves 
to Grade 0-1
Reduce by 2 DL N/A
3-4, 3rd
occurrence
N/A
N/A
Yes
Peripheral 
neuropathy
1-2
No
Reduce by 1 DL N/A 
3-4
N/A
N/A
Discontinue upon onset
DL=dose level; G-CSF=granulocyte colony-stimulating factor; N/A=not applicable.
*In order to avoid treatment delays, secondary prophylaxis with G-CSF will be required for all subsequent cycles if one 
of the following criteria is applicable: 

occurrence of febrile neutropenia or infection in neutropenia at any time or;

occurrence of a NCI-CTC grade 4 neutropenia or;

delay of one therapy cycle because of leukopenia or neutropenia by more than 3 days.
**Participants who experience suspected severe hypersensitivity reaction to docetaxel (eg, generalized rash/erythema, 
hypotension and/or bronchospasm, angioedema or anaphylaxis) should be discontinued from docetaxel
Dose Modification Guidelines for Oxaliplatin
Please refer to criteria for docetaxel dose modification included in Table 11.
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Table 11 Dose Modification Guidelines for Oxaliplatin Drug-related Adverse Events
Category
Toxicity
Grade
Hold until
Dose for Restarting
Oxaliplatin Treatment
Hematologic
Neutropenia 
3
Neutrophil count
resolves to ≥1,500/mm3
No reduction
*consider G-CSF
4
Neutrophil count
resolves to ≥1,500/mm3
Reduce by 1 DL
*recommend G-CSF
Febrile 
neutropenia
3, 1st occurrence
Neutrophil count
resolves to ≥1,500/mm3
Consider G-CSF
3, 2nd
occurrence
Neutrophil count
resolves to ≥1,500/mm3
Dose reduce by 1 DL
*recommend G-CSF
Further 
occurrences
Neutrophil count
resolves to ≥1,500/mm3
Dose reduce by 2 DL
*recommend G-CSF
Thrombocytopenia 
with bleeding
3-4
Platelet count resolves to 
>100,000/mm3
Reduce by 1 DL
Non-
hematologic
Neurotoxicity
Cold-induced 
dysesthesia
N/A
N/A
Paresthesia ≤7 
days 
N/A
N/A
Paresthesia <7-
14 days
N/A
N/A
Paresthesia-
persistent
N/A
Reduce 1DL
Paresthesia with 
pain 7-14 days
N/A
Reduce 1DL
Persistent 
Paresthesia with 
pain
N/A
Reduce 2DL or discontinue
Paresthesia with 
functional 
impairment 
N/A
Reduce 2DL if lasting 7-14 
days or discontinue if persistent
All other non-
hematologic 
toxicities**
3-4,1st
occurrence
N/A
Reduce by 1 DL
3-4, 2nd
occurrence
N/A
Reduce by 2 DL
DL=dose level; G-CSF=granulocyte colony-stimulating factor; N/A=not applicable.
*In order to avoid treatment delays, secondary prophylaxis with G-CSF will be required for all subsequent cycles if one 
of the following criteria is applicable: 

occurrence of febrile neutropenia or infection in neutropenia at any time or; 

occurrence of a NCI-CTC grade 4 neutropenia or;

delay of one therapy cycle because of leukopenia or neutropenia by more than 3 days
**Permanent discontinuation should be considered for any severe or life-threatening event. Participants with intolerable or 
persistent Grade 2 drug-related AEs 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 Grades 0-1 within 12 weeks of the last 
dose.
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Dose Modification for Adjuvant Therapy
Dose modifications are permitted in the study as per Table 5. If participants were treated at 
reduced doses in the pre-operative phase of the study, the same standard of care 
chemotherapy doses will be re-initiated or continued in the post-operative treatment phase. 
Re-escalation of doses is not permitted. Once post-operative treatment is initiated, further 
modification of the study medications will be based on AEs as per Table 5, and specific 
reasons for dose modification must be documented.
If AEs warrant discontinuation of a study medication, the Sponsor must be consulted and a 
decision can be made on a case by case basis.
Method of Treatment Assignment
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).  There are 2 study treatment arms.  
Participants will be assigned randomly in a 1:1 ratio to pembrolizumab + chemotherapy or 
placebo + chemotherapy, respectively.
The chemotherapy regimen chosen by the investigator will be entered into IVRS/IWRS prior 
to treatment randomization assignment by the system.
Stratification
Treatment randomization will be stratified according to the following factors in the Main 
Study (XP/FP) and FLOT Cohort:
1. Geographic regions: Asia versus Non-Asia
2. Tumor staging: II versus III versus IVa
3. Backbone chemotherapy XP/FP versus FLOT
Blinding
A double-blinding technique will be used. Pembrolizumab (MK-3475) and placebo will be 
prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified study
site personnel. The participant and the investigator who is involved in the study treatment 
administration or clinical evaluation of the participants are unaware of the group 
assignments.
Chemotherapy administration will be open label.
See Section 9.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
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Preparation/Handling/Storage/Accountability
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Standard of care chemotherapies will be prepared and administered as per the 
approved product labels. The body surface area (BSA) in m2 should be calculated per local 
guidance.
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 as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
As participants are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision. The total volume of study medication 
infused will be compared with the total volume prepared to determine compliance with each 
dose administered. The instructions for preparing and administering study medications are 
provided in the Pharmacy Manual.
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If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record. 
Refer to Sec. 7.2.1 for dose modification and toxicity management for irAEs associated with 
pembrolizumab and for other allowed dose interruption of pembrolizumab.
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator is to discuss prohibited medications with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study treatment requires the mutual agreement of the investigator, the Sponsor and the 
participant.
Acceptable Concomitant Medications/Therapy
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 (OTC), herbal supplements, and IV 
medications and fluids. If changes occur during the study period, documentation of drug 
dosage, frequency, route, and date may also be included on the eCRF.
During the adjuvant period, participants that do not have surgery or those with R1/R2 
resection, may continue protocol planned adjuvant treatment (including 
pembrolizumab/placebo) and will be permitted to have radiation therapy (RT). Radiation 
therapy is in addition to and at the discretion of the site PI, but not part of protocol-specified 
therapy. If radiation therapy is used, all sites should follow the guidelines below in addition 
to applicable local guidelines and published standards in this disease [Smalley, S. R., et al 
2012] [Stumpf, P. K., et al 2017]:
a.
Do not administer radiation therapy concurrent with protocol-specified adjuvant 
combination chemotherapy (consisting of cisplatin, a fluoropyrimidine and 
pembrolizumab/placebo) at protocol-specified dosages. 
b. If indicated, radiation therapy should be started and completed either: 
-Prior to initiation of protocol-specified adjuvant combination chemotherapy – or –
-Following completion of protocol-specified adjuvant combination chemotherapy 
(estimated to be 3 cycles) and prior to initiation of adjuvant monotherapy consisting 
of pembrolizumab/placebo.
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All concomitant medications received within 30 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded. All concomitant 
medications administered during SAEs or ECIs are to be recorded.  SAEs and ECIs are
defined in Section 9.3.7.
Prohibited Concomitant Medication/Therapy
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phases of this study. Restrict the use of prohibited medications at least 14 days 
prior to the start of therapy:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy during the neo-adjuvant treatment phase

Live or live-attenuated vaccines within 30 days prior to the first dose of study
treatment and while participating in the study. Administration of killed vaccines is 
allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event that is suspected to have an immunologic etiology. The use of systemic 
glucocorticoids for the management of chemotherapy-related toxicities and for the 
management of surgical events in the post-operative period may be allowed after 
consultation with the Sponsor. The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor.
For participants taking capecitabine or 5-FU:

Brivudine, sorivudine analogues, and other inhibitors of the enzyme 
dihydropyrimidine dehydrogenase (DPD).
For participants taking cisplatin:

Phenytoin should not be started with cisplatin therapy.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from treatment. 
Participants may receive other medications that the investigator deems to be medically 
necessary.
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Concomitant Medications to be used with caution:

Cimetidine, metronidazole and interferons may increase levels of 5-FU.

Participants who are taking phenytoin in conjunction with 5-FU should be examined 
regularly due to a potential elevation in phenytoin plasma levels. Hepatotoxic effects 
(rise in alkaline phosphatase, transaminase, or bilirubin levels) are commonly 
observed under the treatment with 5-FU and levamisole.

Caution is advised with the use of CYP2C9 substrates in participants taking 
capecitabine. The guidelines within the local label should be followed.

Administration of leucovorin (calcium folinate) concomitantly with folic acid 
antagonists such as co-trimoxazole or pyrimethamine may reduce their effectiveness 
or even eliminate it.

Leucovorin (calcium folinate) may reduce the effects of anticonvulsants, such as 
phenobarbital, primidone or phenytoin.
The Exclusion Criteria describes other medications which are prohibited during the treatment 
phase of this study. 
Rescue Medications and Supportive Care
Supportive Care Guidelines for Immune-related Adverse Events
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 7.2. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Refer to Table 6 for supportive care guidelines for the following:

Pneumonitis 

Diarrhea/Colitis 

Type 1 diabetes mellitus or hyperglycemia

Hypophysitis

Hyperthyroidism or Hypothyroidism 
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
Elevated liver functions

Nephritis and renal dysfunction

Myocarditis

Other immune-related AEs
Refer to Table 7 for supportive care guidelines for the following:

Management of Infusion Reactions
Supportive Care Guidelines for Cisplatin
Attempts should be made to control nausea and vomiting using non-steroidal therapies 
whenever possible. It is recommended that the participant be provided adequate anti-emetic 
regimens that will enable the administration of the prescribed doses of chemotherapy, with 
every effort to adhere to the protocol specified chemotherapy. To achieve this goal, the use of 
systemic glucocorticoids may be allowed after consultation with the Sponsor. 
The prevention and/or treatment of nausea and vomiting should be managed with:

