Clinical trial NCT03382600
Conditions: Gastric Cancer
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-03-26; Completion date: 2021-05-30
Enrollment: 100 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to estimate objective response rates (ORRs) of pembrolizumab + oxaliplatin + TS-1 and pembrolizumab + cisplatin + TS-1, as first-line treatment for gastric cancer in programmed death-ligand 1 (PD-L1) positive, human epidermal growth factor receptor 2 (HER2/neu)-negative participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Detailed description:
Approximately 45 participants will be assigned to pembrolizumab + oxaliplatin + TS-1 combination therapy (Cohort 1) first, and then 45 participants will be assigned to pembrolizumab + cisplatin + TS-1 combination therapy (Cohort 2).

Arms: arm 1: Participants receive pembrolizumab 200 mg every 3 weeks (Q3W) plus oxaliplatin 130 mg/m\^2 Q3W by intravenous (IV) infusion plus TS-1 twice daily (BID) by continuous oral administration for 14 days, followed by a recovery period of 7 days. Study treatment will be started on Day 1 of each 3-week course, and will continue for up to \~3 years. arm 2: Participants receive pembrolizumab 200 mg Q3W plus cisplatin 60 mg/m\^2 Q3W by IV infusion plus TS-1 BID by continuous oral administration for 14 days, followed by a recovery period of 7 days. Study treatment will be started on Day 1 of each 3-week course, and will continue for up to \~3 years.
Interventions: intervention 1: Pembrolizumab intervention 2: Oxaliplatin intervention 3: TS-1 intervention 4: Cisplatin
Intervention descriptions: intervention 1: 200 mg Q3W on Day 1 by IV infusion intervention 2: 130 mg/m\^2 Q3W on Day 1 by IV infusion intervention 3: 40 to 60 mg orally according to Body Surface Area (BSA) BID Q3W on Days 1-14 intervention 4: 60 mg/m\^2 Q3W on Day 1 by IV infusion

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A phase IIb, clinical trial to study the safety and efficacy of 
Pembrolizumab (MK-3475) in combination with TS-1
+Cisplatin or TS-1+Oxaliplatin as a First Line Chemotherapy 
in participants with Advanced or Recurrent Gastric Cancer 
(KEYNOTE-659)
27-Nov-2017
NCT03382600


Product:  MK-3475 
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Protocol/Amendment No.: 659-00 
MK-3475-659-00 Final Protocol
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Confidential
Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A phase IIb, clinical trial to study the safety and efficacy of Pembrolizumab 
(MK-3475) in combination with TS-1+Cisplatin or TS-1+Oxaliplatin as a First Line 
Chemotherapy in participants with Advanced or Recurrent Gastric Cancer (KEYNOTE-659)
Protocol Number: 659-00
Compound Number: MK-3475
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or MSD)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:   123,482
EudraCT NUMBER: Not Applicable
Approval Date:  27-Nov-2017
 
 
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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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Table of Contents
1.
Synopsis.......................................................................................................................12
2.
Schedule of Activities (SoA) ......................................................................................15
3.
Introduction................................................................................................................18
3.1
Study Rationale .......................................................................................................18
3.2
Background..............................................................................................................18
Pharmaceutical and Therapeutic Background .....................................................18
3.2.1
Pembrolizumab .............................................................................................18
3.2.1.1
TS-1...............................................................................................................19
3.2.1.2
Oxaliplatin.....................................................................................................20
3.2.1.3
Cisplatin........................................................................................................20
3.2.1.4
Pre-clinical and Clinical Studies..........................................................................20
3.2.2
Ongoing Clinical Studies .....................................................................................21
3.2.3
Ongoing Clinical Trials in Gastric Cancer...........................................................21
3.2.4
Information on Other Study-Related Therapy .....................................................22
3.2.5
Current Standard Therapies ..........................................................................23
3.2.5.1
Comparison between Cisplatin and Oxaliplatin ...........................................23
3.2.5.2
S-1 + Cisplatin Regimen...............................................................................24
3.2.5.3
Combination of Pembrolizumab and Chemotherapy....................................24
3.2.5.4
Comparison with Study 062 (Keynote062) ..................................................24
3.2.5.5
3.3
Benefit/Risk Assessment.........................................................................................25
4.
Objectives/Hypotheses and Endpoints.....................................................................26
5.
Study Design...............................................................................................................27
5.1
Overall Design .........................................................................................................27
Study Diagram .....................................................................................................29
5.1.1
Study Duration for each subject....................................................................30
5.1.1.1
Definition of Study Period............................................................................30
5.1.1.2
5.2
Number of Participants ..........................................................................................30
5.3
Beginning and End of Study Definition ................................................................30
Clinical Criteria for Early Study Termination .....................................................31
5.3.1
 
 
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5.4
Scientific Rationale for Study Design....................................................................31
Rationale for Endpoints .......................................................................................31
5.4.1
Efficacy Endpoints......................................................................................31
5.4.1.1
RECIST 1.1............................................................................................31
5.4.1.1.1
iRECIST.................................................................................................31
5.4.1.1.2
Safety Endpoints ...........................................................................................32
5.4.1.2
Rationale for the Trial and Selected Subject Population .....................................32
5.4.2
5.5
Justification for Dose ..............................................................................................32
6.
Study Population........................................................................................................33
6.1
Inclusion Criteria ....................................................................................................33
6.2
Exclusion Criteria ...................................................................................................35
6.3
Histological Classification in Target Patients.......................................................37
6.4
Lifestyle Restrictions...............................................................................................38
Contraception.......................................................................................................38
6.4.1
Pregnancy.............................................................................................................38
6.4.2
Use in Nursing Women........................................................................................38
6.4.3
6.5
Screen Failures ........................................................................................................38
6.6
Participant Replacement Strategy.........................................................................38
7.
Treatments..................................................................................................................39
7.1
Treatments Administered.......................................................................................39
7.2
Dose Modification (Escalation/Titration/Other) ..................................................40
Dose Selection (Preparation) ...............................................................................40
7.2.1
Dose Modification ...............................................................................................40
7.2.2
Dose modification and toxicity management for immune-related AEs 
7.2.3
associated with pembrolizumab...........................................................................41
Other allowed dose interruption for pembrolizumab...........................................46
7.2.4
Dose Modification for Oxaliplatin, Cisplatin and TS-1.......................................46
7.2.5
Timing of Dose Administration ...........................................................................48
7.2.6
Pembrolizumab .............................................................................................48
7.2.6.1
Oxaliplatin.....................................................................................................48
7.2.6.2
Cisplatin........................................................................................................49
7.2.6.3
TS-1...............................................................................................................49
7.2.6.4
 
 
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7.3
Method of Treatment Assignment.........................................................................49
Stratification.........................................................................................................49
7.3.1
7.4
Blinding....................................................................................................................49
7.5
Preparation/Handling/Storage/Accountability ....................................................49
Dose Preparation..................................................................................................49
7.5.1
Handling, Storage and Accountability.................................................................50
7.5.2
7.6
Treatment Compliance...........................................................................................50
7.7
Concomitant Therapy.............................................................................................50
Acceptable Concomitant Medications .................................................................50
7.7.1
Prohibited Concomitant Medication ....................................................................51
7.7.2
Rescue Medications and Supportive Care ...........................................................52
7.7.3
Supportive Care Guidelines for Pembrolizumab ..........................................52
7.7.3.1
Supportive Care Guidelines for Oxaliplatin/ Cisplatin.................................54
7.7.3.2
Supportive Care Guidelines for TS-1 ...........................................................54
7.7.3.3
Diet/Activity/Other Considerations .....................................................................54
7.7.4
Diet................................................................................................................54
7.7.4.1
Contraception................................................................................................55
7.7.4.2
Use in Pregnancy ..........................................................................................56
7.7.4.3
Use in Nursing Women.................................................................................56
7.7.4.4
Pembrolizumab ......................................................................................56
7.7.4.4.1
Oxaliplatin .............................................................................................56
7.7.4.4.2
Cisplatin.................................................................................................56
7.7.4.4.3
TS-1 .......................................................................................................57
7.7.4.4.4
7.8
Treatment After the End of the Study ..................................................................57
7.9
Clinical Supplies Disclosure ...................................................................................57
7.10
Standard Policies.....................................................................................................57
Study Site Retention Samples..............................................................................57
7.10.1
Investigational Product .................................................................................57
7.10.1.1
Packaging and Labeling Information............................................................57
7.10.1.2
Storage and Handling Requirements ............................................................58
7.10.1.3
Discard/Destruction/Returns and Reconciliation..........................................58
7.10.1.4
8.
Discontinuation/Withdrawal Criteria......................................................................58
 
 
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8.1
Discontinuation of Study Treatment .....................................................................58
8.2
Withdrawal from the Study ...................................................................................59
8.3
Lost to Follow Up ....................................................................................................59
9.
Study Assessments and Procedures..........................................................................60
9.1
Administrative and General Procedures ..............................................................60
Informed Consent.................................................................................................60
9.1.1
General Informed Consent............................................................................60
9.1.1.1
Submitting Tumor Sample............................................................................61
9.1.1.2
Inclusion/Exclusion Criteria ................................................................................61
9.1.2
Participant Identification Card.............................................................................61
9.1.3
Medical History ...................................................................................................62
9.1.4
Prior and Concomitant Medications Review .......................................................62
9.1.5
Prior Medications..........................................................................................62
9.1.5.1
Concomitant Medications .............................................................................62
9.1.5.2
Assignment of Screening Number .......................................................................62
9.1.6
Assignment of Treatment/Randomization Number .............................................62
9.1.7
Treatment Administration....................................................................................63
9.1.8
Timing of Dose Administration....................................................................63
9.1.8.1
Discontinuation and Withdrawal .........................................................................63
9.1.9
Participant Blinding/Unblinding..........................................................................63
9.1.10
Calibration of Critical Equipment........................................................................63
9.1.11
9.2
Efficacy Assessments...............................................................................................64
Tumor Imaging and Assessment of Disease........................................................64
9.2.1
Initial Tumor Imaging...................................................................................64
9.2.1.1
Tumor Imaging During the Study.................................................................64
9.2.1.2
End of Treatment and Follow-up Tumor Imaging........................................65
9.2.1.3
RECIST 1.1 Assessment of Disease .............................................................65
9.2.1.4
iRECIST Assessment of Disease ..................................................................65
9.2.1.5
9.3
Adverse Events (AE), Serious Adverse Events (SAE) and Other 
Reportable Safety Events .......................................................................................68
Time Period and Frequency for Collecting AE, SAE and Other 
9.3.1
Reportable Safety Event Information ..................................................................69
Method of Detecting AE, SAE and Other Reportable Safety Events ..................71
9.3.2
 
 
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Follow-up of AE, SAE and Other Reportable Safety Event Information............71
9.3.3
Regulatory Reporting Requirements for SAE .....................................................71
9.3.4
Disease-Related Events and/or Disease-Related Outcomes Not 
9.3.5
Qualifying as AEs or SAEs..................................................................................71
Pregnancy and Exposure During Breastfeeding ..................................................72
9.3.6
Events of Clinical Interest (ECI)..........................................................................72
9.3.7
9.4
Treatment of Overdose...........................................................................................72
9.5
Safety........................................................................................................................73
Physical Examinations .........................................................................................73
9.5.1
Full Physical Exam .......................................................................................73
9.5.1.1
Directed Physical Exam................................................................................73
9.5.1.2
Vital Signs............................................................................................................73
9.5.2
Electrocardiograms ..............................................................................................73
9.5.3
Clinical Safety Laboratory Assessments..............................................................74
9.5.4
Laboratory Safety Evaluations (Hematology, Chemistry, and 
9.5.4.1
Urinalysis).....................................................................................................74
Pregnancy Test..............................................................................................74
9.5.4.2
Performance Assessments....................................................................................74
9.5.5
Eastern Cooperative Oncology Group Performance Scale ...........................74
9.5.5.1
9.6
Pharmacokinetics....................................................................................................74
9.7
Pharmacodynamics.................................................................................................75
9.8
Biomarkers ..............................................................................................................75
9.9
Future Biomedical Research Sample Collection ..................................................75
9.10
Visit Requirements..................................................................................................75
Screening..............................................................................................................75
9.10.1
Treatment Period Visit.........................................................................................76
9.10.2
Post-Treatment Visits...........................................................................................76
9.10.3
Safety Follow-up Visit..................................................................................76
9.10.3.1
Follow-up Visits............................................................................................76
9.10.3.2
Survival Follow-up .......................................................................................76
9.10.3.3
10.
Statistical Analysis Plan ............................................................................................76
10.1
Statistical Analysis Plan Summary........................................................................77
10.2
Responsibility for Analyses ....................................................................................77
 
 
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10.3
Hypotheses/Estimation ...........................................................................................77
10.4
Analysis Endpoints..................................................................................................78
Efficacy Endpoints...............................................................................................78
10.4.1
Primary Efficacy Endpoint ...........................................................................78
10.4.1.1
Secondary Efficacy Endpoints......................................................................78
10.4.1.2
Safety Endpoints ..................................................................................................78
10.4.2
10.5
Analysis Populations...............................................................................................79
Efficacy Analysis Populations .............................................................................79
10.5.1
Safety Analysis Populations ................................................................................79
10.5.2
10.6
Statistical Methods..................................................................................................79
Statistical Methods for Efficacy Analyses ...........................................................79
10.6.1
Statistical Methods for Safety Analyses ..............................................................81
10.6.2
Summaries of Baseline Characteristics, Demographics, and Other 
10.6.3
Analyses...............................................................................................................81
10.7
Interim Analyses .....................................................................................................81
10.8
Multiplicity ..............................................................................................................81
10.9
Sample Size and Power Calculations ....................................................................81
10.10 Subgroup Analyses and Effect of Baseline Factors..............................................83
10.11 Compliance (Medication Adherence)....................................................................83
10.12 Extent of Exposure..................................................................................................83
11.
References...................................................................................................................83
12.
Appendices..................................................................................................................89
12.1
Appendix 1: Study Governance Considerations ..................................................89
Merck Code of Conduct for Clinical Trials .....................................................................89
Financial Disclosure.........................................................................................................91
Data Protection.................................................................................................................91
Confidentiality of Data ....................................................................................................91
Confidentiality of Participant Records.............................................................................91
Confidentiality of IRB/IEC Information..........................................................................92
Publication Policy ............................................................................................................92
Compliance with Study Registration and Results Posting Requirements .......................92
Compliance with Law, Audit and Debarment .................................................................93
 
 
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Data Quality Assurance ...................................................................................................93
Source Documents ...........................................................................................................94
Study and Site Closure.....................................................................................................94
12.2
Appendix 2: Description of the iRECIST Process for Assessment of 
Disease Progression.................................................................................................95
12.3
Appendix 3: Contraceptive Guidance and Pregnancy Testing...........................99
Pregnancy Testing..........................................................................................................101
12.4
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................102
Definition of AE ............................................................................................................102
Definition of SAE ..........................................................................................................103
Additional Events reported in the same manner as SAE ...............................................104
Recording AE and SAE .................................................................................................104
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor................108
12.5
Appendix 5: Clinical Laboratory Tests...............................................................109
12.6
Appendix 6: ECOG Performance Status............................................................110
12.7
Appendix 7: Abbreviations and Trademarks.....................................................111
 
