Conditions: Gastric Cancer Cancer of the Stomach Esophagogastric Junction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 274
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the efficacy and safety of investigational drug relatlimab plus nivolumab in combination with chemotherapy in participants with unresectable, untreated, locally advanced or metastatic gastric or GEJ cancer.

Detailed description:

Arms:
arm 1: BMS-986213 + XELOX or BMS-986213 + FOLFOX or BMS-986213 + SOX arm 2: Nivolumab + XELOX or Nivolumab + FOLFOX or Nivolumab + SOX

Interventions: intervention 1: BMS-986213 intervention 2: Nivolumab intervention 3: XELOX intervention 4: FOLFOX intervention 5: SOX
Intervention descriptions: intervention 1: Relatlimab + Nivolumab specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Oxaliplatin + capecitabine intervention 4: Oxaliplatin + leucovorin + fluorouracil intervention 5: Oxaliplatin + tegafur/gimeracil/oteracil potassium

Protocol document:
Prot_000.pdf: 
Official Title of Study: 
A Randomized, Open-label, Phase II Clinical Trial of Relatlimab (anti-LAG-3) and Nivolumab in 
Combination with Chemotherapy Versus Nivolumab in Combination with Chemotherapy as First- 
Line Treatment in Patients with Gastric or Gastroesophageal Junction Adenocarcinoma 
 
NCT Number: NCT03662659 
Document Date (Date in which document was last revised): June 24, 2019 


Page:
1
Protocol Number:
CA224060
IND Number:
137615
EUDRACT Number:
2018-001069-18
Date:
02-Apr-2018
Revised Date:
24-Jun-2019
Clinical Protocol CA224060
A Randomized, Open-label, Phase II Clinical Trial of Relatlimab (anti-LAG-3) and Nivolumab in 
Combination with Chemotherapy Versus Nivolumab in Combination with Chemotherapy as First-
Line Treatment in Patients with Gastric or Gastroesophageal Junction Adenocarcinoma
Short Title:
An Open Label Study of Relatlimab and Nivolumab with Chemotherapy Versus Nivolumab with 
Chemotherapy in Patients with Gastric or Gastroesophageal Junction Adenocarcinoma
Revised Protocol 03
Incorporates Administrative Letters: 01 and 02
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
2
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
03
24-Jun-2019
Revised to update with current program requirements, updated company 
standards, and to provide additional clarifications throughout
Administrative 
Letter 02
11-Dec-2018
Corrected an error in the Document History page of Revised Protocol 02
Administrative 
Letter 01
30-Nov-2018
Study title was updated to: An Open Label Study of Relatlimab and 
Nivolumab with Chemotherapy Versus Nivolumab with Chemotherapy in 
Patients with Gastric or Gastroesophageal Junction Adenocarcinoma
Revised Protocol 
02
16-Nov-2018
Revised text reflecting addition of Data Monitoring Committee
Modified language requiring pathology report to accompany FFPE tissue 
block or unstained tumor tissue section for biomarker evaluation; 
pathology report is optional
 
 
Revised exclusion for participants who received live or attenuated 
vaccines within 30 days of treatment 
Added prohibition of any live/attenuated vaccine during treatment up to 
100 days post treatment
Removed exclusion of recombinant human erythropoietin within 3 weeks 
of first study drug administration
Added text regarding treatment access rules
Removed a pre-screening consent option 
 
Updated Appendix 3 (AEs and SAEs)
Updated Appendix 8 (added myocarditis management algorithm)
Revised Protocol 
01
29-Jun-2018
Modified PD-L1 stratification levels for statistical analyses
Additional exclusion criterion added
Revised discontinuation from study treatment to include consideration of 
abnormal liver test results and procedures to follow in case of pregnancy
Revised time period and frequency for collecting AE and SAE information
Updated appendix for WOCBP
Updated CTCAE to version 5
Minor formatting and typographical corrections
Original Protocol
02-Apr-2018
Not applicable
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CA224060
BMS-986213
relatlimab-nivolumab FDC
OVERALL RATIONALE FOR REVISED PROTOCOL 03:
This protocol revision serves to update the protocol with updated program requirements, updated 
company standards, as well as providing additional clarifications throughout.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Synopsis, Study Population;
Synopsis, Key Inclusion Criteria;
Synopsis, Objectives and 
Endpoints;
Synopsis, Overall Design;
3, Introduction;
3.2.1, Research Hypothesis;
Table 4-1:  Objectives and 
Endpoints;
5.1, Overall Design;
 