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

Plus Aloxi (palonosetron) 0.25 mg IV
Nausea may also be managed with:
1. Zofran (ondansetron) 8 mg twice a day
2. Or Compazine (prochlorperazine) 10 mg 3 to 4 times per day
In addition, anti-emetic therapies listed in Table 12 may be used. Please refer to the product 
label or local standards of care for additional cisplatin supportive measures.
Supportive Care Guidelines for Capecitabine
Please refer to the product label or local standards of care for capecitabine supportive 
measures.
Supportive Care Guidelines for 5-FU
Please refer to the product label or local standards of care for fluorouracil supportive 
measures.
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Supportive Care Guidelines for the FLOT Regimen
Suggested anti-emetic therapy is provided in Table 12 (provided by Al-Batran S, Institute of 
Clinical Cancer Research; data on file). Attempts should be made to control emesis/nausea 
using non-steroidal therapies; however, the use of systemic glucocorticoids may be allowed 
after consultation with the Sponsor.
Please refer to the appropriate product label or local standards of care for additional 
docetaxel, oxaliplatin, and leucovorin (calcium folinate) supportive measures.
Table 12 Antiemetic Therapy
Day
Drug Class
Example
D1 (approx. 1 hour 
before chemotherapy)
(acute emesis)
Neurokinin-1-receptor-
antagonist and 5-HT3-
receptor-antagonists
1 capsule Akynzeo (300 mg 
netupitant + 0.5 mg palonosetron), 
with or without food
D2 to D3 (delayed 
emesis)
5-HT3-receptor-antagonists
Alternatives: 
granisetron 2 mg PO/ 1 mg IV
ondansetron 16-24 mg PO/ 8 mg IV
tropisetron 5 mg PO/ IV
dolasetron 200 mg PO/ 100 mg IV
palonosetron 0.5 mg PO/ 0.25 mg IV
Approx.=approximately: D=day of therapy; IV=intravenous; PO=per os (orally)
Treatment After the End of the Study
Upon study completion, participants are to be discontinued and may be enrolled in an 
extension study. 
Clinical Supplies Disclosure
This study is blinded but supplies are provided open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies.  Study treatment 
identity (name, strength or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
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 9.1.10). 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.
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See Section 9.1.10 - Participant Blinding/Unblinding, for a description of the method of 
unblinding a participant during the study, should such action be warranted.
Standard Policies
Study site personnel will have access to a central electronic treatment 
allocation/randomization system (IRT system) to allocate participants, to assign treatment to 
participants and to manage the distribution of clinical supplies.
8. Discontinuation/Withdrawal Criteria
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 regimen
will still continue to participate in the study as specified in Section 2 and Section 9.10.3.
Participants may discontinue study treatment at any time for any reason or be dropped 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 9.1.9.
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
Radiographic disease progression outlined in Section 9.2.1.2 (after Sponsor 
communication, the investigator may elect to continue treatment)
o
Unacceptable adverse experiences as described in Section 9.3 and Appendix 4
o
Any progression or recurrence of any malignancy, or occurrence of another malignancy 
that requires active treatment
o
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment
o
Recurrent Grade 2 pneumonitis
o
A confirmed positive serum pregnancy test
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o
Investigator’s decision to withdraw the participant
For participants who are discontinued from study treatment but continue to be monitored in 
the study, see Section 2 and Section 9.10.3 for those procedures to be completed at each 
specified visit.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
Withdrawal from the Study
If a participant repeatedly fails to return for scheduled visits and/or if the study site is unable 
to contact the participant after multiple attempts (ie, is lost to follow-up), the procedures to 
be performed are outlined in Section 8.3.
If a participant decides not continue receiving study intervention, the participant is to be 
encouraged to continue visits in the study for follow-up, imaging, and vital status assessment. 
Participants who withdraw consent during the study
If the participant or participant’s legally acceptable representative withdraws consent, the 
participant must be withdrawn from the study.
Section 9.1.9 delineates the specific procedures performed at the time of withdrawal and 
withdrawal from future biomedical research. 
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 9.3.
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, phone 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 pre-specified statistical data handling and analysis guidelines.
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9. 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 screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before providing documented informed consent may be 
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.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
Informed Consent
The investigator or qualified designee (consistent with local requirements) must obtain 
documented informed consent from each potential participant or their legally acceptable 
representative prior to participating in this clinical study or future biomedical research. If 
there are changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or qualified designee must ensure the appropriate documented 
informed consent is in place. 
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
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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 informed consent form, any subsequent revised informed consent form, and any 
written information provided to the participant must receive the IRB/IEC’s 
approval/favorable opinion in advance of use. The participant or their 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. Specifics about the study 
and the study population are to be included in the study informed consent form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
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.
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Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
Please note that if the participant has lost at least 15 lbs (6.8 kg) over the 3 months prior to 
screening, “weight loss” should be entered as an active condition on the Medical History. As 
well, any autoimmune disorders, regardless of onset date, should be recorded.
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before starting study treatment. Treatment for the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as a prior 
medication. 
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up visit.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 9.3.
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 or treatment 
allocation.  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.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 9.10.1. 
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 
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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.
Treatment Administration
Study treatment will be administered by the investigator or designee according to the 
specifications within the Pharmacy manual.
Study Treatment should begin within 3 days of treatment allocation/randomization.
Timing of Dose Administration
Study treatment will begin on Day 1 of each 3-week dosing cycle after all 
procedures/assessments have been completed as detailed on the SoA (Section 2). Study
treatments may be administered up to 3 days before or after the scheduled day of 
administration.
All study treatments may be administered on an out-patient basis.
For the combination portions of the study, treatment will be administered in the order 
presented below:

XP/FP + pembrolizumab or placebo: Pembrolizumab or placebo infusion is 
administered first, followed by the cisplatin infusion, and then oral capecitabine or 
5-FU infusion.

FLOT + pembrolizumab or placebo: Pembrolizumab or placebo infusion is 
administered first followed by FLOT. Of the FLOT chemotherapies, docetaxel should 
be administered first. Oxaliplatin should be administered before 5-FU. Oxaliplatin 
and leucovorin (calcium folinate) may be administered concurrently using a Y-line 
placed directly at the site of infusion; however, the drugs should not be mixed in the 
same infusion bag.
Treatment may continue with pembrolizumab + chemotherapy or placebo + chemotherapy 
until the participant receives the full protocol allowed cycles (3 neoadjuvant + 14 adjuvant) 
or documented disease progression/recurrence, unacceptable AE(s), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to discontinue the 
participant, participant withdraws consent, pregnancy of the participant, or administrative 
reasons requiring cessation of treatment.
Note: Dosing interruptions are permitted in the case of medical or 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. If a participant’s dosing has been interrupted for more than 3 weeks, a 
Sponsor consultation must occur and be documented before participant can be placed back 
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on study therapy. Day 1 of subsequent cycles should be adjusted accordingly to adhere to 
every 3-week dosing schedule. The reason for interruption must be documented in the 
participant’s study record.
Capecitabine
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 or a meal, with 
approximately 200 ml of water. Please refer to the product label for additional guidance on 
administration procedures for capecitabine. Note that if a participant is dosed later in the day, 
it is acceptable for only 1 dose to be taken on Day 1 of the cycle. Dosing 2 times a day may 
resume on Days 2 to 14 and the final dose will be taken in the morning of Day 15.
See also Section 7.1 for additional information on treatments administered.
Discontinuation and Withdrawal
Participants who withdraw consent from the study should be encouraged to complete all 
applicable activities scheduled for the final study visit at the time of withdrawal.
The End of Treatment and Follow-up visit procedures are listed in the SoA (Section 2) and 
Section 9.10 (Visit Requirements). After the end of treatment, each participant will be 
followed for 30 days for AE monitoring (SAEs will be collected for 90 days after the end of 
treatment or 30 days after the end of treatment if the participant initiates new anti-cancer
therapy, whichever occurs first, as described in Section 9.3.1). Participants who discontinue 
for reasons other than disease progression/recurrence will have post-treatment follow-up 
imaging for disease status until disease progression/recurrence, initiating a non-study cancer 
treatment, withdrawing consent, pregnancy, or end of study, whichever occurs first. After 
documented disease progression/recurrence each participant will be followed by telephone 
for OS until death, withdrawal of consent, or the end of the study, whichever occurs first.
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 
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the participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Procedures for Negative Studies Without Safety Concerns
If the study or a study intervention group discontinues due to futility or the study does not 
demonstrate statistically significant efficacy results per protocol-specified analyses without 
any urgent safety issues, one or more of the following actions may occur:

unblinding of the participants’ treatment assignment (see Section 9.1.11 
blinding/unblinding).

stopping treatment with placebo.

discontinuing participants assigned to a specific control group (see Sections 8.1 and 
9.1.9) or study intervention group unless participants are deriving clinical benefit (see 
Section 9.1.11).