 
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LIST OF TABLES
    
Table 1
Treatments Dose and Schedule.............................................................................27
Table 2
Adequate Organ Function Laboratory Values......................................................35
Table 3
Study Treatments..................................................................................................39
Table 4
Dose Modifications for Trial Medications ...........................................................41
Table 5
Dose modification and toxicity management guidelines for immune-
related AEs associated with pembrolizumab........................................................42
Table 6
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines.............................................................................................................45
Table 7
Dose Modification Guidelines for Oxaliplatin Drug-Related Adverse 
Events ...................................................................................................................46
Table 8
Dose Modification Guidelines for Cisplatin Drug-Related Adverse 
Events ...................................................................................................................47
Table 9
Dose Modification Guidelines for TS-1 Drug-Related Adverse Events ..............47
Table 10
Product Descriptions.............................................................................................57
Table 11
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease..................................................................................................................67
Table 12
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................70
Table 13
Censoring Rules for DOR.....................................................................................80
Table 14
Summary of Analysis Strategy for Efficacy Endpoints........................................80
Table 15
Two sided 95% Confidence interval of ORR with 40 subjects as ASaT .............82
Table 16
Two-sided 95% CI of AE incidence rate with 40 Subjects ..................................82
Table 17
Highly Effective Contraception Methods...........................................................100
Table 18
Protocol-Required Safety Laboratory Assessments ...........................................109
 
 
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LIST OF FIGURES
          
Figure 1
Phase II Trial Design for Enrollment of PD-L1 Positive, HER2/neu 
Negative Subjects with Advanced Gastric or Gastroesophageal Junction 
(GEJ) Adenocarcinoma. .......................................................................................29
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by the 
Investigator ...........................................................................................................68
 
 
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1. Synopsis
Protocol Title:  
A phase IIb, clinical trial to study the safety and efficacy of Pembrolizumab (MK-
3475) in combination with TS-1+Cisplatin or TS-1+Oxaliplatin as a First Line 
Chemotherapy in participants with Advanced or Recurrent Gastric Cancer 
(KEYNOTE-659). 
Short Title: 
Phase IIb study of Pembrolizumab in combination with TS-1+Cisplatin or TS-
1+Oxaliplatin in GC.
Objectives/Hypotheses and Endpoints:
In subjects with PD-L1 positive, advanced gastric or GEJ adenocarcinoma, the following 
objectives will be applied to Cohort 1 and Cohort 2 separately.
Objective/Hypothesis
Endpoint
Primary

To evaluate ORR per RECIST 1.1 
as assessed by blinded independent 
central review (BICR).

ORR is defined as the proportion of 
participants who have a confirmed 
complete response (CR) or partial 
response (PR).
Secondary

To evaluate the Duration of 
Response (DOR) per RECIST 1.1 
and per iRECIST as assessed by 
BICR.

To evaluate ORR per iRECIST by 
BICR.

To evaluate Disease Control Rate 
(DCR) per RECIST 1.1 and per 
iRECIST as assessed by BICR.

To evaluate PFS per RECIST 1.1 
and per iRECIST as assessed by 
BICR.

DOR defined as the time from the 
earliest date of qualifying response until 
earliest date of disease progression or 
death from any cause, whichever comes 
first.

ORR is defined as the proportion of 
participants who have a confirmed 
complete response (CR) or partial 
response (PR).

DCR is defined as the proportion of 
participants who have a stable disease 
(SD) or better prior to any evidence of 
progression.

PFS is defined as the time from date of 
enrollment to the first documented 
progressive disease (PD). Death due to 
any cause, whichever occurs first.
 
 
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
To evaluate Time To Response 
(TTR) per RECIST 1.1 and per 
iRECIST as assessed by BICR.

To assess OS.

To evaluate safety.

TTR is defined as a time from the date 
of enrollment day (a starting day) to the 
first date of confirmed CR or PR

OS is defined as the period from the 
date of enrollment to the date of death 
due to any cause.

Number of participants experiencing 
AEs and number of participants 
discontinuing study drug due to AEs.
Overall Design:
Study Phase
Phase IIb
Clinical Indication
First-line treatment for gastric cancer in programmed 
death-ligand 1 (PD-L1) positive (CPS ≥1%)
Population
Human epidermal growth factor receptor 2 (HER2/neu) 
negative subjects with advanced gastric or 
gastroesophageal junction (GEJ) adenocarcinoma.
Study Type
Interventional
Type of Design
Single-arm multiple cohort
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 30 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related phone call or visit.  
Number of Participants:
Approximately 90 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
Cohort 1: Pembrolizumab 200 mg fixed dose 
administered every 3 weeks (Q3W) + oxaliplatin 130 
mg/m2 IV infusion Q3W + TS-1 continuous oral 
administration twice daily (BID) for 14 days followed by 
a recovery period of 7 days
Cohort 2: Pembrolizumab 200 mg fixed dose 
administered Q3W + cisplatin 60 mg/m2 IV infusion 
Q3W + TS-1 continuous oral administration BID for 14 
days followed by a recovery period of 7 days
 
 
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Duration of 
Participation
Each participant will participate in the study from the 
time the participant signs the informed consent form 
(ICF) through the final protocol-specified contact. After a 
screening phase of 28 days, each eligible participant will 
be assigned to Cohort 1. After the target sample size of 
Cohort 1 is reached, allocation to Cohort 2 will be 
started. The study treatment will continue until disease 
progression is radiographically documented, when 
clinically appropriate, confirmed by the site per modified 
Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics (iRECIST) for participants 
treated with pembrolizumab, unacceptable adverse 
event(s) (AEs), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to 
withdraw the participant, noncompliance with study 
treatment or procedure requirements or administrative 
reasons requiring cessation of treatment, or until the 
participant has received 35 administrations of 
pembrolizumab (approximately 2 years). 
After the end of treatment, each participant will be 
followed for the occurrence of AEs and spontaneously 
reported pregnancy as described under Section 9.3. 
Participants who discontinue for reasons other than 
radiographic disease progression will have post-treatment 
follow-up imaging for disease status until disease 
progression is documented radiographically per RECIST 
1.1, and confirmed by the site per iRECIST (for 
participants treated with pembrolizumab), initiating a 
non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up. All participants will be 
followed by telephone for overall survival until death, 
withdrawal of consent, or the end of the study. 
 
 
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2. Schedule of Activities (SoA)
Trial Period:
Screening Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle
Tumor Tissue 
collection/submission Screening
1
2
3
4
5
Cycle 6 
and  
beyond
Last Dose
Safety 
Follow-
up
Follow 
Up 
Visitsb
Survival 
Follow-
upc
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 
1
Day 
1
Day 
1
Day 1
At time of 
treatment 
discon
30 days
post 
last 
dose
Every 6 
weeks
Every 12 
weeks
post last 
dose
Scheduling Window (Days)d:
-28 to -1
-21 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 14
Administrative Procedures
Informed Consente
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication 
Reviewf
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Eventsg
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weighth
X
X
X
X
X
X
X
X
ECOG Performance Statusi
X
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Status 
X
Trial Treatment Administration
Pembrolizumabj (Cohorts 1 and 2)
X
X
X
X
X
X
Oxaliplatink (Cohort 1)
X
X
X
X
X
X
Cisplatinl (Cohort 2)
X
X
X
X
X
X
TS-1m(Cohorts 1 and 2)
X
X
X
X
X
X
Laboratory
Procedures/Assessments:  Analysis 
performed by LOCAL Laboratory
Pregnancy Test – Serum or Urinen
X
X
X
X
X
X
X
PT/INR and aPTTo
X
CBC with Differentiali
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Paneli
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisi
X
 
 
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Trial Period:
Screening Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle
Tumor Tissue 
collection/submission Screening
1
2
3
4
5
Cycle 6 
and  
beyond
Last Dose
Safety 
Follow-
up
Follow 
Up 
Visitsb
Survival 
Follow-
upc
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 
1
Day 
1
Day 
1
Day 1
At time of 
treatment 
discon
30 days
post 
last 
dose
Every 6 
weeks
Every 12 
weeks
post last 
dose
Scheduling Window (Days)d:
-28 to -1
-21 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 14
T3 (or Free T3), FT4 and TSHi
X
X
X
X
X
Serum 
carcinoembryonic 
antigen 
(CEA)p
X
X
X
Xp
Serum CA19-9p
X
X
X
Xp
Efficacy Measurements
Tumor Imagingq
X
→
→
→
→
→
→
→
→
→
→
→
→
X
Tumor Tissue Collection
Archival or Newly Obtained Tissue 
Collectionr
X
a. Unless otherwise specified, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 6 weeks (± 7 days) until (1) disease progression as assessed by investigator or qualified designee, (2) death, or (3) the end of the study, whichever occurs first.
c. After the start of new anti-cancer treatment or documented disease progression by investigator or qualified designee, the subject should be contacted by telephone every 12 
weeks to assess for survival status. Note: Every effort should be made to ensure telephone contact at least 90 days post discontinuation to capture SAEs/ECIs The Sponsor 
may request survival status be assessed at additional time points during the course of the study.  All subjects who are not known to have died prior to the request for these 
additional survival status time points will be contacted at that time.
d. Unless otherwise specified, the window for each visit is ± 3 days.  Cycle 1 treatment must be given within 8 days after enrollment.
e. Written consent must be obtained prior to performing any protocol specified procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 21 days prior to the first dose of trial treatment).  
Screening number will be assigned when the study informed consent is signed.
f. Concomitant medications – Enter new medications started during the treatment until the Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 
9.3.
g. Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days 
after the last dose of trial treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever occurs first.  Afterwards, report only SAEs 
and ECIs that are related to trial treatment.
h. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured in screening phase only.
i. ECOG PS for screening is to be performed within 3 days of enrollment.  Laboratory tests for screening are to be performed within 7 days of enrollment.  See Section 7.1.3 
for details regarding laboratory tests.  After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  CBC with Differential and Chemistry 
panel are to be performed prior to the administration of all the cycles.  Thyroid function tests should be collected every 6 weeks (every 2 cycles, e.g., Cycles 8, 10, 12, etc).  
Unresolved abnormal labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.  
j. Pembrolizumab should be administered on Day 1 of each 3 week cycle after all procedures/assessments have been completed.  Pembrolizumab 200 mg should be 
 
 
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Trial Period:
Screening Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle
Tumor Tissue 
collection/submission Screening
1
2
3
4
5
Cycle 6 
and  
beyond
Last Dose
Safety 
Follow-
up
Follow 
Up 
Visitsb
Survival 
Follow-
upc
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 
1
Day 
1
Day 
1
Day 1
At time of 
treatment 
discon
30 days
post 
last 
dose
Every 6 
weeks
Every 12 
weeks
post last 
dose
Scheduling Window (Days)d:
-28 to -1
-21 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 14
administered as a 30 minute IV infusion Q3W.  Sites should make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given the 
variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). The order of 
administration of pembrolizumab, oxaliplatin/cisplatin and TS-1, pembrolizumab infusion is administered first followed by the oxaliplatin/cisplatin infusion and then TS-1.
k. Oxaliplatin 130  mg/m2 will be administered as a 120 minute IV infusion Q3W on Day 1 of each treatment cycle.
l. Cisplatin 60 mg/m2 will be administered as a 120 minute IV infusion Q3W on Day 1 of each treatment cycle.  
m. TS-1 40 to 60 mg/body/dose will be orally administered bid at Days 1 to 14 Q3W.  
n. For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to each cycle of trial treatment and 30 days post treatment.  A urine 
test can be considered if serum is not appropriate.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
o. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. And to be performed within 7 days of enrollment.
p. Serum CEA and CA 19-9 should be collected at screening (baseline), Cycle 3 and every 6 weeks (conducted at corresponding study visit; Cycle 5, Cycle 7, etc.) until study 
treatment discontinuation. When overall response is graded as CR, the examination will be performed 4 weeks after the CR assessment (accepted if performed up to 7 days 
after a reference day).
q. Baseline tumor imaging will be performed within 21 days prior to enrollment.  Scans performed as part of routine clinical management are acceptable for use as the baseline 
scan if they are of diagnostic quality and performed within the allotted screening window for each cohort.  The exact same image acquisition and processing parameters are 
recommended throughout the study.  The first on-study imaging time point will be performed 6 weeks (± 7 days) after the subject has been enrolled, or earlier if clinically 
indicated and will continue to be performed every 6 weeks (± 7 days).  When overall response is graded as CR or PR based on RECIST 1.1, the examination interval is 
changed and imaging that will confirm the best overall response (in case of CR, tumor maker levels will also be measured) will be performed 4 weeks after the last 
assessment (accepted if performed up to 7 days after a reference day).  When assessment consecutively results in CR or PR, confirming the best overall response, 
examinations will be performed thereafter at an interval of 6 weeks from the day of enrollment. First examination after confirming the best over response as CR or PR will 
not be required. Imaging should be repeated until PD.  Imaging timing should follow calendar days.  On-study scans (scheduled and unscheduled) should be submitted to the 
BICR.  
r. Tumor tissue from newly obtained core or excisional biopsy (FNA not adequate) and archival tissue sample (where available) should be tested for PD-L1 (evaluation of 
eligibility).  Only PD-L1 positive subjects will be eligible for this trial.  Tumor submission can occur up to 28 days prior to enrollment.  Consent must be obtained prior to 
tumor tissue submission/collection.  Detailed instructions for tissue collection, process and shipment are provided in the Procedures Manual.
 
 
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3. Introduction
3.1
Study Rationale 
Trials evaluating pembrolizumab (MK-3475) in gastric cancer have demonstrated clinical 
activity in subjects with recurrent and/or metastatic disease.  Refer to Section 3.2.4, Ongoing 
Clinical Trials, for results from the studies of pembrolizumab in subjects with gastric cancer 
(KN012 and KN059).
The gastric cancer proof-of-concept from KN012 data was obtained in subjects with a PD-L1
positive expression only; no data is currently available regarding the performance of 
pembrolizumab in subjects without a detectable PD-L1 expression.
3.2
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients 
across a number of indications because of its mechanism of action to bind the PD-1 receptor 
on the T cell. For more details on specific indications refer to the Investigator’s Brochure.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pharmaceutical and Therapeutic Background
3.2.1
Pembrolizumab
3.2.1.1
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies [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 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD L1 and/or PD-L2) 
[Talmadge, J. E., et al 2007] [Usubütün, A., et al 1998].
 
 
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The structure of murine PD-1 has been resolved [Al-Shibli, K. I., et al 2008]. PD-1 and its 
family members are type I transmembrane glycoproteins containing an Ig-variable-type (IgV-
type) domain responsible for ligand binding and a cytoplasmic tail responsible for the 
binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (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 CD3 zeta 
(CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), 
which are involved in the CD3 T-cell signaling cascade [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 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 EBV-
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.
TS-1
3.2.1.2
S-1 is a combination product containing FT, a prodrug of Fluorouracil (5-FU), and 2 
modulators, CDHP and Oxo, in a molar ratio of 1:0.4:1. CDHP increases 5-FU concentration 
by reversible inhibition of dihydropyrimidine dehydrogenase (DPD), an enzyme that 
degrades 5-FU, while Oxo, densely distributed in gastrointestinal tissues, prevents 
gastrointestinal toxicity of 5-FU by inhibiting its local activation.
 