6.1, Inclusion Criteria 2), a) and 
b)
Updated study population 
description.
Clarified the specific 
population.
Synopsis, Key Inclusion Criteria
Updated several criteria and 
added a criterion for left 
ventricular ejection fraction.
Clarified for program 
updates and company 
requirements.
Synopsis, Study Treatment
Updated FOLFOX treatment 
description.
Clarified treatment 
cycles.
Table 2-1:  Screening 
Assessments - All Participants 
(CA224060)
Add clarification of timing to 
Informed Consent.
Clarified timing.
Table 2-2:  On-treatment 
Assessments - Participants 
Assigned to Investigator’s Choice 
XELOX or SOX (CA224060);
Table 2-3:  On-treatment 
Assessments - Participants 
Assigned to Investigator’s Choice 
FOLFOX (CA224060)
Add clarification of timing to 
Troponin assessment.
Clarified timing.
Revised Protocol No.: 03
Date: 24-Jun-2019
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CA224060
BMS-986213
relatlimab-nivolumab FDC
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
5.1.1, Screening Phase
Updated timing of Informed 
Consent and clarified tumor 
tissue sample specifications.
Clarified timing and 
requirements.
5.1.5, Data Monitoring 
Committee
Add language regarding 
adjudication.
Updated to company 
standards.
6.1, Inclusion Criteria 2), d)
Removed criteria for 
evaluable disease.
Removes ambiguity.
6.1, Inclusion Criteria 2), f)
Updated tumor tissue 
requirements.
Clarification for sites.
6.1, Inclusion Criteria 3), a)
Updated to add age of 
majority.
Aligns with company 
standards.
6.2, Exclusion Criteria 1), i), ix)
Added criteria for left 
ventricular ejection fraction 
assessment.
Provides additional 
safety information.
6.2, Exclusion Criteria 3), f)
Updated AST/ALT 
requirements.
Updated for clarification 
for sites.
6.2, Exclusion Criteria 3), h)
Updated troponin assessment.
Updated for clarification 
for sites.
6.4, Screen Failures
Updated reporting 
requirements.
Aligns with company 
standards.
7, Treatment
Added additional text 
describing treatments 
administered.
Aligns with company 
standards.
7.1.1, BMS-986213 or 
Nivolumab Dosing
Added text noting dosing 
visits should not be skipped, 
only delayed.
Clarification to align with 
program standards.
7.1.2, Dose Schedule for BMS-
986213 or Nivolumab Plus 
XELOX
Updated premedications 
language.
Clarification for sites to 
better address patient 
safety.
Revised Protocol No.: 03
Date: 24-Jun-2019
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CA224060
BMS-986213
relatlimab-nivolumab FDC
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
7.1.3, Dose Schedule for BMS-
986213 or Nivolumab Plus 
FOLFOX
Updated FOLFOX treatment 
description;
updated premedications 
language.
Clarified treatment 
cycles;
Clarification for sites to 
better address patient 
safety.
7.1.4, Dose Schedule for BMS-
986213 or Nivolumab Plus SOX
Updated premedications 
language.
Clarification for sites to 
better address patient 
safety.
7.2, Method of Treatment 
Assignment
Added language describing 
participant enrollment;
Moved randomization 
language to blinding section.
Adds clarification for 
sites as well as aligns 
with company standards.
7.3.6, Criteria to Resume BMS-
986213 or Nivolumab Treatment
Updated AST/ALT to AST 
and/or ALT.
Clarification for sites.
7.3.7, Criteria for BMS-986213 
or Nivolumab Discontinuation
Added text requiring periodic 
study visits.
Aligns with program 
standards.
7.8, Blinding
Added new section to 
describe randomization and 
monitoring procedures.
Aligns with company 
standards.
9.1.1, Imaging Assessment for the 
Study
Added text to address 
additional imaging 
assessments.
Aligns with company 
standards.
9.2.1, Time Period and Frequency 
for Collecting AE and SAE 
Information
Updated collection start from 
randomization and removed 
from treatment assignment.
Clarification for sites.
9.2.5, Pregnancy
Added additional language 
regarding pregnancy 
discontinuations;
Added text regarding fetal 
toxicity.
 