participants may be discontinued from parent study and may be enrolled into an 
extension study using pembrolizumab/study intervention if participants are deriving 
clinical benefit.
The investigator or medically qualified designee must inform each participant of these results 
and discuss treatment options.
Participant Blinding/Unblinding
Participants on treatment after IA3 was conducted have been unblinded to study intervention 
to facilitate in a decision by the investigator and participant whether to continue study 
intervention. The investigator may consider continuing study intervention for the participant, 
in consultation with the Sponsor, if the participant is benefitting from the study intervention 
and it is in their best interest to continue (see Section 9.1.10).
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 UNLESS 
NECESSARY.
For emergency situations where the investigator or delegate 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 delegate 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 or delegate must enter the toxicity grade of the adverse events 
observed, the relation to study drug, the reason thereof, etc., in the medical chart.
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Participants whose treatment assignment has been unblinded by the investigator/delegate 
and/or non-study treating physician 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.
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 unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding has 
taken place, the principal investigator, site personnel, and Sponsor personnel may be 
unblinded so that the appropriate follow-up medical care can be provided to the participant.
If there is an adverse event necessitating discontinuation of treatment and unblinding for 
appropriate clinical management of complications: the Sponsor’s Clinical Director must be 
consulted to review the unblinding request documented on the Sponsor consultation form 
(SCF), in order to provide guidance on clinical management and diagnostic procedures. The 
emergency unblinding call center will not perform these intentional unblinds. The 
investigator must use the IRT system. Once an intentional unblinding has taken place, the 
investigator, site personnel, and Sponsor personnel may be unblinded so that the appropriate 
follow-up medical care can be provided to the participant.
In the event of disease progression/recurrence with discontinuation from protocol treatment 
and unblinding required for participant(s) considered for enrollment on an alternate 
immuno-oncologic protocol that requires knowledge of prior treatment with pembrolizumab:
prior to unblinding, the Sponsor’s Clinical Director must be consulted to review the 
unblinding request documented on the Sponsor Consultation Form (SCF). The emergency 
unblinding call center will not perform these intentional unblinds. The investigator must use 
the IRT system. Once an intentional unblinding has taken place, the investigator, site 
personnel, and Sponsor personnel may be unblinded so that the appropriate follow-up 
medical care can be provided to the participant.
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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Efficacy Assessments
Tumor Scans and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
The process for scan collection and transmission to the iCRO can be found in the Site 
Imaging Manual. Tumor scans are strongly preferred to be acquired by CT. Magnetic 
resonance imaging should be used only when CT is contraindicated or for scan of the brain. 
The same scan technique regarding modality and the use of contrast should be used in a 
participant throughout the study to optimize the visualization of existing and new tumor 
burden. 
All scans used to assess tumor burden from the sites will be sent to the iCRO.
Note: The exact same scan acquisition and processing parameters should be used throughout 
the study.
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
randomization. These scans will be considered the baseline assessment for the study. Chest, 
abdomen, and pelvis are to be scanned.
Scans performed as part of routine clinical management are acceptable for use as the baseline 
scan if they are of diagnostic quality, include all required anatomy, and performed within 
28 days prior to randomization.
Tumor Scans During the Study
The first on-study scan will be performed after completion of 3 cycles of pre-operative 
therapy, at approximately 9 weeks (± 7 days) after the first dose of study treatment, before 
surgery (or earlier if clinically indicated). If there is a delay in the pre-operative treatment, 
the scan should be delayed until completion of pre-operative treatment. Participants who 
undergo surgery will have a post-surgery baseline scan. For participants who continue into 
the adjuvant treatment phase, the post-surgery baseline scan must be completed within 
2 weeks prior to the first dose of the adjuvant treatment. Participants who undergo surgery 
are followed by scans every 12 weeks (± 7 days) from the post-surgery baseline scan. During 
the post-operative adjuvant phase, scans will be performed with assessments based on 
disease recurrence. Two years (24 months) after the date of the post-surgery baseline scan, 
the scan schedule will be reduced to every 24 weeks (± 7 days). 
Participants who do not undergo surgery will be followed by scans every 12 weeks (± 7 days)
from the post-neoadjuvant scan. The schedule will be reduced to every 24 weeks (± 7 days), 
2 years after the post-neoadjuvant scan. 
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Scan timing after the first on-study assessment should follow calendar days and should not be 
adjusted for delays in cycle starts. Scans should continue to be performed until disease 
progression/recurrence, the start of new anti-cancer treatment, withdrawal of consent, or 
death, whichever occurs first. 
Partial response, complete response, or disease recurrence will be evaluated per RECIST 1.1
[Eisenhauer, E. A., et al 2009].
Participants may continue treatment and follow the regular scan schedule intervals until 
documented disease progression/recurrence, the start of new anti-cancer treatment, 
withdrawal of consent, death, or the end of the study, whichever occurs first. If indicated, 
repeat scans to confirm progression may be performed at least 4 weeks after site assessed 
first radiologic evidence of PD in clinically stable participants (per irRECIST). Participants 
who have confirmed disease progression, as assessed by the site, may discontinue study
treatment as clinically appropriate. Exceptions are detailed in Section 9.2.1.5.
End of Treatment and Follow-up Tumor Scans
For participants who discontinue study treatment early (before completing 14 cycles of 
treatment), tumor scans should be performed at the time of treatment discontinuation (±4 
week window). If a previous scan was obtained within 4 weeks prior to the date of 
discontinuation, then scan at treatment discontinuation is not mandatory. 

For participants who discontinue study treatment due to documented disease 
progression/recurrence, this is the final required tumor scan. 

For participants who discontinue study treatment without documented disease 
progression/recurrence, every effort should be made to continue monitoring disease 
status by tumor scan until disease progression/recurrence, initiating a non-study 
cancer treatment, withdrawing consent, pregnancy, or end of study, whichever occurs 
first.  
-If a previous scan was obtained within 4 weeks of treatment discontinuation, a 
new scan is not needed. The participant can continue on the same scan schedule 
used while on treatment. (See section 9.2.1.2)
-If the participant has a new scan at the time of treatment discontinuation, this will 
serve as the end of treatment scan. The scan schedule will reset and continue
every 12 weeks (± 7 days) after the end of treatment scan until 2 years after the 
post-surgery scan or the post-neoadjuvant scan (depending on whether the 
participant had surgery), after that the schedule will be reduced to every 24 weeks 
(± 7 days).
RECIST 1.1 Assessment of Disease
CT scan or MRI will be performed for assessment of disease progression/recurrence. 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
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disease progression/recurrence, and as a basis for all protocol guidelines related to disease 
status (eg, discontinuation of study therapy).
If indicated, biopsy confirmation of recurrent lesions will be performed.
All scans used to assess tumor burden should be submitted to the iCRO for disease 
evaluation centrally.
irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. irRECIST will be used by the site 
investigator/local radiology reviewers to assess tumor response and progression and make 
treatment decisions. These data will be collected in the clinical database. In this study, 
irRECIST will only be applied for disease evaluation during the neoadjuvant phase and 
continued throughout treatment for those participants who did not proceed to surgery. 
If applicable to the assessment of the participant, study treatment should not be discontinued 
until progression is confirmed by the local site investigator/radiology assessment and after 
discussion with the Sponsor. 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. Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing nontarget lesion(s)

Development of new lesion(s)
For participants who have shown initial evidence of radiological PD by RECIST 1.1, it is at 
the discretion of the PI whether to continue a participant on study medication until repeat 
scans are obtained (using irRECIST for participant management (see Table 13). This clinical 
judgment decision by the site investigator should be based on the participant’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data. 
Participants may receive study medication and the tumor assessment should be repeated 
≥4 weeks later in order to confirm PD by irRECIST per site assessment. Clinical stability is 
defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values

No decline in ECOG performance status 

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
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Any participant deemed clinically unstable should be discontinued from study treatment at 
first radiologic evidence of PD and is not required to have repeat scans for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and nontarget lesions, as well as any 
incremental new lesion(s).
Disease progression will be considered to be “not confirmed” at repeat scan if ALL of the 
following occur (as assessed by irRECIST):

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved 

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat scan does not confirm PD per irRECIST as assessed by the local site investigator 
and the participant continues to be clinically stable, treatment may continue and follow the 
regular scan schedule. 
Disease progression will be considered to be “confirmed” at repeat scan if ANY of the 
following occur (as assessed by irRECIST):