 
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S-1 is an oral anticancer treatment, which has been developed by combining the three 
components to enhance therapeutic efficacy in comparison with conventional 5-FU products 
and also to reverse the resulting increase in adverse drug reactions.
S-1 has been marketed in Japan since 1999. As of January 2017, S-1 is approved in the 
countries of the world for the treatment of gastric cancer, head and neck cancer, colorectal 
cancer, non-small cell lung cancer, breast cancer, pancreatic cancer and/or biliary tract 
cancer. It is approved under the trade name of TS-1, S-1, TS-ONE or Teysuno in over 45 
countries, including the European countries [mainly the European Union (EU)/ European 
Economic Area (EEA)] and Asian countries (mainly Japan). To date, cumulative post-
marketing exposure to S-1 is estimated to be 1,771,593 patients in Japan since first approval 
in 1999, approximately 126,964 patients in other Asian Countries, and 3,966 patients from 
EEA, Israel, and Russia since marketing on 14 March 2012.
Oxaliplatin
3.2.1.3
Oxaliplatin is a platinum complex-based antitumor agent and the mechanism of the drug is 
considered to be the inhibition of DNA synthesis and the inhibition of protein synthesis from 
cross-link formation with DNA base, like other platinum complex-based antitumor agents.
In Japan, Oxaliplatin was approved for “Unresectable advanced/recurrent gastric cancer” at 
dosage of 130 mg/m2, every 3 weeks in combination with other anticancer agents in March 
2015. In November 2015, when the indication for “postoperative adjuvant chemotherapy in 
gastric cancer” was added, Oxaliplatin was approved for “gastric cancer” at the same dosage 
and dose.
Cisplatin
3.2.1.4
Cisplatin binds to the N7-position of guanine and adenine, which is a constituent base of 
DNA. Since Cisplatin binds to DNA at two chloride sites, it forms cross-link formation 
within the DNA chain and inhibits DNA synthesis and subsequent division of cancer cells. 
Even monotherapy is effective for gastric cancer, Cisplatin is known to show a synergistic 
effect when combined with 5-FU, CPT-11, etc. Cisplatin has renal toxic and requires 
adequate replacement fluid.
Pre-clinical and Clinical Studies
3.2.2
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 mono-therapy or in combination with other 
treatment modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, 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 
mono-therapy as well as in combination with chemotherapy in syngeneic mouse tumor 
models (see the Investigator’s Brochure [IB]).
 
 
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Clinical trials have demonstrated efficacy in subjects with advanced melanoma, non-small 
cell lung cancer, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-negative 
breast cancer, and gastric adenocarcinoma.
Ongoing Clinical Studies
3.2.3
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, a number of advanced solid tumor indications and hematologic malignancies.  For 
study details please refer to the IB.
Ongoing Clinical Trials in Gastric Cancer
3.2.4
Preliminary interim data is available from a cohort of gastric and GEJ adenocarcinoma 
subjects studied in the KEYNOTE 012 trial [Muro, K., et al 2014].  The KEYNOTE 012 trial 
is a multi-cohort, Phase IB study of subjects with recurrent or metastatic gastric or GEJ 
adenocarcinoma who expressed PD-L1 (≥1% by immunohistochemistry).  This cohort 
enrolled 39 subjects (19 from Asia and 20 outside of Asia).  The primary endpoint was 
overall response rate (ORR).  Although 69% of subjects received 2 or more prior 
chemotherapy lines, pembrolizumab monotherapy demonstrated an ORR of 20.5% by 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 per central radiology 
assessment (95% CI: 9.3%, 36.5%; 7 PRs, 1 CR), and was similar in subjects from Asia and 
outside of Asia.  Responses were observed across all lines of treatment.  Forty-four percent 
of the subjects 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 progression-free survival (PFS) and OS was 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 was 
generally well tolerated, with the type, severity, and frequency of AEs in the gastric cancer 
subjects of KEYNOTE 012.
The overall safety results of pembrolizumab in subjects treated with single agent 
pembrolizumab at a dose and frequency of 10 mg/kg every 2 weeks with gastric cancer 
reported in this trial were consistent with the previously established pembrolizumab safety 
profile based on data in melanoma, NSCLC, and head and neck cancer (see the IB for 
information about AEs in other indications).  There were 3 deaths reported in the gastric 
cancer cohort, with none of these death serious adverse events (SAEs) attributed to study 
treatment.
The KEYNOTE 028 study treated 23 patients with PD-L1 positive esophageal cancer; 17 
with squamous cell cancer and 5 with adenocarcinoma [Semrad, T. J. 2015].  Seven out of 23 
patients (30%) had PR and of the 5 patients with adenocarcinoma, 2 patients had PR and 2 
patients had stable disease.
KEYNOTE 059 is a non-randomized, multi-site, open-label trial of pembrolizumab in 
subjects with gastric or GEJ adenocarcinoma.  Enrollment in this trial was completed and 
316 subjects were enrolled across 3 cohorts to examine the safety and efficacy of 
pembrolizumab.  Cohort 1 subjects who had progressed on at least 2 prior systemic 
treatments for advanced disease (third line [3L]+subjects) that received pembrolizumab as 
 
 
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monotherapy; (Cohort 2) subjects who had not previously received systemic therapy for 
advanced disease (1L subjects) received pembrolizumab in combination with cisplatin and 5-
FU.  Sites in Japan also administered pembrolizumab in combination with cisplatin and 
capecitabine; and (Cohort 3) PD-L1-positive subjects who had not previously received 
systemic therapy for advanced disease (1L subjects) who received pembrolizumab as 
monotherapy.  The primary objectives of the trial were to determine the safety, tolerability, 
and ORR of pembrolizumab (200 mg fixed dose every 3 weeks) given as first and third-line 
monotherapy to subjects 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 subjects with gastric or GEJ 
adenocarcinoma.  The trial is currently ongoing and following subjects for OS.
KEYNOTE 061 is a randomized, multi-center, open-label trial of pembrolizumab versus 
paclitaxel in subjects 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 trial was completed and 592 subjects were randomized.  The 
enrollment included all subjects without regard for PD-L1 expression status.  The overall 
study enrollment was driven by the number of subjects with PD-L1 positive expression on 
their tumor (n=360).  That is, enrollment was stopped when approximately 360 subjects with 
PD-L1 positive expression on their tumor had been randomized.  Additionally, there was a 
cap on enrollment (30% of the total) for subjects residing in the Asia Pacific region for this 
study.  The primary efficacy endpoints were PFS and OS.  The primary PFS analysis was 
based on RECIST v1.1 by blinded central radiologists’ review.  RECIST v1.1 was also used 
by the local site for treatment decisions.  The trial is currently ongoing and following subjects 
for OS.
KEYNOTE 062 is a randomized, active-controlled, multi-site, partially blinded, trial 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 
subjects with advanced gastric or GEJ adenocarcinoma.  The trial is currently enrolling with 
a target of approximately 750 subjects to be randomized to compare the efficacy and safety 
of pembrolizumab or pembrolizumab + cisplatin +5-FU versus placebo + cisplatin + 5-FU as 
a first-line treatment.  Subjects will be randomized in a 1:1:1 ratio among the 3 treatment 
arms, stratified by geographic region, disease status, and fluoropyrimidine treatment.  There 
will be 1 interim PFS/OS analysis, 1 planned interim safety analysis, and safety monitoring 
every 6 months.
Information on Other Study-Related Therapy
3.2.5
A variety of chemotherapies are used for subjects with advanced, first line gastric and GEJ 
adenocarcinoma. Early studies demonstrated small survival benefits after treatment with 
cisplatin alone or chemotherapy combinations.
A number of ongoing Phase 3 trials are evaluating the addition of targeted monoclonal 
antibodies or small molecules to standard chemotherapy regimens.  First positive result was 
shown  from ToGA study comparing cisplatin/fluoropyrimidine plus trastuzumab, a 
monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), with the 
same chemotherapy alone in subjects with HER2-positive gastric or gastroesophageal 
adenocarcinoma.. The study demonstrated significantly improved OS associated with the 
 
 
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trastuzumab-containing regimen over chemotherapy alone (median 13.8 and 11.1 months, 
respectively, p = .0048). The outcome of ToGA study supported the approval of Trastuzumab 
for HER2-positive gastric cancer subjects [Bang, Y. J., et al 2010].
Current Standard Therapies
3.2.5.1
With regard to chemotherapy for advanced and metastatic gastric cancer, since MacDonald, 
et al. reported FAM therapy, a triple therapy with 5-FU + doxorubicin + mitomycin C 
[median survival time (MST), 5.5 months] [Macdonald, J. S., et al 1980] in 1980, multidrug 
combination therapy mainly with 5-FU has been most commonly used.  ECF [epirubicin + 
cisplatin + 5-FU] therapy, and EOX [epirubicin + oxaliplatin + capecitabine] therapy of 
which noninferiority to ECF therapy was demonstrated in the results of REAL2 trial 
[Cunningham, D., et al 2008], mainly in Europe; DCF (docetaxel + cisplatin + 5-FU) therapy 
of which superiority to CF (cisplatin + 5-FU) therapy was shown in V325 trial [Van Cutsem, 
E., et al 2006] in the US. At present platinum/fluoropyrimidine doublet regimens are the 
most broadly used for first-line chemotherapy regimen for advanced gastric cancer.
In Japan, combination therapy with fluorinated pyrimidine anticancer agents and platinum-
containing drugs has been recommended as standard treatment.  JCOG9912 Study [5-FU vs. 
irinotecan + cisplatin vs. S-1] [Boku, N., et al 2009] conducted in Japan revealed 
noninferiority of S-1 monotherapy to continuous IV 5-FU infusion, which was the standard 
treatment at that time, in terms of OS, and SPIRITS Study (S-1 vs. S-1 + cisplatin) [Koizumi, 
W., et al 2008] demonstrated that S-1 + cisplatin therapy significantly prolonged OS 
compared with S-1 monotherapy.  ToGA study [Bang, Y. J., et al 2010] involving HER2-
positive gastric cancer patients showed that trastuzumab, a molecular-targeted agent, added 
to capecitabine (or 5-FU) + cisplatin therapy significantly prolonged OS.  On the basis of 
these results, the Japanese gastric cancer treatment guidelines 4th edition (revised in May 
2014) [Japanese Gastric Cancer Association 2017] recommend S-1 + cisplatin therapy and S-
1 monotherapy for HER2-negative patients who are capable of orally taking drugs, and 
capecitabine (or 5-FU) + cisplatin + trastuzumab therapy for patients with HER2-positive, 
advanced or recurrent gastric cancer.
Comparison between Cisplatin and Oxaliplatin
3.2.5.2
When cisplatin and oxaliplatin are compared, hydration for the prevention of renal toxicity 
before administration is required for cisplatin; thus, whether or not cisplatin can be replaced 
with oxaliplatin not requiring hydration has been studied.  Because REAL-2 trial (ECF vs. 
ECX vs. EOF vs. EOX) [Cunningham, D., et al 2008] revealed the noninferiority of the 
oxaliplatin group to the cisplatin group in terms of OS, the efficacy of cisplatin and 
oxaliplatin is considered to be equivalent.  In Japan, G-SOX study (S-1 + cisplatin vs. S-1 + 
oxaliplatin) [Yamada, Y., et al 2015] was conducted to demonstrate the noninferiority of S-1 
+ oxaliplatin therapy to S-1 + cisplatin therapy.  While the noninferiority of S-1 + oxaliplatin 
therapy to S-1 + cisplatin therapy in terms of PFS was shown, the OS result was slightly 
above the upper limit (1.15) of the noninferiority margin (OS, 13.1 months vs. 14.1 months; 
hazard ratio, 0.969 [95% confidence interval, 0.812 to 1.157]).  Nonetheless, an ex-post facto 
analysis using a method to combine 1 subject excluded at the time of the primary analysis 
revealed that the upper limit of the hazard ratio was below 1.15 (hazard ratio, 0.958 [95% 
confidence interval, 0.803 to 1.142]).  In 2009, the Japanese Gastric Cancer Association 
 
 
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submitted a request for the expansion of the indication for oxaliplatin for unresectable 
advanced or recurrent gastric cancer.  On the basis of results of REAL-2 trial and G-SOX 
study, the clinical usefulness of combination therapy with other anticancer agents and 
oxaliplatin for unresectable advanced or recurrent gastric cancer was determined to be a 
medically and pharmacologically known fact; thus, it was included in health insurance 
treatment in September 2014.  In addition, SOPP study (S-1 + cisplatin vs. S-1 + oxaliplatin) 
[Ryu, M. H., et al 2016] conducted in South Korea showed the noninferiority of S-1 + 
oxaliplatin therapy to S-1 + cisplatin therapy in terms of PFS.  Consequently, S-1 + 
oxaliplatin Q3W regimen is likely to be used as a standard first-line chemotherapy regimen 
for patients with metastatic gastric cancer.
With regard to an evaluation of the initial dose of oxaliplatin, in three overseas comparative 
studies involving patients with unresectable advanced or recurrent gastric cancer used in a 
metaanalysis [Montagnani, F., et al 2011], oxaliplatin 130 mg/m2 administered Q3W or 85 
mg/m2 administered every other week was used (drug potency, 43 mg/m2/week for both 
regimens).  The hazard ratios of OS compared with cisplatin were 0.65 to 0.91 in the each 
study and 0.88 (95% confidence interval, 0.78 to 0.99) for all the studies.  Compared with 
these, the point estimate of the hazard ratio in G-SOX study was as high as 0.969, and it 
cannot be denied that oxaliplatin 100 mg/m2 administered Q3W (drug potency, 33 
mg/m2/week) may not adequately exert the effects of this drug.  Consequently, the initial 
oxaliplatin dose of 130 mg/m2 is to be used in this study.
S-1 + Cisplatin Regimen
3.2.5.3
With regard to comparison between S-1 + cisplatin Q3W and Q5W, SOS study (S-1 + 
cisplatin therapy, every 3 weeks vs. every 5 weeks) [Ryu, M. H., et al 2015] revealed 
equivalence between the two groups for OS (MST, 14.1 months vs. 13.9 months), whereas 
the superiority of the Q3W groups for PFS was showed (PFS, 5.5 months vs. 4.9 months; 
hazard ratio, 0.82 [95% confidence interval, 0.68 to 0.99]). In SPIRITS Study [Koizumi, W., 
et al 2008] conducted in Japan, MST was 13.0 months for the S-1 + cisplatin Q5W regimen. 
In consideration of obtaining almost reproducible results for the therapeutic results of S-1 + 
cisplatin therapy while the countries where the studies were implemented varied, the 
superiority of the Q3W group for PFS shown in SOS study, and the dosing interval of 
pembrolizumab, the S-1 + cisplatin Q3W regimen is to be utilized in this study.
Combination of Pembrolizumab and Chemotherapy
3.2.5.4
With ToGA study, mentioned also in Section 3.2.5.1, combination therapy of trastuzumab 
with standard therapy including 5-FU in HER-2-positive patients has become a new standard 
therapy; similarly, combination of MK-3475 with standard therapy in PD-L1-positive 
patients can become a new therapeutic option for treating gastric cancer in Japan.
Comparison with Study 062 (Keynote062)
3.2.5.5
A Phase III global study (Study 062) of pembrolizumab as first-line treatment in patients 
with advanced gastric or GEJ adenocarcinoma is underway with Japan included.  In Study 
062, three groups have been compared: pembrolizumab monotherapy, pembrolizumab + 
cisplatin + 5-fluorouracil/ cisplatin + capecitabine therapy, and placebo + cisplatin + 5-
fluorouracil/ cisplatin + capecitabine.  Capecitabine + cisplatin therapy is a standard 
 
 
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treatment in foreign countries, but the Japanese gastric cancer treatment guidelines 4th 
edition (revised in May 2014) state that it is not a recommended but optional regimen among 
treatments for HER2-negative patients.  Consequently, it has been found to be useful for the 
treatment of gastric cancer in Japan to combine pembrolizumab with TS-1 + oxaliplatin 
therapy or TS-1 + cisplatin therapy, which are standard first-line treatment for Japanese 
patients with advanced gastric or GEJ adenocarcinoma, and to evaluate the efficacy and 
safety of pembrolizumab in combination with these therapies in this study.
3.3
Benefit/Risk Assessment
Participants in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Beneficial effects of pembrolizumab have been seen in several trials to date.  Publications of 
a significantly positive benefit/risk ratio have been reported for melanoma in a single arm 
study encompassing nearly 1,000 patients (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 3.2.4, 
which details responses of the KEYNOTE 012 trial; a multi cohort Phase Ib study of which 1 
cohort enrolled subjects with recurrent or metastatic gastric or GEJ adenocarcinoma that 
expressed PD-L1 (≥1% by immunohistochemistry).  Although two-thirds of subjects 
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% confidence 
interval [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 subjects.  There were 12.8% of 
subjects 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 trial may be found in the accompanying Investigator’s Brochure (IB) and Informed 
Consent documents.
 