Aligns with company 
standards.
Table 9.4.4-1: Laboratory 
Assessment Panels
Updated pregnancy test and 
FSH requirements.
Aligns with company 
standards.
Revised Protocol No.: 03
Date: 24-Jun-2019
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CA224060
BMS-986213
relatlimab-nivolumab FDC
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Appendix 2, Study Governance 
Considerations
Revised text throughout.
Aligns with company 
standards.
Global
Fixed minor typos.
Minimal, therefore not 
summarized.
Revised Protocol No.: 03
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 03: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03 ......................... 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.3 Benefit-risk Assessment .................................................................................... 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Screening Phase ....................................................................................... 
5.1.2 Treatment Phase ...................................................................................... 
5.1.3 Follow-up Phase ...................................................................................... 
5.1.4 Blinded Independent Central Review ....................................................... 
5.1.5 Data Monitoring Committee .................................................................... 
5.2 Number of Participants ..................................................................................... 
5.3 Study Definitions .............................................................................................. 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
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3
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Revised Protocol No.: 03
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6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-in Period ....................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.1.1 BMS-986213 or Nivolumab Dosing ......................................................... 
7.1.2 Dose Schedule for BMS-986213 or Nivolumab Plus XELOX ................. 
7.1.3 Dose Schedule for BMS-986213 or Nivolumab Plus FOLFOX ............... 
7.1.4 Dose Schedule for BMS-986213 or Nivolumab Plus SOX ....................... 
7.1.5 Crossover for Investigator’s Choice Chemotherapy ............................... 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Dosage Modification ......................................................................................... 
7.3.1 Dose Modification Criteria for BMS-986213 or Nivolumab Plus 
Chemotherapy ............................................................................................. 
7.3.2 Dose Modification Criteria for BMS-986213 or Nivolumab ................... 
7.3.3 Dose Modification Criteria for Oxaliplatin-Plus-Fluoropyrimidine 
Treatment .................................................................................................... 
7.3.3.1 General Guidance for Dose Modification of Chemotherapy .......... 
7.3.3.2 Dose Modification Criteria for XELOX .......................................... 
7.3.3.3 Dose Modification Criteria for FOLFOX ....................................... 
7.3.3.4 Dose Modification Criteria for SOX Including Initiation and 
Continuation ......................................................................................... 
7.3.4 Criteria for Oxaliplatin-Plus-Fluoropyrimidine Discontinuation ........... 
7.3.5 Dose Delay Criteria for BMS-986213 or Nivolumab .............................. 
7.3.6 Criteria to Resume BMS-986213 or Nivolumab Treatment .................... 
7.3.7 Criteria for BMS-986213 or Nivolumab Discontinuation ....................... 
7.3.8 Treatment Beyond Disease Progression .................................................. 
7.3.9 Management Algorithms for Immuno-Oncology Agents ......................... 
7.3.10 Treatment of BMS-986213 and Nivolumab Infusion-related Reactions 
7.4 Preparation/Handling/Storage/Accountability of IP ......................................... 
7.4.1 Retained Samples for Bioavailability/Bioequivalence ............................. 
7.5 Treatment Compliance ...................................................................................... 
7.6 Concomitant Therapy........................................................................................ 
7.6.1 Prohibited and/or Restricted Treatments................................................. 
7.6.2 Other Restrictions and Precautions ......................................................... 
7.6.3 Permitted Therapy ................................................................................... 
7.6.4 Imaging Restriction and Precautions ...................................................... 
7.7 Treatment After the End of the Study ............................................................... 
7.8 Blinding............................................................................................................. 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Poststudy Treatment Study Follow-up ..................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-up .............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
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CA224060
relatlimab-nivolumab FDC
Revised Protocol No.: 03
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9.1.2 Methods of Measurement ......................................................................... 
9.1.3 Imaging and Clinical Assessment ............................................................ 