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If repeat scan confirms PD due to any of the scenarios listed above, participants will be 
discontinued from study therapy.
NOTE: If a participant has confirmed radiographic progression (i.e., 2 scans at least 4 weeks 
apart demonstrating PD) per irRECIST, but the participant is achieving a clinically 
meaningful benefit, and there is no further increase in the tumor burden at the confirmatory 
tumor scan, an exception to continue treatment may be considered following consultation 
with the Sponsor. In this case, if treatment is continued, tumor scan should continue to be 
performed following the intervals as outlined in the SoA (Section 2) and be submitted to the 
iCRO.
Additional details about irRECIST are provided in MSD TIP Sheet for RECIST 1.1 and 
irRECIST. 
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Table 13 Scan and Treatment After First Radiologic Evidence of Progressive Disease for 
Participants Receiving Protocol Treatment
Clinically Stable
Clinically Unstable
Scan
Treatment
Scan
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 
Repeat scan at 
4 weeks at site to 
confirm PD
May continue study
treatment at the local 
site investigator’s 
discretion while 
awaiting 
confirmatory tumor 
scan by site by 
irRECIST.
Repeat scan at 
4 weeks to 
confirm PD per 
site investigator 
discretion only
Discontinue 
treatment
Repeat tumor scan
confirms PD by 
irRECIST at the 
local site
No additional 
scan required
Discontinue 
treatment (exception 
is possible upon 
consultation with 
Sponsor)
No additional 
scan required
Not applicable
Repeat tumor scan
shows SD, PR, or 
CR by irRECIST 
at the local site
Continue 
regularly 
scheduled scan
every 9 weeks 
during 
neoadjuvant 
phase and every 
12 weeks during 
adjuvant phase
Continue study
treatment at the local 
site investigator’s 
discretion
Continue 
regularly 
scheduled scan
every 9 weeks 
during 
neoadjuvant 
phase and every 
12 weeks during 
adjuvant phase
May restart study
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor scan should 
occur according to 
the regular scan
schedule
CR=complete response; irRECIST=immune-related response evaluation criteria in solid tumors; PD=progressive disease; 
PR=partial response; SD=stable disease.
Surgery
Within 3 to 9 weeks following Cycle 3 Day 1 of the neoadjuvant treatment phase or early 
discontinuation of neoadjuvant treatment, participants will undergo surgery. The standard 
surgical procedure for this study will be a D2 or D1+ gastrectomy (refer to the Surgical 
Brochure for details).
Adjuvant treatment will begin within 4 to 10 weeks post-surgery and will not occur unless 
participants are adequately recovered to restart chemotherapy. If additional recovery time is 
required, this may be discussed with the Sponsor using a SCF. This is standard practice for
the use of peri-operative chemotherapy in patients after gastrectomy or 
esophagogastrectomy. Details regarding date of surgery, type of surgery, tumor resectability, 
tumor margins, AEs occurring during the surgical period, etc. will be recorded in the 
appropriate eCRF. Detailed pathological staging and assessment of surgical margins will be 
performed by the local pathologist on all the tissues removed during the surgery and recorded 
in the appropriate eCRF.
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Pathological Evaluation of Surgically Resected Tumor Tissue
The specimen submitted to the local pathologist must include an entire surgically resected 
lesion or scar tissue and all resected lymph nodes as per guidelines provided in the Surgical 
Brochure. If gross viable tumor is present, a minimum of 5 sections of the tumor in the mass 
lesion should be evaluated. In order to assess the esophagogastrectomy resection, a 
photograph with the gross lesion must be included. A pathological complete response is 
defined as 100% fibrosis or fibroinflammation within an entire gross lesion without 
microscopic evidence of carcinoma, and no positive lymph nodes. The grading of pathologic 
response will follow the Mandard scale [Mandard, A. M., et al 1994].
The tumor response will be graded from 1 to 5 as follows: 
Grade 1: complete regression/fibrosis with no evidence of tumor cells (100% treatment 
response)
Grade 2: fibrosis with scattered tumor cells (>90% treatment response with <10% viable 
residual tumor)
Grade 3: fibrosis and tumor cells with a dominance of fibrosis (>75% treatment response 
with <25% viable residual tumor)
Grade 4: fibrosis and tumor cells with a dominance of tumor cells (<50% treatment 
response with >50% viable residual tumor)
Grade 5: tumor without evidence of regression (<10% treatment response with >90% 
viable residual tumor)
Pathological Complete Response
pathCR is defined as having no invasive disease within an entirely submitted and evaluated 
gross lesion, and histologically negative nodes. The primary evaluation of pathCR will be 
conducted by the local pathologists. All the samples that local pathologists consider as 
pathCR will be sent to the central laboratory and will be confirmed by central pathologists 
microscopically. The central pathologist’s assessment will overrule the local pathologist’s 
assessment in terms of pathCR if they are different. The samples that local pathologists 
consider as non-pathCR will not be sent to central laboratory.
In all cases, the site pathologists interpreting surgical specimens for assessment of pathCR 
will be blinded to treatment assignment. The site pathologists will complete a form from the 
pathCR vendor that includes information about the operative procedure and surgical margins. 
A photograph or diagram or radiograph of the entire surgically resected specimen will also be 
submitted. The guidelines for submission of specimens to the central reviewer will be 
provided in the Procedures manual.
For participants who do not achieve a pathCR, a tumor tissue sample should be collected and 
submitted to the designated central laboratory for translational research as specified in 
Section 5.4.1.4 – Planned Exploratory Biomarker Research. Any leftover tissue will be 
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archived for future biomedical research (FBR) if the participant has signed the optional 
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Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation/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 
allocation/randomization through 180 days following the last dose of chemotherapy 
or through 120 days following the last dose of pembrolizumab, whichever is greater;
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or through 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 timeframes as indicated in Table 14.
Participants Who Enter the Separate Extension Study:
From the time of treatment allocation/randomization in this study through the signing of the 
informed consent to the extension study, all AEs, SAEs, and other reportable safety events 
must be reported by the investigator in this protocol (ie, the parent study). Laboratory values 
that meet criteria for reporting as AEs performed during the parent study will be collected in 
the parent study.
Note: Once consented to the extension study, AEs and other reportable events meeting the 
criteria of the extension study, including those considered related to study intervention, will 
be collected in the extension study.
Table 14 Reporting Time Periods and Timeframes for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
Specified Follow-
up Period
Reporting 
Time Period:
After the 
Protocol 
Specified 
Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
Specified Follow-
up Period
Reporting 
Time Period:
After the 
Protocol 
Specified 
Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Serious Adverse 
Event (SAE)
including Cancer 
and Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event 
unless the participant 
has received study 
intervention
Report all
Previously 
reported –
Follow to 
completion/ter
mination; report 
outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential DILI
- Require 
regulatory reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 
calendar days
of learning of 
event
Method of Detecting AE, SAE and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
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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, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE
●
Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study 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 Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) 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 Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
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 Appendix 4. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data
are monitored to safeguard the participants in the study. 
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
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reported to the investigator or their designee), including the pregnancy of a male participant’s 
female partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus. 
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) 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 9.4 – Treatment of Overdose, 
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).
Treatment of Overdose
For the study medications (other than pembrolizumab), an overdose will be defined as any 
dose ≥20% of the prescribed dose per cycle. The treatment of an overdose of the study 
medications (other than pembrolizumab) should follow the prescribed information in the 
approved product labels or local guidelines.
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab of 1000 mg or greater (≥5 times the indicated dose). No specific 
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information is available on the treatment of overdose of pembrolizumab. In the event of 
overdose, should be discontinued and the participant should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
Safety
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. A complete physical examination will be conducted as per institutional 
standard. Height and weight will also be measured and recorded; height will be measured at 
Visit 1 only. 
Clinically significant abnormal findings should be recorded as medical history. The time 
points for full physical exams are described in the SoA (Section 2). After the first dose of 
study treatment, new clinically significant abnormal findings should be recorded as AEs.
Directed Physical Exam
For cycles that do not require a full physical exam as defined in the SoA (Section 2), the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to the administration of the study treatment. A brief directed physical 
examination will be conducted as per institutional standard. New clinically significant 
abnormal findings should be recorded as AEs.
Vital Signs
Vital signs include temperature, pulse, respiratory rate, weight and blood pressure. The 
investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of study treatment and during the follow-up period as specified in the SoA
(Section 2).
Electrocardiograms
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures once at screening. Clinically significant abnormal findings should be recorded as 
medical history. Additional time points may be performed as clinically necessary.
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Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG status (see Section 12.5, 
Appendix 5) at screening, prior to dosing on Day 1 of each treatment cycle and at 
discontinuation of study treatment, as specified in the SoA (Section 2).
Clinical Safety Laboratory Assessments
Refer to Appendix 6 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant’s condition.
●
All protocol-required laboratory assessments, as defined in Appendix 6, must be 
conducted in accordance with the laboratory manual and the SoA.
●
If laboratory values from non-protocol 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. 
Details regarding specific laboratory procedures/assessments to be performed in this study
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from pre-study to post-study visits), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per participant can be found in the 
Procedures Manual. Refer to the SoA (Section 2) for the timing of laboratory assessments.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 6.
All laboratory tests will be performed by local laboratories on the days and cycles indicated 
in the SoA (Section 2). Prior to the first dose of study treatment, screening laboratory tests 
must be performed within 10 days. After neoadjuvant Cycle 1, pre-dose laboratory safety 
tests can be collected up to 72 hours prior to dosing unless otherwise noted on the SoA 
(Section 2). 
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Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of study treatment. Unresolved abnormal laboratory 
values that are drug-related AEs should be followed until resolution. Laboratory tests do not 
need to be repeated after the end of treatment if laboratory results are within the normal 
range.
Pregnancy Test
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted prior 
to every cycle and at the end of relevant systemic exposure for all arms. Pregnancy testing 
([urine or serum] as required by local regulations) should be conducted according to Section 2
(SoA) and at the end of relevant systemic exposure for all arms.
-
Pregnancy testing requirements for study inclusion are described in Section 6.1.
-
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
at monthly intervals during treatment.
-
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
for at least 30 days after the last dose of study treatment.
-
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.
Pharmacokinetics
PK parameters will not be evaluated in this study.
Pharmacodynamics
There will be no blood collection for anti-pembrolizumab antibody detection. Collection of 
samples for biomarker analyses is described in Section 9.8.
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA. Sample 
collection, storage, and shipment instructions for the exploratory biomarker specimens will 
be provided in the laboratory manual.

Blood for genetic analysis

Blood for RNA analyses

Blood for serum biomarker analyses
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
Blood for circulating tumor DNA (ctDNA)

Archived or newly obtained tissue collection for biomarker testing
Biomarker sample collection for participants enrolled in China will be dependent on approval 
by the Human Genetic Resources Administration of China.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual.
Samples are to be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/IEC does not approve) sample collection for these purposes, then such samples are 
not to be collected at the corresponding sites. Leftover DNA extracted from planned genetic 
analysis samples will be stored for FBR only if participant provides documented informed 
consent for FBR.
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
following specimens will be obtained as part of future biomedical research:

DNA for future research

Leftover serum from biomarker analyses

Leftover RNA

Leftover plasma from ctDNA

Leftover tumor tissue
Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA). Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Prior to treatment randomization, potential participants will be evaluated to determine that 
they fulfill the entry requirements as set forth in Section 6.1 and Section 6.2. Tumor staging 
prior to enrollment will include Lauren histological classification. Visit requirements and 
screening phase windows are outlined in the SoA (Section 2). Screening procedures may be 
repeated.
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Documented informed consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame. 
Participants may be rescreened once after initially failing to meet the inclusion/exclusion 
criteria. Results from assessments performed during the initial screening period are 
acceptable in lieu of a repeat screening test if performed within the specified time frame and 
the inclusion/exclusion criteria is met. Participants who are rescreened will retain their 
original screening number.
Treatment Period Visit
Visit requirements are outlined in the SoA (Section 2). Specific procedure-related details are 
provided in Section 9. 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.
Post-treatment Follow-up
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 initiation of a new anti-cancer treatment, whichever 
comes first. 
Efficacy Follow-up Visits
Participants who discontinue study treatment for a reason other than disease 
progression/recurrence will move into Efficacy Follow-up and should be assessed every 
12 weeks (72 ±7 days) by scan until disease progression/recurrence to monitor disease status.
Participants should remain on the same scan schedule used while on treatment. For 
participants that have had surgery, scans should be performed every 12 weeks (±7 days) until 
2 years after the date of the post-surgery baseline scan, when the scan schedule will be 
reduced to every 24 weeks (±7 days). For participants that do not have surgery, scans should 
be performed every 12 weeks (±7 days) until 2 years after the date of the post-neoadjuvant 
treatment scan, when the scan schedule will be reduced to every 24 weeks (±7 days) (See 
Section 9.2.1.3 for additional information). Every effort should be made to collect 
information regarding disease status until disease progression/recurrence, 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). Participants who 
complete all efficacy assessments and/or will not have further efficacy assessments must 
enter Survival Follow-up.
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Survival Follow-up Assessments
Participant survival follow-up contact will occur approximately every 12 weeks to assess for 
survival status until death, withdrawal of consent, or the end of the study, whichever occurs 
first.
The first survival follow-up assessment should be scheduled as described below:
1. For participants who discontinue treatment and who will not enter the Efficacy 
Follow-up Phase, the first survival follow-up contact will be scheduled 12 weeks after 
the Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
2. For participants who completed assessments in the Efficacy Follow-up Phase, the first 
survival follow-up contact will be scheduled 12 weeks after the last efficacy 
assessment follow-up visit has been performed.
Vital Status
To ensure current and complete vital status for survival data is available at the time of 
database locks, updated vital status for survival data may be requested during the study by 
the Sponsor. For example, updated vital status for survival data may be requested prior to but 
not limited to: an external DMC review, interim analysis (IA), and/or final analysis (FA). 
Upon Sponsor notification, all participants who do not/will not have a scheduled study visit 
or study contact during the Sponsor defined time period will be contacted for their vital status 
for survival data (excluding participants that have a previously recorded death event in the 
collection tool).
10. Statistical Analysis Plan
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to unblinding, will be documented in a 
supplemental statistical analysis plan (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study. Post hoc exploratory analyses will be clearly identified in the CSR.
Details pertaining to the statistical analyses for participants who will be potentially enrolled 
in a possible China extension will be provided in a separate sSAP.
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Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 10.2 through 10.12.  
Study Design Overview
A Phase III, Randomized, Double-blind Clinical Trial of Pembrolizumab 
(MK-3475) plus Chemotherapy (XP or FP) versus Placebo plus Chemotherapy 
(XP or FP) as Neoadjuvant/Adjuvant Treatment for Gastric and
Gastroesophageal Junction (GEJ) Adenocarcinoma (KEYNOTE-585).
Treatment Assignment
Main study (XP/FP):
Approximately 800 participants will be randomized in the main study in a 1:1 
ratio to receive pembrolizumab (MK-3475) plus chemotherapy (XP/FP) or 
placebo plus chemotherapy (XP/FP). The main study (XP/FP) is 
double-blinded. 
FLOT Cohort:
Approximately 200 participants will be randomized in a 1:1 ratio to receive 
pembrolizumab plus FLOT or placebo plus FLOT. The FLOT Cohort is 
double blinded.
Stratification factors are: 1) Geographic regions: (Asia versus Non-Asia), 2) 
Tumor staging: II versus III versus IVa, and 3) Backbone chemotherapy 
XP/FP versus FLOT.
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoints
Main study (XP/FP): 