 
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4. Objectives/Hypotheses and Endpoints
In subjects with PD-L1 positive, advanced gastric or GEJ adenocarcinoma, the following 
objectives will be applied to Cohort 1 and Cohort 2 separately. 
Objective/Hypothesis
Endpoint
Primary

To evaluate ORR per RECIST 1.1 as 
assessed by BICR.

ORR is defined as the proportion of 
participants who have a confirmed 
complete response (CR) or partial 
response (PR).
Secondary

To evaluate the Duration of Response 
(DOR) per RECIST 1.1and per 
iRECIST as assessed by BICR.

To evaluate ORR per iRECIST by 
BICR.

To evaluate Disease Control Rate 
(DCR) per RECIST 1.1and per 
iRECIST as assessed by BICR.

To evaluate PFS per RECIST 1.1 and 
per iRECIST as assessed by BICR.

To evaluate Time To Response (TTR) 
per RECIST 1.1 and per iRECIST as 
assessed by BICR.

To assess OS

To evaluate safety

DOR defined as the time from the 
earliest date of qualifying response 
until earliest date of disease 
progression or death from any cause, 
whichever comes first.

ORR is defined as the proportion of 
participants who have a confirmed 
complete response (CR) or partial 
response (PR).

DCR is defined as the proportion of 
participants who have a stable disease 
(SD) or better prior to any evidence of 
progression.

PFS is defined as the time from date of 
enrollment to the first documented 
progressive disease (PD). Death due to 
any cause, whichever occurs first.

TTR is defined as a time from the date 
of enrollment day (a starting day) to the 
first date of confirmed CR or PR

OS is defined as the period from the 
date of enrollment to the date of death
due to any cause.

Number of participants experiencing 
AEs and number of participants 
discontinuing study drug due to AEs.
 
 
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5. Study Design 
5.1
Overall Design 
This is a nonrandomized, multi-site, open-label trial to estimate overall response rates 
(ORRs) of pembrolizumab + oxaliplatin + TS-1 and pembrolizumab + cisplatin + TS-1, as 
first-line treatment for gastric cancer in programmed death-ligand 1 (PD-L1) positive, human 
epidermal growth factor receptor 2 (HER2/neu) negative subjects with advanced gastric or 
gastroesophageal junction (GEJ) adenocarcinoma.
First, 45 subjects will be assigned to Cohort 1, pembrolizumab + oxaliplatin + TS-1 
combination therapy, and then, 45 subjects will be assigned to Cohort 2,  pembrolizumab + 
cisplatin + TS-1 combination therapy.
In all the Cohorts, the study treatment will be started at Day 1 of each 3-week course.
Table 1
Treatments Dose and Schedule
Cohort
Treatment Dose and Schedule
Cohort 1
Pembrolizumab 200 mg Q3W + oxaliplatin 130 mg/m2 Q3W IV infusion + 
TS-1 BID continuous oral administration for 14 days followed by a recovery 
period of 7 days 
Cohort 2
Pembrolizumab 200 mg Q3W + cisplatin 60 mg/m2 Q3W IV infusion + TS-1 
BID continuous oral administration for 14 days followed by a recovery 
period of 7 days
The body surface area [BSA (m2)] should be calculated by the web registration system using the following 
DuBois formula:
BSA (m2) = ([body weight (kg)]0.425 × [body height  (cm)]0.725) × 0.007184
The administration of oxaliplatin may be interrupted or reduced at the discretion of the investigator because 
the incidence of neuropathy has been reported to increase with increases in the dose.
The administration of cisplatin may be interrupted or reduced at the discretion of the investigator because the 
incidence of hearing impaired has been reported to increase with increases in the dose.
The study treatment should be started within 8 days after the day of enrollment.
Participation in this trial will be dependent upon supplying a tumor tissue specimen.  Newly 
obtained endoscopic biopsy or core biopsy of a metastatic site if obtained as part of 
normal clinical practice is preferred to archived samples.  Both formalin solution and 
formalin-fixed, paraffin embedded (FFPE) block specimens are acceptable.  If submitting 
unstained slides, the slides should be freshly cut and received at the testing laboratory within 
14 days from site slide section date, otherwise a new specimen will be requested.  The 
specimen will be evaluated at a central laboratory facility for expression status of PD-L1 in a 
prospective manner.  Only subjects whose tumors express PD-L1 (are PD-L1+) as 
determined by the central laboratory facility will be eligible for enrollment in this study.  
Subjects will also be required to be HER-2/neu negative.
Subjects will undergo the first imaging evaluation 6 weeks (± 7 days) after enrollment.  
Subsequently, subjects will be evaluated every 6 weeks (42 days ± 7 days), independent of 
any treatment delays, with radiographic imaging to assess response to treatment using 
 
 
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Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).  When overall 
response is graded as CR or PR based on RECIST 1.1, the examination interval is changed 
and imaging that will confirm the best overall response (in case of CR, tumor maker levels 
will also be measured) will be performed 4 weeks after the last assessment (accepted if 
performed up to 7 days after a reference day).  When assessment consecutively results in CR 
or PR, confirming the best overall response, examinations will be performed thereafter at an 
interval of 6 weeks from the day of enrollment. Subsequent scheduled examination after 
confirming the best over response as CR or PR will not be required. RECIST 1.1 responses 
as assessed by the BICR will be used as the primary efficacy endpoint; Overall Response 
Rate (ORR). The treatment will be continued until the first documented PD. RECIST 1.1 will 
be used by the local site for treatment decisions.  Following verification of PD, treatment 
decision may be made by the adaptation of RECIST 1.1 [Ji, Y., et al 2010], as described in 
Section 9.2.1.5, termed immune-related RECIST (iRECIST) to accommodate for the tumor 
response patterns seen with pembrolizumab treatment (e.g., tumor flare).
Adverse events (AE) will be monitored throughout the trial and graded in severity according 
to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.   
Treatment will continue until documented clinical PD, unacceptable AE(s), intercurrent 
illness that prevents further administration of treatment, investigator’s decision to withdraw 
the subject, subject withdraws consent, subject’s request to discontinue, pregnancy of the 
subject, noncompliance with trial treatment or procedure requirements, 35 administrations of 
pembrolizumab (approximately 2 years), or administrative reasons.
Subjects who have evidence of PD by imaging but are clinically stable may continue to be 
treated at the discretion of the investigator.  In addition, subjects who attain an investigator-
determined confirmed complete response (CR) may stop the trial treatment after receiving at 
least 8 administrations of pembrolizumab and at least two additional treatments of 
pembrolizumab between the confirmation of CR and the treatment discontinuation.
After the end of treatment, each subject will have a 30 day follow-up assessment for AE 
monitoring (serious adverse events and events of clinical interest (ECI) will be collected for 
90 days after the end of treatment or 30 days after the end of treatment if the subject initiates 
new anticancer therapy, whichever is earlier). Subjects who discontinue treatment for 
reasons other than PD will have post-treatment follow-up for disease status until PD, 
withdrawing consent, or becoming lost to follow-up.  All subjects will be followed for OS by 
telephone and other systems every 12 weeks (±7 days) or more frequently based on the 
necessity until death, withdrawal of consent or the end of the trial, whichever comes first.
This study will be conducted in conformance with Good Clinical Practices.
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.
No safety and/or efficacy interim analysis is planned.  Statistical analyses will be carried out 
at the key evaluation time point for each cohort and the end of the study.  More details are in 
Section 10.7.
 
 
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Study Diagram
5.1.1
The study design is depicted in Figure 1.
HER2/neu negative is defined as:  IHC (0, or 1+), or FISH negative (HER2:CEP17 ratio < 2). In place of FISH, available in 
situ hybridization (ISH) techniques, e.g., dual color in situ hybridization (DISH), can be employed according to trial site-
specific guidelines.
Figure 1
Phase II Trial Design for Enrollment of PD-L1 Positive, HER2/neu Negative 
Subjects with Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma.
 
 
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Study Duration for each subject
5.1.1.1
Study periods for each subject are defined from below start date to end date.
Start date: the day the ICF is signed
End date: the day subjects complete the Safety Follow-up
Definition of Study Period
5.1.1.2
Study periods for each subject are defined below.
Pre-Study duration: until the day the ICF is signed
Study duration: Begins the day the ICF is signed and lasts until the day prior to completion 
the Safety Follow-up
Administration period: Defined as the day IP is administered
Recovery period: Defined as the day IP is not administered
Safety Follow-up: Defined as the day after the end of study treatment until 30 days (non-
serious adverse events) 
90 days after the end of treatment or 30 days after the end of treatment if the subject initiates 
new anticancer therapy, whichever is earlier (serious adverse events and ECI)
Tumor Imaging/ Survival Follow-up: Defined as the day after the end of Safety Follow-up
5.2
Number of Participants
Approximately 90 participants will be allocated into the study.
5.3
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent form (ICF).  
The overall study ends when the last participant completes the last study-related phone-call 
or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to be 
contacted by the investigator).  
 
 
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Clinical Criteria for Early Study Termination
5.3.1
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.
5.4
Scientific Rationale for Study Design 
Rationale for Endpoints
5.4.1
Efficacy Endpoints
5.4.1.1
This study will use ORR based on RECIST 1.1 criteria as assessed by BICR as the primary 
endpoint. Objective response rate (ORR) is an acceptable measure of clinical benefit for a 
late stage study that demonstrates superiority of a new antineoplastic therapy, especially if 
the magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. The 
use of BICR and RECIST 1.1 to assess ORR is typically considered acceptable by regulatory 
authorities.  Images will be read by a BICR to minimize bias in the response assessments.
RECIST 1.1
5.4.1.1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (Section 9.2.1.4). Although traditional RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ.
iRECIST
5.4.1.1.2
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 9.2.1.5). Immunotherapeutic agents such 
as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and patients treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1 may, not provide an 
accurate response assessment of immunotherapeutic agents such as pembrolizumab. Based 
on an analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had progressive disease (PD) by RECIST 1.1 but not by the immune-related 
response criteria [Wolchok, J. D., et al 2009] had longer overall survival than participants 
with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest that RECIST 
1.1 may underestimate the benefit of pembrolizumab in approximately 15% of participants. 
These findings support the need to apply a modification to RECIST 1.1 that takes into 
account the unique patterns of atypical responses in immunotherapy and enables treatment 
beyond initial radiographic progression, if the participant is clinically stable. 
 
 
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Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of non-target lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by investigators to assess tumor 
response and progression and make treatment decisions, as well as for exploratory efficacy 
analyses where specified.
Safety Endpoints
5.4.1.2
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of adverse events (AEs)/serious adverse events (SAEs); and changes 
in vital signs and laboratory values. Adverse events will be assessed as defined by CTCAE, 
Version 4.0.
Rationale for the Trial and Selected Subject Population
5.4.2
Trials evaluating pembrolizumab (MK-3475) in gastric cancer have demonstrated clinical 
activity in subjects with recurrent and/or metastatic disease.  Refer to Section 3.2.4, Ongoing 
Clinical Trials. This trial is selected PD-L1 positive subjects like a KN062. There is no safety 
data of pembrolizumab in combination with oxaliplatin in the previous studies, the first 45 
participants will be assigned to Cohort 1 to accumulate the data in combination with
oxaliplatin prior to cisplatin.
5.5
Justification for Dose 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-
based PK [PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and 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 Cohort B2, KN001 Cohort D, KN002, KN010, 
 
 
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and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort 
B3, KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and 
exposure-response relationships across the doses studied representing an approximate 5- to 
7.5 fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar 
responses to the highest doses studied. Subsequently, flat dose-exposure-response 
relationships were also observed in other tumor types including head and neck cancer, 
bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W 
as the appropriate dose independent of the tumor type. These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and 
not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
6. Study Population
Male/Female participants with locally advanced unresectable or metastatic gastric or GEJ 
adenocarcinoma of between 18 and 75 years of age 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.
6.1
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. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 to ≤ 75 years of age on day of signing informed consent.
3. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale at the timing of enrollment.
4. Have histologically or cytologically confirmed diagnosis of locally advanced 
unresectable or metastatic gastric or GEJ adenocarcinoma. 
 
 
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5. Have a PD-L1 positive tumor as determined by IHC at a central laboratory.
Note: PD-L1 positive is defined as a CPS of ≥1% by IHC 22C3 PharmDx assay
6. Have measurable disease as defined by RECIST 1.1 as determined by investigator 
assessment. Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.
Note:  The exact same image acquisition and processing parameters are 
recommended throughout the study.
7. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test at the timing of enrollment. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.
8. Female subjects of childbearing potential (Section 7.7.4.2) must be willing to use an 
adequate method of contraception as outlined in Section 7.7.4.2 – Contraception,  for 
the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
9. Male subjects of childbearing potential (Section 5.6.2) must agree to use an adequate 
method of contraception as outlined in Section 5.6.2- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
10. Demonstrate adequate organ function as defined in Table 2.  All screening labs 
should be performed within 7 days of enrollment.
 
 
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Measured or calculatedb creatinine clearance
≥60 mL/min
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × 
ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Albumin
≥ 2.5 g/dL
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase 
(serum glutamic oxaloacetic transaminase); 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 Creatinine clearance (CrCl) should be calculated using the Cockcroft-Gault estimation formula as shown below.
Estimated creatinine clearance (mL/min)= (140 - age) x Body weight (kg) / [72 x Serum creatinine (mg/dL)]
For women, the obtained value is multiplied by a factor of 0.85..
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.
6.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has squamous cell or undifferentiated gastric cancer.
2. Participants with human epidermal growth factor receptor 2 (HER2)-positive status. 
3. Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ 
cancer. Subjects may have received prior neoadjuvant or adjuvant therapy as long as 
it was completed at least 6 months prior to enrollment. 
4. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation 
(see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.
5. Has received prior therapy with a platinum-based anti-cancer drug.
 