9.1.4 BICR Confirmation of Progression ......................................................... 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug-induced Liver Injury ....................................................... 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital Signs ................................................................................................ 
9.4.3 Electrocardiograms ................................................................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
9.4.5 Imaging Safety Assessment ...................................................................... 
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CA224060
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Revised Protocol No.: 03
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10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Demographics and Baseline Characteristics......................................... 
10.3.2 Efficacy Analyses ................................................................................... 
10.3.3 Safety Analyses....................................................................................... 
10.3.9 Interim Analyses ..................................................................................... 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) 
 ........................ 
APPENDIX 6 ECOG STATUS SCALE ...................................................................... 
APPENDIX 7 COUNTRY SPECIFIC REQUIREMENTS ......................................... 
APPENDIX 8 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 9 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
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CA224060
relatlimab-nivolumab FDC
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
1
SYNOPSIS
Protocol Title: 
A Randomized, Open-label, Phase II Clinical Trial of Relatlimab (anti-LAG-3) and Nivolumab in 
Combination with Chemotherapy Versus Nivolumab in Combination with Chemotherapy as First-
Line Treatment in Patients with Gastric or Gastroesophageal Junction Adenocarcinoma
Short Title:
An Open Label Study of Relatlimab and Nivolumab with Chemotherapy Versus Nivolumab with 
Chemotherapy in Patients with Gastric or Gastroesophageal Junction Adenocarcinoma
Study Phase: 2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Study Population:
The study population includes adult participants with unresectable, and either locally advanced or 
metastatic GC or GEJ adenocarcinoma, independent of LAG-3 expression, with no prior systemic 
treatment.
Key Inclusion Criteria:
•
Males and females, ≥18 years of age or age of majority
•
Eastern Cooperative Oncology Group performance status score of 0 or 1 
−
Tumor tissue must be provided for analysis prior to randomization. In order to be 
randomized, the participant’s tumor associated immune cells must have an evaluable 
LAG-3 status (≥1% or <1%; no indeterminate allowed) and must have an evaluable PD-
L1 status (CPS < 1 or indeterminate, CPS ≥1 to <5, CPS ≥5).
•
Participants must have histologically- or cytologically-confirmed diagnosis of unresectable,
and either locally advanced or metastatic GC or GEJ adenocarcinoma. The documentation of 
GEJ involvement can include biopsy, endoscopy, or imaging.
•
Participants must be previously untreated with systemic treatment (including HER 2 inhibitors) 
given as primary therapy for unresectable, and either locally advanced or metastatic GC or GEJ 
adenocarcinoma
•
Participants must have at least one measurable lesion by computed tomography or magnetic 
resonance imaging per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria; 
radiographic tumor assessment should be performed within 28 days prior to randomization.
Key Exclusion Criteria:
•
Participants with HER2 positive status [IHC3+ or FISH positive (HER2:CEP17 ratio > 2) or 
IHC2+/FISH+]
•
Participants with known untreated central nervous system (CNS) metastases 
•
Participants with ascites which cannot be controlled with appropriate interventions
•
Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following:
−
Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months prior to 
consent
−
Uncontrolled angina within the 3 months prior to consent
−
Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, torsades de pointes or poorly controlled atrial fibrillation)
−
QTc prolongation > 480 msec
−
History of other clinically significant cardiovascular disease (ie, cardiomyopathy, 
congestive heart failure with New York Heart Association functional classification III-IV, 
pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly 
controlled deep venous thrombosis, etc)
−
Cardiovascular disease-related requirement for daily supplemental oxygen
−
History of 2 or more MIs OR 2 or more coronary revascularization procedures
−
Participants with history of myocarditis, regardless of etiology
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
−
Left ventricular ejection fraction (LVEF) < 50% by either transthoracic echocardiogram 
(TTE) or multiple gated acquisition (MUGA) scan (TTE is preferred test) within 6 months
prior to date of first study drug administration.
•
Troponin T (TnT) or I (TnI) > 2 × institutional upper limit of normal (ULN). Participants with 
TnT or TnI levels between > 1 to 2 × ULN will be allowed to enroll if a repeat assessment 
remains within ULN or patient has no cardiac symptoms and participant undergoes a cardiac 
imaging evaluation found to have no significant myocardial disease or dysfunction. When
repeat levels within 24 hours are not available, a repeat test should be conducted as soon as 
possible. 
Objectives and Endpoints:
Objective
Endpoint
Primary
•
To compare objective response rate (ORR) of BMS-
986213 in combination with chemotherapy, with 