Event-free Survival (EFS) assessed by investigators

Rate of Pathological Complete Response (pathCR)

Overall Survival (OS)
FLOT Cohort:

AEs; Study treatment discontinuations due to AEs
Secondary Endpoints
Main study (XP/FP):

Disease-free Survival (DFS) assessed by investigators

AEs; Study treatment discontinuations due to AEs
Main study (XP/FP) and FLOT Cohort Combined: 

Overall Survival (OS)

Event-free Survival (EFS) assessed by investigators

AEs; Study treatment discontinuations due to AEs
Statistical Methods for 
Key Efficacy Analyses
The primary hypothesis for EFS and OS will be evaluated by comparing 
pembrolizumab (MK-3475) plus chemotherapy (XP/FP) to placebo plus 
chemotherapy (XP/FP) using a stratified log-rank test. Estimation of the 
hazard ratio will be done using a stratified Cox regression model. Event rates 
over time will be estimated within each treatment group using the 
Kaplan-Meier method. Treatment comparison of the pathCR rates will be 
performed using the stratified Miettinen and Nurminen method in the Main 
Study (XP/FP).
Same methods will be used for the analysis of OS and EFS in the Main Study
(XP/FP) and the FLOT Cohort combined as secondary hypotheses too. 
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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 M&N method [Miettinen, O. and Nurminen, M. 1985].
Interim Analysis (IA)
 Results will be reviewed 
by an external DMC. Details are provided in Section 10.7. 
Multiplicity
The overall type I error over the primary and secondary endpoints (OS, EFS 
and pathCR rate) is strongly controlled at 2.5% (one-sided), 
 
By using the graphical approach of Mauer and Bretz [Maurer, W. and Bretz, F. 
2013], if one hypothesis is rejected, the alpha will be shifted to other 
hypotheses.
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Sample Size and Power 
The planned sample size is approximately 800 participants in the Main Study 
(XP/FP), and approximately 200 in the FLOT Cohort.  
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 or scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS.
Planned efficacy interim analyses are described in Section 10.7. Blinding to treatment 
assignment will be maintained at all investigational sites.
Treatment-level results of the interim analysis will be provided by the unblinded external 
statistician to the external DMC, which will review the safety and/or efficacy data. Limited 
additional Sponsor personnel may be unblinded to the treatment level results of the interim 
analysis (analyses), if required, in order to act on the recommendations of the DMC. The 
extent to which individuals are unblinded with respect to results of interim analyses will be 
documented in the DMC charter (see Appendix 1). 
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The DMC will serve as the primary reviewer of the interim analyses and will make 
recommendations for discontinuation of the study or modification to an executive oversight 
committee of the Sponsor. Depending on the recommendation of the DMC, the Sponsor may 
prepare a regulatory submission. If the DMC recommends modifications to the design of the 
protocol or discontinuation of the study, this executive oversight committee may be 
unblinded to results at the treatment level in order to act on these recommendations. 
Additional logistical details, revisions to the above plan and data monitoring guidance will be 
provided in the DMC Charter (see Appendix 1).
Treatment-level results (only safety data) from the FLOT Safety Cohort will be provided by 
the unblinded external statistician to the siDMC, which will review the data to determine if 
the FLOT regimen may be incorporated as one of the standard of care chemotherapy 
backbones in the main study. As above, limited additional Sponsor personnel may be 
unblinded to the treatment-level results of these analyses if required, in order to act on the 
recommendations of the siDMC. The extent to which individuals are unblinded with respect 
to results of these analyses will be documented. Further details on the processes by which 
recommendations and decisions are reached and communicated will be documented in the 
siDMC charter (see Appendix 1). 
As of Amendment 06, the FLOT Safety Cohort will be expanded to 200 participants to 
further characterize the safety profile of the combination of FLOT with pembrolizumab and 
will be designated the FLOT Cohort. Future interim analyses of the FLOT Cohort data will 
be monitored by the external DMC. As above, limited additional Sponsor personnel may be 
unblinded to the treatment level results of the interim analysis (analyses), if required, in order 
to act on the recommendations of the DMC. The extent to which individuals are unblinded 
with respect to results of interim analyses will be documented in the DMC charter (see 
Appendix 1). 
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.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4. 
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Analysis Endpoints
Efficacy Endpoints
Primary

Event-free survival (EFS) based on RECIST 1.1 as assessed by the investigator.
EFS is defined as the time from randomization to the first of the following events:

Radiographic disease progression per RECIST 1.1 

Local or distant recurrence as assessed by CT scan or biopsy if indicated (for 
participants who are disease free after surgery)

Clinical progression as evidenced by peritoneal carcinomatosis confirmed by pre-
operative laparoscopy or laparotomy (for participants who are confirmed to be free 
of peritoneal involvement by laparoscopy at screening)

Death due to any cause
A second primary malignancy is not considered as an EFS event.
Radiographic PD during the neoadjuvant phase that does not preclude successful 
surgery (ie, disease free after surgery) is not considered as an EFS event.
For participants with documented peritoneal carcinomatosis found prior to surgery (as 
evidenced by pre-operative laparoscopy or laparotomy) but without radiographic PD
during the neoadjuvant phase and do not undergo screening laparoscopy, EFS data 
will be censored as of the time of the pre-operative laparoscopy or laparotomy. See 
Section 10.6.1.1 for the definition of censoring.

Pathological Complete Response (pathCR) Rate: pathCR rate is defined as the 
proportion of participants having pathCR. Pathologic complete response (pathCR) is 
defined as no invasive disease within an entirely submitted and evaluated gross 
lesion, and histologically negative nodes. 

Overall survival (OS) is defined as the time from randomization to death due to any 
cause. Participants without documented death at the time of analysis will be censored 
at the date of last known alive.
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Secondary

Disease-free survival (DFS) based on RECIST 1.1 as assessed by investigator. DFS is 
defined as the time from post-surgery baseline scan until the first occurrence of:

Local or distant recurrence;

Death from any cause.
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, AEs leading to discontinuation, SAEs, fatal AEs, physical examination, vital signs, 
ECOG performance status, and lab values. Furthermore, specific events will be collected and 
designated as ECIs as described in Section 9.3.7.
Patient-Reported Outcome Endpoints
Health-related QoL assessments using the EORTC QLQ-C30 and EORTC QLQ-STO22;
utility assessments using EQ-5D 5L.
Analysis Populations
Extension Portion of the Study in China
After the sample size required for the Global portion is reached, the study may remain open 
to randomize participants in China until the sample size for the Chinese participants meets 
the target for China. The Chinese participants randomized after the enrollment of the Global 
portion is closed will not be included in the primary analysis population which is based on 
the Global portion. The China portion will also be analyzed separately per local regulatory 
requirement. 
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for OS, EFS and pathCR 
rate. All randomized participants will be included in this population. Participants will be 
included in the treatment group to which they are randomized. ITT population consists of all 
randomized participants whether or not treatment was administered. Any participant who 
receives a randomization number will be considered to have been randomized.
DFS analysis population will be those participants who are disease free at the post-surgery 
baseline scan.
Details on the approach to handling missing data are provided in Section 10.6, Statistical 
Methods.
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Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety 
data. The APaT population consists of all randomized participants who received 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 cycle but receives the correct 
treatment for all other cycles will be analyzed according to the correct treatment group and a 
narrative will be provided for any events that occur during the cycle for which the participant 
is incorrectly dosed. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 10.6 Statistical Methods.
Patient-reported Outcome Analysis Populations
Patient-reported Outcome analyses are based on the PRO Full Analysis Set (FAS) 
population, defined as participants who have at least one PRO assessment available and have 
received at least one dose of study treatment.
Statistical Methods
Statistical Methods for Efficacy Analyses
In this section, for the stratified analyses, small strata may be collapsed. Additional details 
will be provided in the sSAP.
Event-free Survival (EFS)
The non-parametric Kaplan-Meier method will be used to estimate the EFS curve in each 
treatment group. The treatment difference in EFS will be assessed by the stratified log-rank 
test and the p-value will be provided. 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 groups. The HR and its 95% CI from the stratified 
Cox model for the treatment covariate will be reported. The stratification factors used for 
randomization (see Section 7.3.1) will be applied to both the stratified log-rank test and the 
stratified Cox model. In case of small strata, the stratification factors will be combined in 
stratified analysis and details will be provided in the sSAP.
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For the primary analysis of EFS as assessed by investigators, the true date of disease 
progression/recurrence will be approximated by the date of the first assessment at which 
event is objectively documented, regardless of discontinuation of study drug, missed study 
visits, or initiation of new anti-cancer therapy. Participants who do not experience an event at 
the time of analysis will be censored at the last disease assessment. As a sensitivity analysis, 
this same approach will also be applied to analysis of EFS as assessed by BICR. Sensitivity 
analyses may be conducted using different censoring rules and will be documented in the 
sSAP.
Pathological Complete Response (pathCR) Rate
The stratified Miettinen and Nurminen’s method with strata weighted by sample size will be 
used for the comparison of pathCR rates between pembrolizumab with chemotherapy
(XP/FP) and chemotherapy alone. The stratification factors used for randomization (see 
Section 7.3.1) will be applied. In case of small strata, the stratification factors will be 
combined in stratified analysis and details will be provided in the sSAP.
Overall Survival (OS)
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 measured by the hazard ratio (HR). The HR and its 
95% CI from the Cox model for the treatment covariate will be reported. The stratification 
factors used for randomization (See Section 7.3.1) will be applied to both the stratified log-
rank test and the stratified Cox model. In case of small strata, stratification factors will be 
combined to ensure a sufficient number of events in each stratum.  Details regarding the 
combining of strata will be specified in the sSAP prior to database lock for any efficacy 
interim or final analysis based on a blinded review of event counts by stratum. Participants 
without documented death at the time of analysis will be censored at the date the participant 
was last known to be alive.
Analysis Strategy for Key Efficacy Variables
Table 15 the primary analysis approach for key efficacy endpoints.
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Table 15 Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable 
(Description, 
Time Point)
Statistical Method†
Analysis 
Population
Missing Data Approach
EFS
Test: stratified Log-rank test 
Estimation: stratified Cox 
model with Efron’s tie 
handling method
ITT