 
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6. Has had major surgery, open biopsy or significant traumatic injury within 28 days 
prior to enrollment, or anticipation of the need for major surgery during the course of 
study treatment.
7. Has had radiotherapy within 14 days of enrollment.  Subjects who received 
radiotherapy >14 days prior to enrollment must have completely recovered from any 
radiotherapy related AEs/toxicities.
8. 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.
9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, ie, without evidence of progression for at least 4 weeks by repeat imaging 
(note that the repeat imaging should be performed during study screening),  clinically 
stable and without requirement of steroid treatment for at least 14 days prior to first 
dose of study treatment.
10. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.   
11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.
12. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis
13. Has an active infection requiring systemic therapy.
14. Being on flucytosine at the time of enrollment.
15. Has grade ≥ 2 peripheral sensory neuropathy.
16. Has poorly controlled diarrhea (e.g., watery stool, uncontrollable bowel movement 
with drugs, grade ≥ 2 and number of defecations, ≥ 5/day).
17. Accumulation of pleural, ascitic, or pericardial fluid requiring drainage within 2 
weeks prior to enrollment.
18. Has a history or current evidence of any condition (e.g. known deficiency of the 
enzyme dihydropyrimidine dehydrogenase [DPD]), therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.
 
 
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19. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
20. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days 
after the last dose of study treatment.
21. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, 
CTLA-4, OX 40, CD137).
22. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
23. 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.
24. Is currently participating in and receiving study therapy or has participated in a study 
of an investigational agent and received study therapy or used an investigational 
device within 4 weeks prior to the first dose of trial treatment.
25. Has received a live vaccine within 30 days of planned start of study therapy.
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.
6.3
Histological Classification in Target Patients
Target adenocarcinoma in the trial is provided below.
Common Type
Papillary adenocarcinoma (pap)
Tubular adenocarcinoma (tub)
Well-differentiated type (tub1)
Moderately-differentiated type (tub2)
Poorly-differentiated adenocarcinoma (por)
Solid type (por1)
Non-solid type (por2)
Signet-ring cell carcinoma (sig)
Mucinous adenocarcinoma (muc)
 
 
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6.4
Lifestyle Restrictions
Contraception
6.4.1
Pembrolizumab may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 5) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of study medication. If there is any question that a participant of 
childbearing potential will not reliably comply with the requirements for contraception, that 
participant should not be entered into the study.
Pregnancy
6.4.2
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment. The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 7.7.4.3.
Use in Nursing Women
6.4.3
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment.
6.5
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the data entry guidelines.
6.6
Participant Replacement Strategy
A participant who discontinues from the trial will not be replaced.
 
 
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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 
enrollmentparticipants.  Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
7.1
Treatments Administered
The study treatments to be used in this study are outlined below in Table 3.
Table 3
Study Treatments
Study Treatment 
Name:
Pembrolizumab 
(MK-3475)
Oxaliplatin*
Cisplatin**
TS-1***
Dosage 
Formulation:
Solution for 
infusion
Solution for 
infusion
Solution for 
infusion
Capsule
Unit Dose 
Strength(s):
100 mg/vial
20 mg/capsule
25 mg/capsule
Dosage Level(s):
200 mg Q3W
Day 1
130 mg/m2 Q3w
Day 1
60 mg/m2 Q3W
Day 1
40 to 60 
mg/body/dose BID 
Q3W Day 1-14
Route of 
Administration:
IV infusion
IV infusion
IV infusion
Oral
Sourcing:
Provided centrally 
by the Sponsor
Locally by the 
study site
Locally by the 
study site
Provided centrally 
by the Sponsor
*The administration of oxaliplatin may be interrupted or reduced at the discretion of the investigator because the 
incidence of neuropathy has been reported to increase with increases in the dose; however, treatment with TS-1 
should be continued per protocol.
**The administration of cisplatin may be interrupted or reduced at the discretion of the investigator because the 
incidence of hearing impaired has been reported to increase with increases in the dose; however, treatment with 
TS-1 should be continued per protocol.
*** For the initial dose, TS-1 shall be administered orally twice daily after breakfast and after dinner according to 
the following dose depending on the BSA.
Body Surface Area (m2)
Dosage in each dose
(Number of capsules)
Total daily dose
(Number of capsules)
< 1.25
40 mg (2)
80 mg (4)
≥1.25 - < 1.5
50 mg (2)
100 mg (4)
≥1.5
60 mg (3)
120 mg (6)
All supplies indicated in 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 7.2.6 for details regarding administration of the study treatment.
The study treatment should be started within 8 days after the day of enrollment.
Pembrolizumab and TS-1 will be provided by the designee, depending on regulatory 
requirements.
 
 
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For any commercially available product that is provided by the trial site, designee every 
attempt will be made to source these supplies from a single lot/batch number. 
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
7.2
Dose Modification (Escalation/Titration/Other)
Dose Selection (Preparation)
7.2.1
The rationale for selection of dose of pembrolizumab to be used in this trial is provided in 
Section 4.0– Background & Rationale.  Details on preparation and administration of 
pembrolizumab are provided in the Pharmacy Manual.
Preparation of oxaliplatin, cisplatin, and TS-1 should follow the local product label.  The 
body surface area (BSA) in m2 should be calculated by the web registration system using the 
DuBois formula.  The dose of oxaliplatin and cisplatin shall not be recalculated by body 
weight fluctuation in principle, but for 10% or higher fluctuation of body weight, 
recalculation is possible at the discretion of the investigator. When recalculation, the BSA 
will be calculated using the DuBois formula.
Dose Modification
7.2.2
The Investigator may attribute each toxicity event to oxaliplatin, cisplatin, TS-1 or 
pembrolizumab alone and use a stepwise dose reduction according to Table 4 to Table 8.  
Dose modification should be performed with the following taken into consideration.

Treatment for each new cycle may be delayed if the scheduled off-drug periods are 
not adequate to allow for recovery to the guideline for restarting each study treatment.  

Pembrolizumab dose reductions are not permitted.  Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity.  

If a dose reduction for toxicity occurs with any agent, the dose may not be re-
escalated.  

Subjects can have a maximum of 2 dose modifications (if applicable) to the TS-1, a 
maximum of 3 dose modifications to the oxaliplatin and cisplatin, throughout the 
course of the study for toxicities.  If a subject experiences several toxicities and there 
are conflicting recommendations, please follow the most conservative dose 
adjustment recommended (dose reduction appropriate to the most severe toxicity).  

Reduction of one 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, 
in the opinion of the Investigator, the toxicity is related to the combination of both
chemotherapy agents, both drugs may be considered to be reduced according to 
recommended dose modifications.  If the toxicity is related to the combination of 
three agents, chemotherapy may be considered to be reduced, interrupted or 
discontinued, pembrolizumab should be interrupted or discontinued according to the 
recommended dose modifications.
 
 
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
Both cohorts may have the oxaliplatin, cisplatin and TS-1 discontinued and continued 
on pembrolizumab alone.

Both cohorts may have the pembrolizumab discontinued and continued on TS-1 + 
oxaliplatin or TS-1 + cisplatin. Also, both cohorts may have the oxaliplatin and 
cisplatin discontinued and continued on TS-1 alone. But both cohorts may not have 
the TS-1 discontinued and continued on oxaliplatin or cisplatin alone.
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be 
used to grade the severity of adverse events.  All dose modifications should be based on the 
AE requiring the greatest dose modification.  Dose modifications are detailed in Table 4
through Table 8.  Exceptional circumstances to following the dose modification tables below 
may be considered after consultation with the Sponsor.
Table 4
Dose Modifications for Trial Medications
Dose level 0
Dose level -1
Dose level -2
Dose level -3
Dose level -4
Oxaliplatin
130 mg/m2
100 mg/m2
75 mg/m2
50 mg/m2
Not specified*
Cisplatin
60 mg/m2
50 mg/m2
40 mg/m2
30 mg/m2
Not specified*
TS-1
60 mg/dose
50 mg/dose
40 mg/dose
50 mg/dose
40 mg/dose
Not specified*
40 mg/dose
Not specified*
Not specified*
Not specified*
Not specified*
Not specified*
Not specified*
Not specified*
Not specified*
Pembrolizumab
200 mg fixed 
dose
Dose reductions 
are not 
permitted
Dose reductions 
are not 
permitted
Dose reductions 
are not 
permitted
Dose reductions 
are not 
permitted
*Because there are no further criteria for dose reductions, the treatment may be resumed or started at the lowest dose if the
criteria for resuming the treatment in the cycle or for starting the next cycle are met.
If a toxicity is not otherwise specified, investigators should refer to the label or local 
guidelines for oxaliplatin, cisplatin and TS-1 for dose adjustments.
Dose modification and toxicity management for immune-related AEs associated 
7.2.3
with pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 5. 
 
 
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Table 5
Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper
over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-
related AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
Pneumonitis
Grade 2
Withhold 
• Administer 
corticosteroids (initial 
dose of 1-2mg/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
Grade 3 or 4, 
or recurrent 
grade 2
Permanently 
discontinue
Diarrhea / colitis
Grade 2 or 3
Withhold
• Administer 
corticosteroids (initial 
dose of 1-2mg/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.
Grade 4
Permanently 
discontinue
 
 
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General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper
over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-
related AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
Bilirubin
Grade 2
Withhold
• Administer 
corticosteroids (initial 
dose of 0.5- 1mg/kg 
prednisone or 
equivalent) followed by 
taper
• Administer 
corticosteroids (initial 
dose of 1-2mg/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
Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withhold
• Initiate insulin 
replacement therapy for 
participants with 
T1DM 
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia
• Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes.
Hypophysitis
Grade 2
Withhold
• Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.
• Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
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 
discontinue1
Hypothyroidism
Grade 2-4
Continue
• Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per 
standard of care
• Monitor for signs and 
symptoms of thyroid 
disorders.
Nephritis and 
renal 
dysfunction
Grade 2
Withhold 
• Administer 
corticosteroids 
(prednisone 1-2mg/kg 
or equivalent) followed 
by taper.
• Monitor changes of 
renal function
Grade 3 or 4
Permanently 
discontinue
 
 
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General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper
over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-
related AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
All Other 
immune-related 
AEs
Grade 3, or 
intolerable/ 
persistent 
Grade 2
Withhold
• Based on severity of 
AE administer 
corticosteroids
• Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may 
be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case 
of T1DM).
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 6.
 
 
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Table 6
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
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 (e.g. 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 1.5h (± 30 
minutes) prior to infusion of 
_____ with:
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Participant is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov
 
 
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Other allowed dose interruption for pembrolizumab 
7.2.4
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 patient's study record.
Dose Modification for Oxaliplatin, Cisplatin and TS-1
7.2.5
Please refer to criteria for oxaliplatin, cisplatin and TS-1 dose modification included in 
Table 7, Table 8, and Table 9, respectively. 
Table 7
Dose Modification Guidelines for Oxaliplatin Drug-Related Adverse Events
Category
Toxicity
Hold 
Oxaliplatin 
Treatment for 
Grade
Timing for 
Restarting
Oxaliplatin 
Treatment
Dose for Restarting
Oxaliplatin Treatment
Hematologic1
Neutropenia5
2-32
≥1,500/mm3
No Reduction
If the criteria for starting the 
course are not met at Day 22, 
reduce by 1 DL.
42
≥1,500/mm3
Reduce by 1 DL
Febrile neutropenia
3-42
Toxicity resolves
Reduce by 1 DL
Thrombocytopenia
2-42
≥75,000/mm3
Reduce by 1 DL
If a platelet count is
≥ 75,000/mm3 to
< 100,000/mm3 at Day 223
Non-
  hematologic
Creatinine 
increased
≥1.5 mg/dL2
<1.5 mg/dL
No reduction
Peripheral sensory 
neuropathy4
2
May be 
interrupted at the 
discretion of the 
investigator
3-42
Grade 0-2
Grade 0-2
Consider a reduction by 1 
DL at the discretion of the 
investigator
Reduce by 1 DL
1 Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.
2 Permanent discontinuation should be considered for any severe or life-threatening event.  Consult Sponsor before 
restarting treatment after Grade 4 drug-related AE.
3 If ≥75,000/mm3 and < 100,000/mm3 persist in the next and subsequent courses, a dose reduction is not mandatory.
4 Administration may be interrupted or reduced at the discretion of the investigator.
5 See the package insert of each G-CSF drugs for administration of G-CSF for neutropenia.
 
 
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Table 8
Dose Modification Guidelines for Cisplatin Drug-Related Adverse Events
Category
Toxicity
Hold Cisplatin 
Treatment for 
Grade
Timing for 
Restarting
Cisplatin 
Treatment
Dose for Restarting
Cisplatin Treatment
Hematologic1
Neutropenia4
2-32
≥1,500/mm3
No Reduction
If the criteria for starting the 
course are not met at Day 22, 
reduce by 1 DL.
42
≥1,500/mm3
Reduce by 1 DL
Febrile neutropenia
3-42
Toxicity resolves
Reduce by 1 DL
Thrombocytopenia
2
≥75,000/mm3
No Reduction
3-42
≥75,000/mm3
Reduce by 1 DL
Non-
  hematologic
Creatinine 
increased
>1.2 x ULN2
≤1.2 x ULN
Reduce by 1 DL
Ototoxicity or 
Peripheral sensory 
neuropathy3
3-42
Grade 0-2
Reduce by 1 DL
1 Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.
2 Permanent discontinuation should be considered for any severe or life-threatening event.  Consult Sponsor before 
restarting treatment after Grade 4 drug-related AE.
3 Administration may be interrupted or reduced at the discretion of the investigator.
4 See the package insert of each G-CSF drugs for administration of G-CSF for neutropenia.
Table 9
Dose Modification Guidelines for TS-1 Drug-Related Adverse Events
Category
Toxicity
Hold TS-1 
Treatment for 
Grade
Timing for 
Restarting
TS-1 Treatment
Dose for Restarting
TS-1 Treatment
Hematologic1
Neutropenia3
32
≥1,500/mm3
No Reduction
If the criteria for starting the 
course are not met at Day 22, 
reduce by 1 DL.
42
≥1,500/mm3
Reduce by 1 DL
Febrile neutropenia
3-42
Toxicity resolves
Reduce by 1 DL
Thrombocytopenia
3-42
≥75,000/mm3
Reduce by 1 DL
Non-
  hematologic
Diarrhoea, 
Mucositis, or Hand 
and foot syndrome
2-42
Grade 0-1
Reduce by 1 DL
Creatinine 
increased
[Cohort 1]
≥1.5 mg/dL2
[Cohort 2]
> 1.2 x ULN2
[Cohort 1]
<1.5 mg/dL
[Cohort 2]
≤ 1.2 x ULN
No Reduction
AST, ALT
> 2.5 x ULN2
> 5 x ULN for 
subjects with 
liver metastases
≤2.5 x ULN
≤5 x ULN for 
subjects with liver 
metastases
Reduce by 1 DL
1 Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.
2 Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before restarting 
treatment after Grade 4 drug related AE.
3 See the package insert of each G-CSF drugs for administration of G-CSF for neutropenia.
 
 
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Timing of Dose Administration
7.2.6
Study treatment in all the cohorts will begin on Day 1 of each 3-week dosing cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatments may be administered up to 3 days before or after the scheduled Day 1 
of each cycle due to administrative reasons.
All trial treatments may be administered on an outpatient basis.
Treatment will be administered in the order presented below:
•
Pembrolizumab infusion is administered first followed by the oxaliplatin or cisplatin 
infusion and then TS-1 administration.
•
Treatment may continue with pembrolizumab+chemotherapy until documented 
confirmed disease progression, unacceptable AE(s), intercurrent illness that prevents 
further administration of treatment, Investigator’s decision to withdraw the subject, 
subject withdraws consent, subject’s request to discontinue, pregnancy of the subject, 
noncompliance with trial treatment or procedure requirements, or administrative reasons 
requiring cessation of treatment, or until the participant has received 35 administrations 
of pembrolizumab (approximately 2 years).
Note: Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons (i.e. elective surgery, unrelated medical events, subject vacation, and holidays) not 
related to study therapy. Subjects should be placed back on study therapy as soon as 
clinically appropriate per the investigator, and not exceeding 3 weeks from the interrupted 
dosing. For all study drugs, Day 1 of subsequent cycles should be adjusted accordingly to 
adhere to every 3 week dosing schedule. Discuss with the Sponsor if subjects cannot restart 
study medication within 3 weeks. The reason for interruption should be documented in the 
subject's study record.
Pembrolizumab
7.2.6.1
Regardless of clinical benefit, subjects may only receive 35 administrations (approximately 2 
years) with pembrolizumab. Pembrolizumab 200 mg fixed dose will be administered as a 30 
minute IV infusion Q3W.  Sites should make every effort to target infusion timing to be as 
close to 30 minutes as possible.  However, given the variability of infusion pumps from site 
to site, a window of -5 minutes and +10 minutes is permitted (i.e., 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.
Oxaliplatin
7.2.6.2
Oxaliplatin 130 mg/m2 will be administered as a 120 minute IV infusion Q3W on Day 1 of 
each treatment cycle after all procedures and assessments are completed according to the 
“TRIAL FLOW CHART in Section 6.0” and pembrolizumab infusion is completed.  The 
administration of oxaliplatin may be interrupted or reduced at the discretion of the 
investigator because the incidence of neuropathy has been reported to increase with increases 
in the dose.
 
 
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Cisplatin
7.2.6.3
Cisplatin 60 mg/m2 will be administered as over 120 minute (120 minute or more is 
recommended. If it is difficult due to the time, 60 minute or more is allowed.) IV infusion 
Q3W on Day 1 of each treatment cycle after all procedures and assessments are completed 
according to the “TRIAL FLOW CHART in Section 6.0” and pembrolizumab infusion is 
completed.  The administration of cisplatin may be interrupted or reduced at the discretion of 
the investigator because the incidence of hearing impaired has been reported to increase with 
increases in the dose.
TS-1
7.2.6.4
As tegafur, TS-1 40 to 60 mg/body/dose  BID according to the BSA will be administered 
Q3W at Days 1 to 14 after completion of all procedures and assessments according to the 
“TRIAL FLOW CHART in Section 6.0,” and pembrolizumab and oxaliplatin or cisplatin 
infusion.  An interval of at least 8 hours should be kept between the evening and morning 
doses of TS-1.  The subjects should have a meal and take the drug within 60 minutes after the 
meal.  For additional guidance on the treatment method of TS-1, see the package insert.
Note: If subject is enrolled later in the day, it is acceptable for only 1 dose taken on Day 1, 
and BID dosing can resume on Days 2-14 and the final dose will be taken in the morning of 
D15.
7.3
Method of Treatment Assignment 
Participants participating in this trial will be allocated by non-random assignment. The 
subjects will be enrolled in the study using web registration system (IWRS).  There are 2 
cohorts, and the first approximately 45 subjects will be assigned to Cohort 1. After 
enrollment in Cohort 1 is completed, enrollment in Cohort 2 will be started.
Stratification
7.3.1
No stratification based on age, sex or other characteristics will be used in this study.
7.4
Blinding 
This study is an open-label trial; therefore, the Sponsor, investigator and participant will 
know the treatment administered.
7.5
Preparation/Handling/Storage/Accountability
Dose Preparation
7.5.1
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Concomitant chemotherapeutic agents will be prepared and administered as per the 
approved product label(s).
 
 
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Handling, Storage and Accountability
7.5.2
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.
7.6
Treatment Compliance
Interruptions from the protocol specified treatment plan for more than 12 weeks between 
pembrolizumab doses for nondrug-related or administrative reason require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
7.7
Concomitant Therapy
Acceptable Concomitant Medications
7.7.1
All treatments that the investigator considers necessary for a subject’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 case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.
All concomitant medications received during the trial through 30 days after the last dose of 
trial treatment should be recorded.  Concomitant medications administered after 90 days after 
the last dose of trial treatment should be recorded for SAEs and ECIs as defined in Section 
7.2.
 
 
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Prohibited Concomitant Medication
7.7.2
Subjects are prohibited from receiving the following therapies during Screening to the day of 
Treatment discontinuation of this trial:
•
Antineoplastic systemic chemotherapy or biological therapy not specified in the protocol
•
Immunotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab
•
Radiation therapy; palliative radiation therapy to a symptomatic lesion (e.g. bony 
metastasis), or to the brain may be permitted after consultation with the Sponsor. 
•
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. The killed virus vaccines used for seasonal influenza vaccines for 
injection are allowed; however live attenuated intranasal influenza vaccines (e.g. Flu -
Mist®) are not allowed.
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology or cisplatin supportive care.  
The use of physiologic doses of corticosteroids may be approved after consultation with 
the Sponsor (e.g., for control of acute asthma symptoms).
•
For subjects assigned to Cohort 2:
•
Phenytoin should not be started with cisplatin therapy.
•
Flucytosine
•
Tegafur/Uracil and calcium folinate
Subjects who, in the assessment by the investigator, require the use of any of the
aforementioned treatments for clinical management should be removed from treatment.  
Subjects may receive other medications that the investigator deems to be medically necessary.
Concomitant Medications to be used with caution
•
Warfarin potassium (The effect of warfarin potassium may be enhanced.)
•
When other observation or tests suggested any abnormality, an international 
normalized ratio (INR), etc. should be measured to pay attention to changes in 
clotting ability, and the warfarin dose should be, as necessary, adjusted.
•
Phenytoin (Phenytoin addiction may occur.)
•
The subject’s condition should be monitored if they are on phenytoin.  If any 
abnormality is noted, appropriate therapeutic measures such as a dose reduction and 
treatment discontinuation should be taken.
•
For subjects assigned to Cohort 2:
•
Aminoglycoside antibiotics, vancomycin hydrochloride, and furosemide 
(concomitant administration of these drugs with cisplatin may enhance renal 
disorder and ototoxicity).
 
 
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•
Amphotericin B for injection (concomitant administration of the drug with cisplatin 
may enhance renal disorder).
•
Piretanide (concomitant administration of the drug with cisplatin may enhance 
ototoxicity).
Rescue Medications and Supportive Care
7.7.3
Supportive Care Guidelines for Pembrolizumab
7.7.3.1
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the 
ECI guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.  Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document.
•
Pneumonitis: 
•
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. See the guidelines shown in Table 5 for recurrent Grade 2 Pneumonitis.
•
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed.
•
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.
•
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
•
All subjects who experience 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.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis.
 
 
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•
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
•
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.  
•
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
•
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA)
•
For T1DM or Grade 3-4 Hyperglycemia
•
Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
•
Evaluate subjects with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
•
Hypophysitis:
•
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered.
•
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
•
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
•
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
•
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy.
•
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care.
•
Grade 3-4 hyperthyroidism 
•
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered.
 
 
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•
Hepatic:
•
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
•
Treat with IV or oral corticosteroids
•
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
•
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
•
Renal Failure or Nephritis:
•
For Grade 2 events, treat with corticosteroids.
•
For Grade 3-4 events, treat with systemic corticosteroids.
•
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
•
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. Table 6 shows treatment guidelines for subjects who experience 
an infusion reaction associated with administration of pembrolizumab (MK-3475).
Supportive Care Guidelines for Oxaliplatin/ Cisplatin
7.7.3.2
Prevention and/or treatment of nausea and vomiting should be managed with:
1. IV EMEND (fosaprepitant) 150 mg IV or oral EMEND (aprepitant) 3 day pack 125 
mg day 1, 80 mg day 2, 80 mg day 3
2. Plus Aloxi (Palonosetron) 0.25 mg IV
Nausea may also be managed with:
1. Zofran (Ondansetron) 8 mg twice a day
2. Or Compazine (Prochlorperazine) 10 mg 3-4 times per day
Additionally, use of steroids for oxaliplatin/ cisplatin associated anti-emetic support is 
allowed and is to follow the NCCN guideline, the local guidelines or institutional guidelines. 
Please refer to the product label or local standards of care for additional oxaliplatin/ cisplatin 
supportive measures.
Supportive Care Guidelines for TS-1
7.7.3.3
Please refer to the product label or local standards of care for TS-1 supportive measures.
Diet/Activity/Other Considerations
7.7.4
Diet
7.7.4.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
 
 
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Contraception
7.7.4.2
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if MK-
3475 has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either:
•
She is postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age 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. In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.); 
•
She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
•
She has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:  
•
practice abstinence† from heterosexual activity; 
•
use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
•
Single method (one of the following is acceptable):
o
intrauterine device (IUD)
o
vasectomy of a female subject’s male partner 
o
contraceptive rod implanted into the skin
•
Combination method (requires use of two of the following):
o
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
o
cervical cap with spermicide (nulliparous women only)  
o
contraceptive sponge (nulliparous women only) 
o
male condom or female condom (cannot be used together)
 
 
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o
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an 
acceptable method of contraception for subjects participating at sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study.
Use in Pregnancy
7.7.4.3
If a subject inadvertently becomes pregnant while on treatment the subject will immediately 
be discontinued from trial treatment.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the SPONSOR without delay and within 24 
hours if the outcome is a SAE (e.g., death, abortion, congenital anomaly, or other disabling 
or life-threatening complication to the mother or newborn).  The study investigator will make 
every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to the SPONSOR.
Use in Nursing Women
7.7.4.4
Since many drugs are excreted in human milk, and because of the potential for SAEs in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.  Specific 
additional information follows for individual agents used in this trial.
Pembrolizumab
7.7.4.4.1
It is unknown whether pembrolizumab is excreted in human milk.  
Oxaliplatin
7.7.4.4.2
Oxaliplatin has been reported to be excreted in breast milk in an animal experiment (rats). 
Whether or not oxaliplatin is excreted in human milk is unknown.  Subjects who receive 
oxaliplatin IV infusion should not breast-feed because it inhibits DNA replication and 
transcription.
Cisplatin
7.7.4.4.3
Cisplatin has been reported to be found in human milk; subjects receiving Cisplatin injection 
should not breast-feed.
 
 
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TS-1
7.7.4.4.4
Women who received tegafur/ uracil were reported to have given birth to deformed infants.  
It is not known whether TS-1 is excreted in human milk.  TS-1 inhibits DNA biosynthesis 
and impairs RNA function so that subjects receiving TS-1 should not breast-feed.
7.8
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
7.9
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Study treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
7.10 Standard Policies
Study Site Retention Samples
7.10.1
Investigational Product
7.10.1.1
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 10. 
Table 10
Product Descriptions.
Product Name & Potency
Dosage Form
Additional Information
Pembrolizumab (MK-3475), 
25 mg/mL
Injection
Provided centrally by the 
Sponsor or designee
Cisplatin, 
1 mg/mL
Injection
The drug used in the trial site 
will be used.
Oxaliplatin, 
50 mg/mL
Injection
The drug used in the trial site 
will be used.
TS-1
20 mg and 25 mg
Capsule
Provided centrally by the 
Sponsor or designee
Packaging and Labeling Information
7.10.1.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
MK-3475 will be provided in kits (boxes) containing 2 vials of MK-3475 each.
TS-1 will be provided in a kit (box) containing 56 capsules of TS-1 20 mg or 56 capsules of 
TS-1 25 mg.
 
 
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Storage and Handling Requirements
7.10.1.3
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
For other details, Study Drug Management Procedures must be followed.
Discard/Destruction/Returns and Reconciliation
7.10.1.4
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned, and the amount 
remaining at the conclusion of the trial. For all trial 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.
For other details, Study Drug Management Procedures must be followed.
8. Discontinuation/Withdrawal Criteria 
8.1
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period 
regimen will still continue to participate in the study as specified in Section 2 - Schedule of 
Activities and Section 9.1.9 – Withdrawal/Discontinuation, or if available, Protocol 
Clarification Letter.
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 – Withdrawal/Discontinuation.
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
Unacceptable adverse experiences as described in Appendix 4
 
 
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o
The participant interrupts study treatment administration for more than 12 consecutive 
weeks.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
o
The participant has a confirmed positive serum pregnancy test.
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
o
Noncompliance with study treatment or procedure requirements
o
Recurrent Grade 2 pneumonitis
o
Completion of 35 treatments (approximately 2 years) with pembrolizumab
Note: The number of treatments is calculated starting with the first dose.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
8.2
Withdrawal from the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study is outlined in Section 9.1.9 – Withdrawal/Discontinuation. The procedures to be 
performed should a participant repeatedly fail to return for scheduled visits and/or if the 
study site is unable to contact the participant are outlined in Section 8.3 Lost to Follow Up .
8.3
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 signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained 
from the participant.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
9.1
Administrative and General Procedures
Informed Consent
9.1.1
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical study. 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 consent is in place. 
General Informed Consent
9.1.1.1
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use.  
 
 
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The participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the study.  The communication of this information 
will be provided and documented via a revised consent form or addendum to the original 
consent form that captures the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
Submitting Tumor Sample
9.1.1.2
Tumor tissue sample for assessment of PD-L1 status must meet the following requirement: 
Either pre-existing archived or newly-obtained (fresh tissue) biopsy specimens from either 
primary or metastatic tumor of gastric origin, whichever most recent. 
•
Newly-obtained (fresh tissue) is defined as a specimen obtained up to 42 days prior to 
administration of study treatment on Day 1 of Cycle 1, and no additional anti-cancer 
treatment has been given after the specimen was obtained.  
•
Pre-existing, archived tissue must be obtained prior to time point that any anti-cancer 
treatment was given. 
A fine needle aspirate (FNA) or cytologic specimen will not be acceptable.  In the event the 
most recent available tumor tissue specimen is an FNA or cytologic specimen, a previous 
specimen obtained prior to any anti-cancer therapy was given may be submitted (provided it 
is not an FNA or cytologic specimen). 
Where available, both newly-obtained (fresh tissue) and pre-existing archived tissues are 
requested; however, the tissue specimen obtained closest to study treatment initiation on Day 
1 of Cycle 1 will be used to determine eligibility for study participation.
Tumor tissue specimen submitted in either formalin solution or FFPE block is acceptable.  If 
submitting unstained cut slides from FFPE block, freshly cut slides should be received by the 
central laboratory within 14 days from when the slides are prepared.  Please refer to the 
Procedures Manual for additional details.
Inclusion/Exclusion Criteria
9.1.2
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
9.1.3
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 written informed consent. At the time of 
 
 
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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.
Medical History
9.1.4
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the subject’s 
gastric or GEJ adenocarcinoma will be recorded separately and not listed as medical history.
Please note that if the subject has lost at least 15 lbs. (6.8 kg.) over the three 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
9.1.5
Prior Medications
9.1.5.1
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record details regarding the subject’s gastric or 
GEJ adenocarcinoma separately.
Concomitant Medications
9.1.5.2
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study from the day of first dose until the Safety Follow-up visit.
Assignment of Screening Number
9.1.6
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 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.  
A screening numbers is a “XX (trial site number)-1-” and 2-digit number in Cohort 1, and 
“XX (trial site number)-2-” and 2-digit number in Cohort 2.The 2-digit numbers are serial 
numbers in each trial site.
Assignment of Treatment/Randomization Number
9.1.7
At the time of confirmation of subjects’ eligibility, the subjects will be assigned to Cohort 1 
or 2 one by one, by Interactive Web Response System (IWRS).  For detailed procedures for 
assignment, see procedures which are provided separately.
 