Primary censoring rule 

Sensitivity analysis 
(More details provided in
the sSAP)
pathCR rate
Stratified M&N method
ITT*
Participants with relevant 
data missing are considered 
non-responders
OS
Test: stratified Log-rank test 
Estimation: stratified Cox 
model with Efron’s tie 
handling method 
ITT
Censored at last known alive 
date 
EFS=event-free survival; ITT=intention to treat; OS=overall survival
†Statistical models are described in further detail in the text. For stratified analyses, the stratification factors 
used for randomization (See Section 7.3.1 – Stratification) will be applied to the analysis model. In case of 
small strata, the stratification factors will be combined in stratified analysis and details will be provided in 
the sSAP.
*For IA1 in Section 10.7 pathCR rate analysis, participants randomized at least 6 months before the data 
cutoff will be included.
Disease-free Survival (DFS)
The non-parametric Kaplan-Meier method will be used to estimate the DFS curve for each 
treatment group. 
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, etc.
Adverse Events
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Activities (MedDRA) and grouped system organ class. AEs will be graded by the 
investigator according to the CTCAE, version 4.0.
The analysis of safety results will follow a tiered approach as shown in Table 16. The tiers 
differ with respect to the analyses that will be performed. 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 
groups in this study. Based on the safety knowledge accumulated across the program to date, 
there are no events that warrant consideration for Tier 1. 
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Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event. The threshold of at least 10% of participants was chosen for Tier 2 events because 
the population enrolled in this study is in critical condition and usually experiences various 
AEs of similar types regardless of treatment; events reported less frequently than 10% of 
participants would obscure the assessment of the overall safety profile and add little to the 
interpretation of potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs 
(≥5% of participants in 1 of the treatment groups) and SAEs (≥2% of participants in 1 of the 
treatment groups) will be considered Tier 2 endpoints. Because many 95% CIs may be 
provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in safety review, not as a formal method for assessing the 
statistical significance of the between-group differences.
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Table 16 Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
AEs (≥10% of participants in one of the treatment 
groups)
X
X
Grade 3-5 AEs (≥5% of participants in one of the 
treatment groups)
X
X
SAEs (≥2% of participants in one of the treatment 
groups)
X
X
Tier 3
Any AE 
X
Any Serious AE
X
Any Grade 3-5 AE
X
Any Drug related AE
X
Any Serious and Drug related AE
X
Any Grad 3-5 and Drug related AE
X
Discontinuation due to AE
X
Any AE leading to death
X
Specific AEs, SOCs (incidence <10% of participants 
in all of the treatment groups)
X
Change from baseline results (laboratory test toxicity 
grade, vital signs)
X
AE=adverse event; CI=confidence interval; SAE=serious adverse event; SOC=system organ class; X = 
results will be provided.
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Statistical Methods for Patient-reported Outcome Analyses
Methods related to the exploratory objectives addressing PROs will be described in the 
sSAP.
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.
Interim Analyses
Both efficacy and safety results will be reviewed by an external DMC. The timing of safety 
reviews will be documented in the DMC Charter based on consultation with external DMC 
members.
 
 
 
 
. Details of the multiplicity strategy for group sequential design are provided 
in Section 10.8.
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Multiplicity
The multiplicity strategy specified in this section will be applied to the primary and 
secondary hypotheses including EFS in the Main Study (XP/FP) (H1), pathCR rate in the 
Main Study (XP/FP) (H2), OS in the Main Study (XP/FP) (H3), OS in Main Study (XP/FP) 
and FLOT Cohort combined (H4), and EFS in the Main Study (XP/FP) and FLOT Cohort 
combined (H5), respectively. The graphical approach of Maurer and Bretz [Maurer, W. and 
Bretz, F. 2013] will be taken to strongly control the overall Type I error rate for testing of 
multiple endpoints at 2.5% 1-sided. See Figure 3 for the multiplicity strategy diagram of the 
study. The weights for re-allocation from each hypothesis to the others are shown in the 
boxes on the lines connecting hypotheses. For EFS and OS hypotheses, the Lan-DeMets 
O'Brien-Fleming approximation alpha spending function is used to control multiplicity for 
the interim analyses and final analysis.
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To account for any multiplicity concerns raised by the DMC review of unplanned efficacy 
data when prompted by safety concerns, a sensitivity analysis for OS will be pre-specified in 
the sSAP. This analysis will be 
 
Event-free Survival
Figure 3 shows that the EFS hypothesis in the Main Study (XP/FP) (H1)
 
 
 
 
 
 
 
 
 
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Overall Survival
Figure 3 shows that the 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Pathological Complete Response
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Sample Size and Power Calculations
The main study (XP/FP) will randomize approximately 800 participants in a 1:1 ratio 
between the 2 groups while the FLOT Cohort will randomize approximate 200 participants in 
a 1:1 ratio as well.
Main Study (XP/FP)
PathCR rate:
The pathCR rate analysis will be performed at IA1. Participants randomized in the Main 
Study (XP/FP) at least 6 months before the IA1 data cutoff will be included in pathCR rate 
analysis.
It is estimated that ~800 participants in the Main Study will be included. 
EFS:
The final analysis of EFS 
 
 
 
 
 
 
 
OS: 
If EFS in the Main Study (XP/FP) (H1) is rejected, 
 
 
 
 
 
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All sample size and power calculations were performed using the R software package 
gsDesign.
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS and EFS (with a nominal 95% CI) will be estimated 
and plotted within each category of the following classification variables: 

Geographic region (Asia versus Non-Asia)

Tumor staging (II versus III versus IVa)

Tumor location (Stomach versus GEJ)

PD-L1 (+ versus -)

Age category (<65 versus ≥65 years)

Gender (Male versus Female)

Race (Asian versus Non-Asian)