 
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All eligible subjects will receive a patient number.  The patient number identifies the subject 
for all procedures occurring after enrollment.  Once a patient number is assigned to a subject, 
it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 patient number.
Trial treatment should begin within 8 days after the day of enrollment.
A patient number is a “659-1-” and 2-digit number in Cohort 1, and “659-2-” and 2-digit 
number in Cohort 2.  The 2-digit numbers are serial numbers in each cohort of the trial (not 
each trial site).
Treatment Administration
9.1.8
Administration of Pembrolizumab, Oxaliplatin and Cisplatin will be witnessed by the 
investigator and/or trial staff. Study Treatment should begin within 8 days after the day of 
enrollment.
Timing of Dose Administration
9.1.8.1
Refer to section 7.2.6 for details regarding administration of the study treatment.
Discontinuation and Withdrawal
9.1.9
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final trial visit should be performed (at the time of withdrawal).  Any 
adverse events which are present at the time of withdrawal should be followed in accordance 
with the safety requirements outlined in Section 9.3 Adverse Events (AE), Serious Adverse 
Events (SAE) and Other Reportable Safety Events.
Participant Blinding/Unblinding
9.1.10
This is an open label study; there is no blinding for this study.
Calibration of Critical Equipment
9.1.11
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical study that provides 
important information about inclusion/exclusion criteria and/or safety or efficacy parameters 
shall be suitably calibrated and 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.
Critical Equipment for this study includes:
•
Laboratory equipment – as required for inclusion labs and trial assessments
•
Imaging equipment – as required for study objectives
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Site 
Imaging Manual (SIM) and iRECIST Tip Sheet.
 
 
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9.2
Efficacy Assessments 
Tumor Imaging and Assessment of Disease
9.2.1
The process for image collection and transmission to the BICR can be found in the Site 
Imaging Manual (SIM). Tumor imaging is strongly preferred to be acquired by computed 
tomography (CT). For the abdomen and pelvis, contrast-enhanced magnetic resonance 
imaging (MRI) may be used when CT with iodinated contrast is contraindicated, or when 
mandated by local practice. MRI is the strongly preferred modality for imaging the brain. 
The same imaging technique regarding modality, ideally the same scanner, and the use of 
contrast should be used in a participant throughout the study to optimize the reproducibility 
of the assessment of existing and new tumor burden and improve the accuracy of the 
assessment of response or progression based on imaging. 
All scheduled images for all study participants from the sites will be submitted to the BICR. 
In addition, images (including via other modalities) that are obtained at an unscheduled time 
point to determine disease progression, as well as imaging obtained for other reasons, but 
captures radiologic progression based on investigator assessment, should also be submitted to 
the BICR. 
When the investigator identifies radiographic progression per RECIST 1.1, the BICR will 
perform expedited verification of radiologic PD and communicate the results to the trial site 
and Sponsor (See [Section 9.2.1.4] and Figure 2). Treatment should continue until PD has 
been verified. Regardless of whether PD is verified, if the investigator considers the 
participant has progressed, but elects to implement iRECIST, the investigator will assess for 
confirmation of progression by iRECIST at subsequent time points. Images should continue 
to be submitted to the BICR.
Initial Tumor Imaging
9.2.1.1
Initial tumor imaging at Screening must be performed within 21 days prior to the date of 
allocation. The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1.
Tumor Imaging During the Study
9.2.1.2
The first on-study imaging assessment should be performed within 21 days prior to the date 
of allocation. Subsequent tumor imaging should be performed every 6 weeks (42 days ±7 
days) or more frequently if clinically indicated. After 6 weeks, participants who remain on 
treatment will have imaging performed every 6 weeks. Imaging timing should follow 
calendar days and should not be adjusted for delays in cycle starts. Imaging should continue 
to be performed until disease progression is identified by the investigator (unless the 
investigator elects to continue treatment and follow iRECIST), the start of new anticancer 
treatment, withdrawal of consent, or death, or notification by the Sponsor, whichever occurs 
first. All supplemental imaging must be submitted to the BICR. 
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
 
 
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confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note:  Response does not typically need to be verified in real time by the BICR.
Per iRECIST (Section 9.2.1.5), disease progression should be confirmed by the site 4 to 8 
weeks after site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants who have unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site, provided they have 
met the conditions detailed in Section 9.2.1.5. Participants who receive confirmatory imaging 
do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; 
tumor imaging may resume at the subsequent scheduled imaging time point, if clinically 
stable. Participants who have confirmed disease progression by iRECIST, as assessed by the 
site, will discontinue study treatment. Exceptions are detailed in Section 9.2.1.5.
End of Treatment and Follow-up Tumor Imaging
9.2.1.3
For participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study treatment due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment (every 6 weeks in Year 1 or every 6 
weeks after Year 1) until the start of a new anticancer treatment, disease progression, death, 
withdrawal of consent, or the end of the study, whichever occurs first.
RECIST 1.1 Assessment of Disease
9.2.1.4
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study treatment). Although RECIST 1.1 references a maximum of 5 
target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in 
total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
iRECIST Assessment of Disease
9.2.1.5
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 2. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
 
 
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Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of 
disease
•
No decline in ECOG performance status 
•
No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
BICR for potential retrospective BICR. 
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 7, 
study treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging
should continue to be performed following the intervals as outlined in Section 2 and 
submitted to the BICR. 
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 11 and illustrated as a flowchart in Figure 2.
 
 
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Table 11
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically 
Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.
May continue 
study treatment at 
the investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
investigator 
assessment
No additional 
imaging 
required.
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per investigator 
assessment
Repeat imaging 
at 4 to 8 weeks 
to confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
treatment at the 
investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
treatment at the 
investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST 
unconfirmed progressive disease; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1.
Note:  If progression has been centrally verified, further management is by the site, based on iRECIST. Any further imaging 
should still be submitted to the BICR, but no rapid review will occur.
 
 
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Figure 2
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by the Investigator
9.3
Adverse Events (AE), Serious Adverse Events (SAE) and Other Reportable Safety 
Events 
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 4.
Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 – Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
 
 
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Time Period and Frequency for Collecting AE, SAE and Other Reportable 
9.3.1
Safety Event Information 
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event 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 120 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new anticancer therapy  
must be reported by the investigator. 
●
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event is 
considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 12.
 
 
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Table 12
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
Serious Adverse 
Event (SAE)
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
 
 
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Method of Detecting AE, SAE and Other Reportable Safety Events
9.3.2
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.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
9.3.3
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
9.3.4
●
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 
9.3.5
or SAEs
Progression of the cancer under study is not considered a reportable event. 
The Sponsor will monitor aggregated efficacy endpoint events and safety data to ensure the 
safety of the participants in the trial.  Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to global safety as a SAE within 24 
hours of determination that the event is not progression of the cancer under study.
 
 
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Pregnancy and Exposure During Breastfeeding
9.3.6
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee) that occurs during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Events of Clinical Interest (ECI)
9.3.7
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).
9.4
Treatment of Overdose
For this study, an overdose will be defined as any dose exceeding the prescribed dose for the 
standard treatments by ≥20% and as 1000 mg or greater (≥5 times the indicated dose) of 
pembrolizumab. 
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product, 
the adverse event(s) is reported as a SAE, even if no other seriousness criteria are met.
If a dose of Sponsor's product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported as 
a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.”
 
 
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All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by paper. Paper reporting procedures can 
be found in the Investigator Trial File Binder (or equivalent).
9.5
Safety 
Details regarding specific safety procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in Procedures 
Manual.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
9.5.1
Full Physical Exam
9.5.1.1
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 2. After the first 
dose of study treatment, new clinically significant abnormal findings should be recorded as 
AEs.
Directed Physical Exam
9.5.1.2
For cycles that do not required a full physical exam as defined in Section 2, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to the 
administration of the study treatment. New clinically significant abnormal findings should be 
recorded as AEs.
Vital Signs
9.5.2
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart- Section 2.  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only.
Electrocardiograms
9.5.3
A standard 12-lead 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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Clinical Safety Laboratory Assessments
9.5.4
Refer to Appendix 5 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator 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 5, 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. 
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
9.5.4.1
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 5.
Pregnancy Test
9.5.4.2
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal (defined as: a woman who is ≥45 years of age and 
has not had menses for greater than 1 year), must be tested for pregnancy at the timing of 
enrollment. If a urine test is positive or not evaluable, a serum test will be required. 
Participants must be excluded/discontinued from the study in the event of a positive test 
result.
Performance Assessments
9.5.5
Eastern Cooperative Oncology Group Performance Scale
9.5.5.1
The investigator or qualified designee will assess ECOG status (see Appendix 6) at 
screening, prior to the administration of each dose of study treatment and during the follow-
up period as specified in the Study Flow Chart (Section 2).
9.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
 
 
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9.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
9.8
Biomarkers
Biomarkers are not evaluated in this study except for PD-L1 to confirm the eligibility.
9.9
Future Biomedical Research Sample Collection
Future Biomedical Research Samples will not be collected in this study.
9.10 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
9.10.1
Within 21 days prior to treatment allocation, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 6.  Screening 
procedures may be repeated after consultation with the Sponsor.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the protocol SOA, including consent review. 
Rescreen procedures cannot be conducted the day prior to treatment allocation if there are 
Day -1 procedures planned per protocol. 
Written 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. Screening procedures are to be completed within 21 days prior to the first dose of 
study treatment except for the following:
•
Laboratory tests are to be performed within 21 days prior to the first dose of study 
treatment. An exception is hepatitis testing which may be done up to 28 days prior to 
the first dose of study treatment.
•
Evaluation of ECOG is to be performed within 3 days prior to date of allocation. 
•
For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of study treatment. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory).
•
Archival tumor sample collection is not required to be obtained within 28 days prior 
to the first dose of study treatment. Newly obtained tumor tissue may be obtained 
within 90 days of treatment initiation.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
 
 
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screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
Treatment Period Visit
9.10.2
Visit requirements are outlined in the Study Flow Chart (Section 2). Specific procedure-
related details are provided in Section 9.1.
Post-Treatment Visits
9.10.3
Safety Follow-up Visit
9.10.3.1
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anticancer treatment, whichever 
comes first. 
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Participants with 
an AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anticancer therapy, whichever occurs first. Serious AEs and ECI that 
occur within 30 days of the end of treatment or before initiation of a new anticancer 
treatment should also be followed and recorded.
Follow-up Visits
9.10.3.2
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 6 weeks (± 7 days) until PD. 
Every effort should be made to collect information regarding disease status until the start of 
new anti-cancer therapy, disease progression, death, end of study. Information regarding 
post-study anticancer treatment will be collected if new treatment is initiated.
Survival Follow-up
9.10.3.3
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone every 12 
weeks (± 14 days) to assess for survival status until death, withdrawal of consent, or the end 
of the trial, whichever occurs first. 
The Sponsor will request survival status to be assessed at additional time points during the 
course of the trial. All participants who are in the Survival Follow-Up Phase and not known 
to have died prior to the request for these additional survival status time points will be 
contacted at that time.
10. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to data lock, changes made to the statistical methods related to 
the primary analysis for the primary endpoint, then the protocol will be amended (consistent 
with ICH Guideline E-9).  Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to data lock, will be documented in a 
 
 
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supplemental SAP (sSAP) and referenced in the Clinical Study Report (CSR) for the study.  
Post hoc exploratory analyses will be clearly identified in the CSR.  
10.1 Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 10.2 to Section 10.12.
Study design 
Overview
Phase IIb study of Pembrolizumab in combination with TS-1+Cisplatin or 
TS-1+Oxaliplatin in GC
Treatment 
Assignment
Approximately 90 participants will be enrolled. First, 45 subjects will be 
assigned to Cohort 1, pembrolizumab + oxaliplatin + TS-1 combination 
therapy, and then, 45 subjects will be assigned to Cohort 2,  pembrolizumab 
+ cisplatin + TS-1 combination therapy.
Analysis 
Populations
Efficacy: All Subjects as Treated (ASaT) 
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
Overall Response Rate (ORR) based on RECIST 1.1 as assessed by BICR
Secondary 
Endpoints
•
Duration of Response (DOR), per RECIST 1.1 and per iRECIST based 
on BICR 
•
ORR, per iRECIST by BICR
•
Disease Control Rate (DCR) , per RECIST 1.1 and per iRECIST based 
on BICR 
•
Progression Free Survival (PFS) , per RECIST 1.1 and per iRECIST 
based on BICR 
•
Time To Response (TTR) , per RECIST 1.1 and per iRECIST based on 
BICR 
•
Overall survival (OS)
•
Safety and tolerability
Statistical Methods
for Key Efficacy 
Analyses
The main analytical objective of the trial is to estimate ORR of Cohort 1 and 
Cohort 2 assessed by the BICR to estimate the magnitude of add-on effect 
of pembrolizumab co-administered with TS-1 + oxaliplatin and TS-1 + 
cisplatin in PD-L1 positive advanced gastric or gastroesophageal junction 
(GEJ) adenocarcinoma. 95% CI for ORR will be calculated using Exact 
method based on binomial distribution.
Statistical Methods 
for Key Safety 
Analyses
Count and percentage of AE will be provided.
Interim Analyses
No efficacy interim analysis is planned.  
Multiplicity
This is an estimation study. No multiplicity adjustment will be applied.
Sample Size and 
Power Calculations
A total of 80 subjects (Cohort 1, 40 subjects; Cohort 2, 40 subjects) will be 
included in the ASaT.  A total of 90 subjects (Cohort 1, 45 subjects; Cohort 
2, 45 subjects) will be enrolled.
10.2 Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the 
sponsor and the statistics department of the contracted third party.
10.3 Hypotheses/Estimation
This is an estimation study.  Objectives and hypotheses of the study are stated in Section 4.0.
 
 
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10.4 Analysis Endpoints
The definition of the efficacy and safety endpoints is shown below.
Efficacy Endpoints
10.4.1
Primary Efficacy Endpoint
10.4.1.1

Objective response rate (ORR) - RECIST 1.1 assessed by BICR 
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR).
Secondary Efficacy Endpoints
10.4.1.2

Objective response rate (ORR) - per iRECIST assessed by BICR.

Duration of Response (DOR) – per RECIST 1.1 assessed by BICR and per iRECIST 
assessed by BICR.
For subjects who demonstrated CR or PR, response duration is defined as the time from the 
date of first response (CR or PR) until the date of disease progression or death.

Disease Control Rate (DCR): - per RECIST 1.1 assessed by BICRand per iRECIST 
assessed by BICR. 
DCR is defined as proportion of subjects in the analysis population who have CR or PR or 
stable disease (SD).