Backbone therapy (FP versus XP [versus FLOT*])
Subgroup analyses will be performed on the Main Study (XP/FP) as well as on the Main 
Study (XP/FP) and FLOT Cohort combined. The consistency of the treatment effect will be 
assessed descriptively via summary statistics by category for the classification variables 
listed above. If the number of participants in a category of a subgroup variable is less than 
10% of the ITT population, the subgroup analysis will not be performed for this category of 
the subgroup variable, and this subgroup variable will not be displayed in the forest plot.
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*Category of FLOT for the subgroup variable of backbone therapy is only applicable to the 
subgroup analyses for the Main Study (XP/FP) and FLOT Cohort combined. 
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in months, number of 
cycles or administrations as appropriate.
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Oncol. 2011 Nov 20;29(33):4387-93.
[04KK7J]
[Semrad, T. J. 2015]
Semrad TJ. ASCO 2015 update on 
gastrointestinal 
cancer: 
Checkpoint 
inhibition, multimodality strategies and 
secondary prevention. Surg Oncol. 2015 
Dec;24(4):371-4.
[04PJW5]
[Sharpe, A. H. and Freeman, 
G. J. 2002]
Sharpe AH, Freeman GJ. The B7-CD28 
superfamily. 
Nat 
Rev 
Immunol 
2002;2(2):116-26.
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[Siegel, R. L., et al 2017]
Siegel RL, Miller KD, Jemal A. Cancer 
statistics, 2017. CA Cancer J Clin. 2017 
Jan;67(1):7-30.
[04MRQC]
[Smalley, S. R., et al 2012]
Smalley SR, Benedetti JK, Haller DG, 
Hundahl SA, Estes NC, Ajani JA, et al. 
Updated analysis of SWOG-directed 
intergroup study 0116: a phase III trial of 
adjuvant 
radiochemotherapy 
versus 
observation after curative gastric cancer 
resection. J Clin Oncol. 2012 Jul 
1;30(19):2327-33.
[04JCWW]
[Stumpf, P. K., et al 2017]
Stumpf PK, Amini A, Jones BL, Koshy M, 
Sher DJ, Lieu CH, et al. Adjuvant 
radiotherapy improves overall survival in 
patients 
with 
resected 
gastric 
adenocarcinoma: A National Cancer Data 
Base 
analysis. 
Cancer. 
2017 
Sep 
1;123(17):3402-3409.
[04S3SL]
[Symmans, W. F., et al 2007]
Symmans WF, Peintinger F, Hatzis C, 
Rajan R, Kuerer H, Valero V, et al. 
Measurement of residual breast cancer 
burden 
to 
predict 
survival 
after 
neoadjuvant chemotherapy. J Clin Oncol 
2007;25(28):4414-22.
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[Talmadge, J. E., et al 2007]
Talmadge JE, Donkor M, Scholar E. 
Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev 
2007;26(3-4):373-400.
[00VMPH]
[Thompson, R. H., et al 2007]
Thompson RH, Dong H, Lohse CM, 
Leibovich BC, Blute ML, Cheville JC, et 
al. PD-1 is expressed by tumor-infiltrating 
immune cells and is associated with poor 
outcome for patients with renal cell 
carcinoma. 
Clin 
Cancer 
Res 
2007;13(6):1757-61.
[00VMNX]
[Torre, L. A., et al 2015]
Torre LA, Bray F, Siegel RL, Ferlay J, 
Lortet-Tieulent J, Jemal A. Global cancer 
statistics, 2012. CA Cancer J Clin. 2015 
Mar;65(2):87-108.
[043HKG]
[Usubütün, A., et al 1998]
Usubütün A, Ayhan A, Uygur MC, Özen 
H, Toklu C, Ruacan S. Prognostic factors 
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[00VMPJ]
[Van Cutsem, E., et al 2006]
Van 
Cutsem 
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Moiseyenko 
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Tjulandin S, Majlis A, Constenla M, Boni 
C, et al. Phase III study of docetaxel and 
cisplatin plus fluorouracil compared with 
cisplatin and fluorouracil as first-line 
therapy for advanced gastric cancer: a 
report of the V325 Study Group. J Clin 
Oncol. 2006 Nov 1;24(31):4991-7.
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[Wolmark, N., et al 2001]
Wolmark N, Wang J, Mamounas E, 
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[Ychou, M., et al 2011]
Ychou M, Boige V, Pignon JP, Conroy T, 
Bouche O, Lebreton G, et al. Perioperative 
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12. Appendices
Appendix 1: Study Governance Considerations
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 (eg, contract research organizations, collaborative research efforts). This Code 
is not intended to apply to trials that are observational in nature, or which are 
retrospective. Further, this Code does not apply to investigator-initiated trials, which are 
not under the full control of MSD.
II.Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven 
to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic indices of 
MSD or comparator products. Alternatively, MSD may conduct outcomes research 
trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to 
address the specific purpose of the trial and shall respect the data protection rights of 
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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 using 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 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 prespecified plans for data analysis. To the extent scientifically appropriate, MSD 
seeks to publish the results of other analyses it conducts that are important to patients, 
physicians, and payers. Some early phase or pilot trials are intended to be hypothesis 
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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.
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C.Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only the 
investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or 
regulatory authorities will have access to confidential medical records that might 
identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
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.
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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.
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (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.
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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/case report form data.  By signing the consent form, the participant 
agrees to this process.  If study documents will be photocopied during the process of 
verifying worksheet/case report form information, the participant will be identified by unique 
code only; full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Committees Structure
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (SAC).  
The SAC comprises 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.
Study Steering Committee
This study will be conducted in consultation with a Study Steering Committee which will 
provide guidance on the operational aspects of the study as needed. The Study Steering 
Committee comprises:
•
Sponsor personnel 
•
Investigators participating in the study
•
Consulting therapeutic-area experts and clinical trialists 
1. Surgical oncologists will provide guidance for standardization of the surgical 
procedure to be used for the treatment of participants on this study, in the form of a 
Surgical Brochure that will accompany the protocol for implementation at all 
participating sites globally
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2. Pathologists will provide guidance for development of a tumor regression grading 
system to evaluate treatment responses and standardized guidelines for the diagnosis 
of pathCR
3. Medical oncologists will provide guidance on the standardization of the therapeutic 
regimen and other aspects of neoadjuvant and adjuvant trials
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
external Data Monitoring Committee (DMC) regarding the study.
Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external Data
Monitoring Committee (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 10.7 -
Interim Analyses) and recommend to the EOC if 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.
To supplement the routine monitoring outlined in this protocol, a separate standing internal 
Data Monitoring Committee (siDMC) will monitor the safety only data from the FLOT 
Safety Cohort. The siDMC comprises members of Sponsor Senior Management, none of 
whom are directly associated with the conduct of this trial.
As of Amendment 06, the FLOT Safety Cohort will be expanded and designated the FLOT 
Cohort. Future interim analyses of the FLOT Cohort will be monitored by the external DMC.
The siDMC will monitor the FLOT Safety Cohort for evidence of adverse effects of trial 
treatment as described in the detailed monitoring guidelines. The siDMC will determine 
whether the FLOT + pembrolizumab/placebo regimen should continue according to the 
protocol and if FLOT can be added as a chemotherapy backbone choice. The siDMC will 
also make recommendations to the Sponsor protocol team regarding steps to ensure both 
participant safety and the continued ethical integrity of the trial.
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Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
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.
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 
participant to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and 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.
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 Good 
Clinical Practice (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 good clinical practice); and all 
applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
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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.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the study documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
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Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents including participants’ documented informed consent pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. 
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.
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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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 Research
The specimens consented and/or collected in this study as outlined in Section 9.9 –
Future Biomedical Research Sample Collection 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.
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3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
Future Biomedical Research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the participants on the visit designated in 
the SoA.  If delayed, present consent at next possible Participant Visit.  Consent 
forms signed by the participant will be kept at the clinical study site under secure 
storage for regulatory reasons.  
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for Future Biomedical Research will be 
captured in the electronic Case Report Forms (eCRFs). Any specimens for which 
such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the SoA. In general, if additional blood specimens are being collected for 
Future Biomedical Research, these will usually be obtained at a time when the 
participant is having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical study site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
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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 Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (eg, a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. 
If medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable.  
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
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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 Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants.  Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
The Sponsor has developed strict security, policies and procedures to address participant 
data privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute: https://www.cancer.gov/publications/dictionaries/cancer-
terms?cdrid=45618
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; 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. 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. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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Appendix 3: Contraceptive Guidance and Pregnancy Testing
Definitions
Woman 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
●
Congenital or acquired condition that prevents childbearing
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
○
Bilateral tubal ligation/occlusion at least 6 weeks prior to screening.
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 post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with 2 FSH measurements in the postmenopausal range is required.
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in Section 6.1:
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.
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Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.

The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM).
Male condom with cap, diaphragm, or sponge with spermicide.
Male and female condom cannot be used together.

Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
Female Participants
Female participants of reproductive potential must agree to consistent and correct use of a 
highly effective method of contraception as described in Table 22 while receiving study drug 
and through 180 days after the last dose of chemotherapy; or through 120 days after the last 
dose of pembrolizumab, whichever is last.
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Table 22 Highly Effective Contraception Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantb,c
IUSc
Non-hormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review 
of the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
Male condoms must be used in addition to female participant hormonal contraception.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even though 
it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose of study treatment without any associated clinical symptoms or 
abnormal laboratory results is reported using the terminology “accidental or intentional 
overdose without adverse effect.”
●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 9.3.5 for additional details.
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
●
Refer to section 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation.  (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical 
condition that is diagnosed prior to the use of an MSD product and is documented in 
the patient’s medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events reported in the same manner as SAE
Additional Events which require reporting in the same manner as SAE
●
In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
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Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related 
to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse 
Events (CTCAE), version 4.0. Any adverse event which changes CTCAE grade over 
the course of a given episode will have each change of grade recorded on the adverse 
event case report forms/worksheets.
●
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
●
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation or hospitalization indicated; disabling; limiting self-
care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
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Assessment of Causality
●
Did the Sponsor's product cause the adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event will be provided by an investigator who is a qualified physician.  The 
investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified 
assessment of causality was done.  This initialed document must be retained for the 
required regulatory time frame.  The criteria below are intended as reference 
guidelines to assist the investigator in assessing the likelihood of a relationship 
between the test product and the adverse event based upon the available 
information
●
The following components are to be used to assess the relationship between the 
Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the 
Sponsor's product caused the adverse event:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product such as:  reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor's product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to 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.)
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●
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 ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S 
PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the case report forms /worksheets 
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product.  The temporal sequence of 
the AE onset relative to the administration of the Sponsor's product is reasonable.  
The AE is more likely explained by the Sponsor's product than by another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product.  (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
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●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
●
For studies in which multiple agents are administered as part of a combination 
regimen, the investigator may attribute each adverse event causality to the combination 
regimen or to a single agent of the combination.  In general, causality attribution 
should be assigned to the combination regimen (ie, to all agents in the regimen). 
However, causality attribution may be assigned to a single agent if in the investigator’s 
opinion, there is sufficient data to support full attribution of the adverse event to the 
single agent.
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
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●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or secure 
e-mail of the SAE paper CRF is the preferred method to transmit this information to 
the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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Appendix 5: Eastern Cooperative Oncology Group (ECOG) Performance Status
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed 
or chair
5
Dead
[Oken, M. M., et al 1982]
http://ecog-acrin.org/resources/ecog-performance-status
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Appendix 6: Clinical Laboratory Tests

The tests detailed in Table 23 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
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Table 23 Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Count
Hemoglobin
Hematocrit
WBC Count with Differential 1
Neutrophils 1
Lymphocytes 1
Chemistry
Blood Urea 
Nitrogen (BUN) or 
Urea 
Potassium
Aspartate 
Aminotransferase (AST)/ 
Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)
Total Bilirubin (and Direct 
Bilirubin, if total bilirubin is 
elevated above the upper 
limit of normal)
Albumin
Carbon dioxide 
(CO2 or 
Bicarbonate) 2
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase (ALT)/ 
Serum Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose
Calcium
Alkaline Phosphatase
Lactate dehydrogenase
Routine 
Urinalysis

Specific gravity

Glucose, protein, blood, by dipstick

Microscopic examination (if blood or protein is clinically significant)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing potential 
only)

Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for women of 
childbearing potential) 3

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody), 
anti-HBc (total and IgM), anti-HBe, if applicable 4

PT/INR

aPTT/PTT

Total T3 or free T3, FT4, and TSH 5
aPTT=activated partial thrombin time; FT4=free thyroxine; anti-HBe=anti-hepatitis B envelope; HBsAg=hepatitis B 
surface antigen; HCV=hepatitis C virus; IgM=gamma M immunoglobulin; INR=International Normalized Ratio; 
PT=prothrombin time; PTT=partial thromboplastin time; RBC=red blood cells; T3=triiodothyronine; TSH=thyroid 
stimulating hormone (thyrotropin); WBC=white blood cells.
NOTES :
1
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
2
If this test is not done as part of local standard of care, this test does not need to be performed. 
3
For women of reproductive potential, a pregnancy test must be performed within 72 hours prior to administration of 
study treatment on the days and cycles indicated in the SoA (Section 2), and 30 days post-treatment discontinuation. If 
a urine test is positive or not evaluable, a serum test will be required. 
4
No testing for HIV, hepatitis B, or Hepatitis C is required unless mandated by local health authority.
5
Total T3 is preferred; if not available, free T3 may be tested.
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Appendix 7: Technical Note for the Statistical Model
Poisson Mixture Model
The Poisson mixture model is applied to account for the failure rates decreasing over time in 
the study which is a mixture of participants suffering disease recurrence and others who have 
excellent long-term results. The survival function [de Castro, M., et al 2010] as a function of 
time t for a control group (c) is:  
S(t)=e-θ(1-e^(-λt)),
where θ = -log(Cure_Rate), λ is a constant hazard rate, and t ≥ 0.
The parameters in this Poisson mixture model on the control group in the Main Study 
(XP/FP) are based on published literature MAGIC study [Cunningham, D., et al 2006] and 
ACTS-GC study [Sasako, M., et al 2011]. The MAGIC study had only Western patients and 
the ACTS-GC study had only Asian participants. Since KEYNOTE 585 is a global study, the 
parameters were chosen to be in the range of the MAGIC and ACTS-GC studies. It is 
assumed that ~ 40% participants could achieve excellent long-term results (ie, the cure rate is 
40%), median EFS of 30 months, and median OS of 42 months on the control group in 
KEYNOTE 585.
Figure 4 and Figure 5 show the shape of the survival curves of EFS and OS for Poisson 
Mixture Model and exponential distribution model with the same assumption of the median 
on the control group in the Main Study (XP/FP).
Figure 4 Survival Curves of EFS Under Poisson Mixture Model and Exponential 
Distribution Model
0.4
0.6
0.8
1.0
12
24
36
48
60
72
84
96
Month
Survival
Treatment
Control
Experimental
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Figure 5 Survival Curves of OS Under Poisson Mixture Model and Exponential Distribution 
Model
Similarly, Poisson mixture model has been assumed for the control group in the FLOT 
Cohort as well, with median EFS of 30 months and median OS of 50 months [Fuchs, C. S., et 
al 2019].
Approximated Overall HR for the Main Study (XP/FP) and FLOT Cohort 
Combined
Assume the endpoint of interest (either EFS or OS) follows a Poisson Mixture distribution 
with different cure rate: 
denote XP/FP cure rate as e-θ and FLOT cure rate as e-θρ, 
and a common constant hazard rate (λ) in each of the 4 populations: the XP/FP control group, 
FLOT control group, XP/FP experiment group, FLOT experiment group. 
Further assume the hazard ratio in the Main Study (XP/FP) and the FLOT Cohort can be 
different and denote by HRF=0.78 and HRNF=0.72 for EFS and HRF=0.80 and HRNF=0.74
for OS, respectively. Then the survival function for each of the cohort are with the form: 
XP/FP
Control
Group
FLOT
Control
Group
XP/FP 
Experiment
Group
FLOT
Experiment
Group
Survival 
Function
e-θ(1-e^(-λt))
e-θρ(1-e^(-λt))
e-θ*HRNF*(1-e^(-λt))
e-θ*ρ*HRF*(1-e^(-λt))
0.4
0.6
0.8
1.0
12
24
36
48
60
72
84
96
Month
Survival
Treatment
Control
Experimental
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Above survival functions for control groups can be used to calculate the parameters (θ,λ,ρ)
given control group information including cure rate of the main study (XP/FP) and the 
control medians (either median EFS or median OS) from both the Main Study (XP/FP) and 
the FLOT Cohort. The EFS or OS survival rate based on each of the above survival functions 
can be explicitly calculated with assumed hazard ratios from both the Main Study (XP/FP) 
and the FLOT Cohort as well as the calculated parameters (θ,λ,ρ).
Let the percentage of participants in FLOT Cohort compared with XP/FP and FLOT 
combined be P (P=200/100=20%). Then the control group survival function can be written as
Pe-θρ(1-e^(-λt)) + (1-P)e-θ(1-e^(-λt))     …(Eq.1),
which can be approximated by a Poisson mixture model at a preselected landmark time of t:
e-θν0 (1-e^(-λt))   …(Eq.2).
Here ν0 is calculated so that the survival rate at time t is the same for the 2 survival functions 
in Eq. 1. and Eq. 2.  
Similarly, the experimental group survival function can be written as
Pe-θ*ρ*HRF*(1-e^(-λt)) + (1-P)e -θ*HRNF*(1-e^(-λt))   …(Eq.3),
which can be approximated by a Poisson mixture model at a preselected landmark time of t: 
e-θν1 (1-e^(-λt))    …(Eq.4).
Here ν1 is calculated so that the survival rate at time t is the same for the 2 survival functions 
in Eq. 3. and Eq. 4. 
Then ν1/ν0 can be considered as an approximated overall HR for sample size/power 
calculation for the Main Study (XP/FP) and FLOT Cohort combined.  
In gastric neoadjuvant/adjuvant trials, 5-year OS rate and 3-year EFS rate provide clinically 
meaningful information and are often reported in the literature. Thus t=36 months and t=60 
months are assumed as the landmark times for the computation of the overall approximated 
HR in the main study and FLOT Cohort combined for EFS and OS, respectively. The
approximated overall HR for the Main Study (XP/FP) and FLOT Cohort Combined was 
calculated to be 0.75 for OS and 0.73 for EFS.  
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Appendix 8: Abbreviations and Trademarks
Abbreviation/Term
Definition
1L
first line
2L
second line
3L
third line
5-FU
5-fluorouracil
ACTS-GC
Adjuvant Chemotherapy Trial of TS1 for Gastric Cancer
AE
adverse event
ALT
alanine aminotransferase
APaT
all participants as treated (population)
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review
bid
2 times a day
BSA
body surface area
CBC
complete blood count
CD
cluster of differentiation
CI
confidence interval
CLASSIC
Capecitabine and Oxaliplatin Adjuvant Trial in Stomach Cancer
Cmax
serum maximum concentration
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CrCl
calculated creatinine clearance
CRF
case report form
CRT
chemoradiation therapy
CSR
clinical study report
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
serum minimum concentration
DFS
disease-free survival
DL
dose level
DMC
data monitoring committee
DPD
dihydropyrimidine dehydrogenase
DNA
deoxyribonucleic acid
DSS
disease-specific survival
ECF
epirubicin + cisplatin + 5-FU
ECG
electrocardiogram
ECI
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
e-CRF
electronic case report form
ECX
epirubicin + cisplatin + capecitabine
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Abbreviation/Term
Definition
EFS
event-free survival
EMA
European Medicines Agency
EOC
executive oversight committee
EOF
epirubicin + oxaliplatin + 5-FU
EORTC
European Organization for Research and Treatment of Cancer
EORTC QLQ-C30
The European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-C30
EORTC QLQ-STO22
The European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-STO22
EOX
epirubicin + oxaliplatin + capecitabine 
ePRO
electronic patient-reported outcome(s)
EQ-5D-5L
EuroQol-5 Dimension Questionnaire
FA
final analysis
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFCD
The Fédération Francophone de Cancérologie Digestive
FLAGS
Phase III trial to compare the oral fluoropyrimidine S1 plus 
cisplatin versus 5-FU plus cisplatin
FLOT
docetaxel, oxaliplatin, fluorouracil, and leucovorin (calcium 
folinate)
FNA
fine needle aspirate
FP
cisplatin + 5-fluorouracil
GCP
Good Clinical Practice
GEJ
gastroesophageal junction
GFR
glomerular filtration rate
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
Health Related Quality of Life
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
iCRO
Imaging Contract Research Organization
IEC 
independent ethics committee
IFN
interferon
Ig
immunoglobulin 
IHC
immunohistochemistry
IL-10
interleukin 10
INR
international normalized ratio
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Abbreviation/Term
Definition
irAE
immune-related adverse event
irRECIST
immune-related Response Evaluation Criteria in Solid Tumors
IRB
institutional review board
IRT
interactive response technology
ITIM
immunoreceptor tyrosine-based inhibition motif
ITSM
immunoreceptor tyrosine-based switch motif
ITT
intention to treat
IV
intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
MAGIC
The Medical Research Council Adjuvant Gastric Infusional 
Chemotherapy study
MedDRA 
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
N/A
not applicable
NCI
National Cancer Institute
NSAID
non-steroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
OTC
over-the-counter
pathCR
pathological complete response
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
PFS
progression-free survival
PIN
personal identification number
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PR
partial response
PRO
patient-reported outcome(s)
PT
prothrombin time
PS
performance status
Q2W
every 2 weeks
Q3W
every 3 weeks
QLQ 
Quality of Life Questionnaire
QoL
quality of life
R0
complete surgical resection
R1
microscopic involvement at the margins
R2
evidence of macroscopic residual disease
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Abbreviation/Term
Definition
RCC
renal cell cancer
REAL-2
Randomized ECF for Advanced and Locally Advanced 
Esophagogastric Cancer
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RNA
ribonucleic acid
RR
response rate
RT
radiation therapy
SAC
scientific advisory committee
SAE
serious adverse event
SCF
Sponsor consultation form
siDMC
standing internal Data Monitoring Committee
SLAB
supplemental lab tests (CRF)
SNP
single nucleotide polymorphism
SoA
Schedule of Activities
SOP
standard operating procedure
SPIRITS
The S 1 Plus cisplatin versus S 1 In RCT In the Treatment for 
Stomach cancer study
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction(s)
T1DM
Type 1 Diabetes Mellitus
TB
tuberculosis
TEA
Treatment Eligibility Assessment
TSH
thyroid stimulating hormone
WBC
white blood cells
WOCBP 
Women of child-bearing potential
XP
cisplatin + capecitabine
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Appendix 9: Country-specific Requirements
France-specific Requirements
For all sites in France, participants with creatinine clearance ≤60 mL/min should not be 
allowed to participate in this study.
Sites in France will not participate in the FLOT Cohort and will not use the FLOT regimen
before authorization by the Agence Nationale de Sécurité du Médicament et des Produits de 
Santé (ANSM).
Section 7.2.1 Dose Modification and Toxicity Management Guidelines for
Pembrolizumab
Pembrolizumab treatments must be suspended in the event of the following adverse events of 
immunological origin: 

Grade 3 skin or suspected Stevens-Johnson syndrome (SJS)

Suspected toxic epidermal necrolysis 
Pembrolizumab treatments must be discontinued in the event of the following confirmed 
adverse events of immunological origin: 

Stevens-Johnson syndrome

Toxic epidermal necrolysis
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