Time to Response (TTR) - per RECIST 1.1 assessed by BICR and per iRECIST assessed 
by BICR. 
Time to response is defined as a time from the date of enrollment day to the first date of 
confirmed CR or PR.

Progression-free Survival (PFS) - per RECIST 1.1 assessed by BICR and per iRECIST 
assessed by BICR. 
PFS is defined as the time from the date of enrollment day to the first documented disease 
progression or death due to any cause, whichever occurs first.

Overall survival (OS)
OS is defined as the time from the date of enrollment day to death due to any cause. Subjects 
without documented death at the time of the final analysis will be censored at the date of the 
last follow-up.
Safety Endpoints
10.4.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, fatal AEs, laboratory tests, and vital signs as described in Section 9.5.
Furthermore, specific events will be collected and designated as ECIs as described in 
Section 9.3.7.
 
 
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10.5 Analysis Populations
Efficacy Analysis Populations
10.5.1
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR, DCR, 
TTR, PFS, and OS. ASaT population consists of all subjects who received at least one dose 
of study treatment.
The analysis population for DOR consists of responders who have best response of CR or PR 
in the ASaT.
Safety Analysis Populations
10.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  
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.
10.6 Statistical Methods
Statistical Methods for Efficacy Analyses
10.6.1
The main analytical objective of the trial is to estimate ORR of TS-1 + oxaliplatin + 
pembrolizumab therapy (Cohort 1) and TS-1 + cisplatin + pembrolizumab therapy (Cohort 2) 
assessed by the BICR to estimate the magnitude of add-on effect of pembrolizumab co-
administered with TS-1 + oxaliplatin and TS-1 + cisplatin in PD-L1 positive advanced 
gastric or gastroesophageal junction (GEJ) adenocarcinoma. The point estimate and 95% 
confidence interval will be provided using exact binomial method proposed by Clopper and 
Pearson (1934). Subjects in the primary analysis population (ASaT) without ORR data will 
be counted as non-responder.
For DOR. PFS, TTR and OS, Kaplan-Meier (KM) curves and median estimates from the KM 
curves will be provided as appropriate. 
Censoring rules for DOR are summarized in Table 13.
 
 
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Table 13
Censoring Rules for DOR
Situation
Date of progression or censoring
Outcome
No progression nor death, no new 
anti-cancer therapy initiated
Last adequate assessment
Censor 
(non-event)
No progression nor death, new 
anti-cancer therapy initiated
Last adequate assessment before new 
anti-cancer therapy initiated
Censor 
(non-event)
Death or progression after ≥ 2 
consecutive missed adequate 
disease assessments
Last adequate assessment prior to ≥ 2  
missed adequate disease assessments
Censor 
(non-event)
Death or  progression after ≤1 
missed adequate disease 
assessments
Death or progression
End of response 
(Event)
Patients are considered to have an ongoing response if censored, alive, have not progressed, have not started 
a new anti-cancer therapy and have not been determined to be lost to follow-up.
For each Cohort, the efficacy endpoints, analysis population, and statistical methods 
(including missing data handling) that will be employed for the efficacy analyses are 
presented in Table 14.
Table 14
Summary of Analysis Strategy for Efficacy Endpoints
Endpoint
Statistical Method
Analysis Population
Missing data 
approach
Primary Endpoint
ORR
•
RECIST 1.1 by BICR
Exact method based 
on binomial 
distribution
ASaT in all below 
populations:
Cohort 1
Cohort 2
Subjects with missing 
data are considered 
non-responders
Secondary Endpoints
ORR
•
iRECIST  by BICR
Exact method based 
on binomial 
distribution
ASaT in all below 
populations:
Cohort 1
Cohort 2
Subjects with missing 
data are considered 
non-responders
DCR
•
RECIST 1.1 by BICR
•
iRECIST by BICR
Exact method based 
on binomial 
distribution
ASaT in all below 
populations:
Cohort 1
Cohort 2
Subjects with missing 
data are considered as 
disease not under 
control
TTR
•
RECIST 1.1 by BICR 
•
iRECIST by BICR
Summary statistics 
using Kaplan-Meier 
method
ASaT in all below 
populations:
Cohort 1
Cohort 2
Censored at last 
assessment date
PFS
•
RECIST 1.1 by BICR 
•
iRECIST by BICR 
OS
Summary statistics 
using Kaplan-Meier 
method
ASaT in all below 
populations:
Cohort 1
Cohort 2
Censored at last 
assessment date
DOR
•
RECIST 1.1 by BICR 
•
iRECIST by BICR
Summary statistics 
using Kaplan-Meier 
method
Responders in below 
populations:
Cohort 1
Cohort 2
Censored at last 
assessment date 
 
 
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Statistical Methods for Safety Analyses
10.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs. Count and percentage of AE will be 
provided. 
Summaries of Baseline Characteristics, Demographics, and Other Analyses
10.6.3
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed.  Demographic variables 
(e.g., age, gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical tables 
for all enrolled subjects.
10.7 Interim Analyses
No interim analysis is planned in this study.
10.8 Multiplicity
No multiplicity adjustment will be applied.
10.9 Sample Size and Power Calculations
A total of 80 subjects (TS-1 + oxaliplatin + pembrolizumab group [Cohort 1], 40 subjects; 
TS-1 + cisplatin + pembrolizumab group [Cohort 2], 40 subjects) will be included in the all 
participants as treated (ASaT).  A total of 90 subjects (Cohort 1, 45 subjects; Cohort 2, 45 
subjects) will be enrolled.
The sample size set with 90 subjects (Cohort 1 45 subjects; Cohort 2 45 subjects) that can 
expect a similar confidence interval of ORR to the previous studies of the first line treatment 
for gastric cancer for the purpose of the estimation of the ORR.
Considering approximately 10% of untreated subjects excluded, a total of 90 subjects 
(Cohort 1, 45 subjects; Cohort 2, 45 subjects) will be enrolled and a total of 80 subjects 
(Cohort 1, 40 subjects; Cohort 2, 40 subjects) will be included as ASaT.
Table 15 show the two-sided 95% confidence interval of ORR when the number of subjects 
is 80 (40 subjects in Cohort 1 and 40 subjects in Cohort 2).
 
 
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Table 15
Two sided 95% Confidence interval of ORR with 40 subjects as ASaT
Number of Observed 
Responders
ORR Estimates
95% CI of ORR (%)
16
40.0%
(24.9, 56.7)
17
42.5%
(27.9, 59.)
18
45.0%
(29.3, 61.5)
19
47.5%
(31.5, 63.9)
20
50.0%
(33.8, 66.2)
21
52.5%
(36.1, 68.5)
22
55.0%
(38.5, 70.7)
23
57.5%
(40.9, 73.0)
24
60.0%
(43.3, 75.1)
25
62.5%
(45.8, 77.3)
26
65.0%
(48.3, 79.4)
27
67.5%
(50.9, 81.4)
28
70.0%
(53.5, 83.4)
29
72.5%
(56.1, 85.4)
30
75.0%
(58.8, 87.3)
31
77.5%
(61.5, 89.2)
32
80.0%
(64.4, 90.9)
There will be approximately 40 subjects enrolled for each cohort, Table 16 shows the two-
sided 95% CI of AE rate with 40 subjects.
Table 16
Two-sided 95% CI of AE incidence rate with 40 Subjects
Number of AE
AE incidence rate estimates
95% CI of incidence rate (%)
1
2.5%
(0.00, 13.2)
2
5.0%
(0.61, 16.9)
3
7.5%
(1.57, 20.4)
4
10.0%
(2.8, 23.7)
5
12.5%
(4.2, 26.8)
6
15.0%
(5.7, 29.8)
7
17.5%
(7.3, 32.8)
8
20.0%
(9.1, 35.7)
9
22.5%
(10.8, 38.5)
 
 
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Number of AE
AE incidence rate estimates
95% CI of incidence rate (%)
10
25.0%
(12.7, 41.2)
11
27.5%
(14.6, 43.9)
12
30.0%
(16.6, 46.5)
13
32.5%
(18.6, 49.1)
14
35.0%
(20.6, 51.7)
15
37.5%
(22.7, 54.2)
10.10 Subgroup Analyses and Effect of Baseline Factors
The estimate of the treatment effect for the primary endpoint will be estimated and/or plotted 
within each category of selected factors (e.g., analyses for each patient background factors). 
The details will be described in the sSAP.
10.11 Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
10.12Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion.  Summary statistics will be provided on Extent of Exposure 
for ASaT population.
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12. Appendices
12.1 Appendix 1: Study Governance Considerations
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participant safety is the overriding concern 
in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck 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 which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC 
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care. Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants may withdraw from a Merck trial at any time, without any influence on their access to, 
or receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding participant confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential 
medical records that might identify the research participant by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck 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.
Merck does not pay for participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/IEC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck 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 including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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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.
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 
 
 
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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.
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 subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
 
 
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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.
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 Merck 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 
 
 
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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. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
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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12.2 Appendix 2: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained (using iRECIST for participant management (see Table 11 
and Figure 2). This decision by the investigator should be based on the participant’s overall 
clinical condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of 
disease
•
No decline in ECOG performance status 
•
No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at  
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
BICR for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% 
and ≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.
•
Unequivocal progression of non-target lesion(s) identified at baseline
•
Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
 
 
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of ≥5 
mm, compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:
•
An increase in the new lesion sum of diameters by ≥5 mm from a prior 
iUPD time point 
•
Visible growth of new non-target lesions 
•
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial 
PD threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
 
 
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Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 2 and submitted to the BICR.
Detection of Progression at Visits after Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression.
•
Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so 
for the first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth 
of non-target lesions, taken as a whole.
•
New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
 
 
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o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication 
[Seymour, L., et al 2017].
 
 
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12.3 Appendix 3: Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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.
●
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 18 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
 
 
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Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 17
during the protocol-defined time frame in Section 6.1. 
Table 17
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c 
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner 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. 
●
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 treatment. 
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.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for participants of 
clinical studies. 
a) Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, condoms 
must be used in addition to the hormonal contraception during the treatment period and for at least [X days, 
corresponding to time needed to eliminate study treatment plus 30 days for study treatments with genotoxic 
potential]  after the last dose of study treatment .
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation. 
 
 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements.  This test should be repeated a maximum of 
24-hours before the first dose/vaccination.
Following initiation of treatment additional pregnancy testing will be performed at monthly 
intervals during the treatment period and at [X days/weeks (corresponding to time needed to 
eliminate any study treatment(s) (MK and or any active comparator/combination) plus 30 
days (a menstruation cycle) for study treatments with risk of evidence of genotoxicity at any 
dose)] after the last dose of study treatment and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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12.4 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.
e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
 
 
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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.
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.
 
 
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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 of hospitalization indicated; disabling; limiting 
self-care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of Causality
●
Did the 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)?
 
 
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●
Likely Cause:  Is the AE not reasonably explained by another etiology such 
as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
●
Dechallenge: Was the Sponsor's product discontinued or 
dose/exposure/frequency reduced?
●
If yes, did the AE resolve or improve?
●
If yes, this is a positive dechallenge. 
●
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor's product; (3) the study is a single-dose drug study); or (4) 
Sponsor's product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
study?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death 
or permanent disability, or (2) the study is a single-dose drug study); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN 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 
 
 
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another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product.  (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
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.
 
 
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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.
●
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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12.5 Appendix 5: Clinical Laboratory Tests 

The tests detailed in Table 18 will be performed by the local laboratory. 
Table 18
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase 
(ALT)
Protein
aPTT
WBC count
Aspartate aminotransferase 
(AST)
Specific gravity 
Total triiodothyronine (T3) 
or Free T3
Percentages of 
Neutrophils 
Calcium 
Microscopic exam, if 
abnormal results are noted 
Free thyroxine (T4)
Percentages of 
Eosinophils
Chloride 
Urine pregnancy testa
Thyroid stimulating 
hormone (TSH)
Percentages of  
Basophiles
Creatinine 
Percentages of  
Lymphocytes
Glucose 
Percentages of  
Monocytes
Phosphorus 
Potassium 
Sodium 
Total Bilirubin 
Direct Bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Blood Urea Nitrogen/Ureab
Uric acid 
Creatinine clearance 
a. Perform on women of childbearing potential only.  Serum pregnancy test is preferred but urine test can be 
considered if serum not appropriate. 
b. Blood Urea Nitrogen is preferred; if not available urea may be tested.
Laboratory tests for screening should be performed within 7 days of enrollment.  For Cycle 1 
and 2, laboratory tests should be performed within 72 hours prior to dosing and every week 
(accepted if performed within 3 days before and after a reference day) after dosing.  After 
Cycle 3, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment.
Serum/Urine β-hCG
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal (defined as: a woman who is ≥45 years of age and has not had 
menses for greater than 1 year), will be tested for pregnancy within 72 hours prior to each 
cycle of trial treatment and 30 days post treatment. Subjects must be excluded/discontinued 
in the event of a positive or borderline-positive test result. If a urine test is positive or 
borderline a serum β -HCG test will be required.
 
 
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12.6 Appendix 6: 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, e.g., 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, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
 
 
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12.7 Appendix 7: Abbreviations and Trademarks
Abbreviation/Term
Definition
1L
First Line
2L
Second Line
5-FU
5-fluorouracil
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline Phosphatase
APaT
All Patients as Treated
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BICR
Blinded Independent Central Review
BID
Twice a Day
ß-HCG
Beta Human Chorionic Gonadotropin
BSA
Body Surface Area
CBC
Complete Blood Count
CI
Confidence Interval
CNS
Central Nervous System
CR
Complete Response
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
CTU
Computed Tomography Urography
DCR
Disease Control Rate
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DR
Drug Related
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FA
Final Analysis
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin-Fixed, Paraffin-Embedded
FNA
Fine Needle Aspirate
FP
Cisplatin + 5-fluoruracil
GCP
Good Clinical Practice
GEJ
Gastroesophageal Junction
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HER2/neu
Human Epidermal Growth Factor Receptor 2
 
 
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Abbreviation/Term
Definition
HIV
Human Immunodeficiency Virus
HNSCC
Head and Neck Squamous Cell Carcinoma
HPV
Human Papillomavirus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
INR
International Normalized Ratio
iPR
iRECIST partial response
irAEs
Immune-related Adverse Events
iRECIST
modified RECIST for immune-based therapeutics
IRB
Institutional Review Board
iSD
iRECIST stable disease
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intention To Treat
iUPD
iRECIST unconfirmed progressive disease
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
KN
KEYNOTE
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
mcL
Microliters
MEL
Melanoma 
Mg
Milligram
Mg/kg
Milligram per Kilogram
mL
Milliliter
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
Maximum Tolerated Dose
NA or 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
PD
Progressive Disease
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PFS
Progression Free Survival
PGt
Pharmacogenetic
PIN
Personal Identification Number
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/Pharmacodynamic
PO
Oral Administration
PR
Partial Response
PRO
Patient Reported Outcomes
 
 
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Abbreviation/Term
Definition
PT
Prothrombin Time
PS
Performance Status
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RR
Response Rate
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
SAC
Scientific Advisory Committee
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SFU
Survival Follow-Up
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
siDMC
Standing Internal Data Monitoring Committee
SOC
Standard of Care
SOP
Standard Operating Procedures
T1DM
Type 1 Diabetes Mellitus
TIL
Tumor Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WBC
White Blood Cell
 
 
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