ORR 
of 
nivolumab 
in 
combination 
with 
chemotherapy, by BICR, in randomized participants 
with untreated, unresectable, and either locally 
advanced or metastatic LAG-3 positive GC or GEJ 
adenocarcinoma.
•
ORR in participants who are LAG-3 positive. ORR 
is defined as the number of participants with a best 
overall response (BOR) of CR or PR divided by the 
number of randomized participants in each arm. 
BOR is defined as the best response designation as 
determined by the blinded independent central 
review (BICR), recorded between the date of 
randomization and the date of objectively 
documented progression (per Response Evaluation 
Criteria in Solid Tumors [RECIST 1.1]), death due 
to any cause, or the date of subsequent anti-cancer 
therapy, whichever occurs first.
Secondary
•
To assess the overall safety and tolerability of BMS-
986213 in combination with chemotherapy vs. 
nivolumab in combination with chemotherapy in 
treated participants with advanced or metastatic GC 
or GEJ cancer.
•
The incidence of adverse events (AEs), serious AEs 
(SAEs), AE leading to discontinuation, deaths, and 
laboratory abnormalities in each arm.
•
To compare objective response rate (ORR) of BMS-
986213 in combination with chemotherapy, with 
ORR 
of 
nivolumab 
in 
combination 
with 
chemotherapy, as assessed by investigator, in 
randomized 
participants 
with 
untreated, 
unresectable, and either locally advanced or 
metastatic 
LAG-3 
positive
GC 
or 
GEJ 
adenocarcinoma.
•
ORR is defined as above, as the number of 
participants with a BOR of CR or PR as assessed by 
the investigator using RECIST 1.1, divided by the 
number of randomized participants in each
Treatment Arm, 
•
To compare ORR by BICR and by investigator of 
BMS-986213 in combination with chemotherapy 
with ORR of nivolumab in combination with 
chemotherapy in randomized participants with 
advanced or metastatic LAG-3 negative GC or GEJ 
adenocarcinoma, and in the overall population 
(arcoss LAG-3 negative and positive groups).
•
ORR in the LAG-3 negative group or in the overall 
population is defined as above, as the number of 
participants in each population with a BOR of CR or 
PR divided by the number of randomized 
participants in each Treatment Arm, for that 
population.
•
To estimate Duration of Response (DOR) of BMS-
986213 in combination with chemotherapy and 
DOR 
of 
nivolumab 
in 
combination 
with 
•
DOR (based on BICR and investigator) is defined as 
the time between the date of first documented 
response (CR or PR) and the date of the first disease 
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Objective
Endpoint
chemotherapy in randomized participants with 
advanced or metastatic LAG-3 positive GC or GEJ 
adenocarcinoma, by BICR and by the investigator.
progression, per RECIST 1.1, death due to any 
cause, or the date of subsequent anti-cancer therapy
whichever occurs first. .
•
To estimate DOR of BMS-986213 in combination 
with chemotherapy and DOR of nivolumab in 
combination with chemotherapy in randomized 
participants with advanced or metastatic LAG-3
negative GC or GEJ adenocarcinoma, and in the 
overall population, by BICR and by the investigator
•
DOR in participants with advanced or metastatic 
LAG-3 negative GC or GEJ adenocarcinoma and 
for participants in the overall population (across the 
LAG-3 groups) is defined as above.
•
To assess the difference in the overall survival 
(OS) of BMS-986213 in combination with
chemotherapy and OS of Nivolumab in 
combination with chemotherapy in randomized 
participants with untreated, unresectable, and either 
locally advanced or metastatic GC or GEJ 
adenocarcinoma separately in the LAG-3 positive 
and LAG-3 negative groups and overall.
•
Overall survival. OS is defined as the time between 
the date of randomization and the date of death. For 
those without documentation of death, OS will be 
censored on the last date the participant was known 
to be alive.
•
To assess the difference in the progression-free 
survival (PFS) of BMS-986213 in combination 
with chemotherapy and PFS of nivolumab in 
combination with chemotherapy as assessed by 
BICR and investigator in randomized participants 
with untreated, unresectable, and either locally 
advanced or metastatic GC or GEJ adenocarcinoma
separately in the LAG-3 positive and LAG-3 
negative groups and overall.
•
PFS is defined as the time between the date of 
randomization and the date of the first documented 
PD per BICR or investigator or death due to any 
cause. Participants who die without a reported prior 
PD per BICR or investigator (and die without start 
of subsequent therapy) will be considered to have 
progressed on the date of death. Those who did not 
have documented PD per RECIST1.1 criteria and 
who did not die, will be censored at the date of the 
last evaluable tumor assessment on or prior to 
initiation of subsequent anti-cancer therapy. 
Participants who did not have any on-study tumor 
assessments and did not die (or died after initiation 
of subsequent anti-cancer therapy) will be censored 
at the randomization date. Those who started any 
subsequent anti-cancer therapy without a prior 
reported PD will be censored at the last tumor 
assessment prior to or on the initiation of the 
subsequent
anti-cancer 
therapy. 
Participants 
receiving treatment beyond progression must 
continue tumor assessments until such treatment has 
been discontinued.
Overall Design:
•
This is a Phase 2, randomized, open-label, two-arm study of BMS-986213 (fixed-dose 
combination [FDC] relatlimab/nivolumab) or nivolumab in combination with investigator’s 
choice chemotherapy as first-line treatment in participants with untreated, unresectable, and 
either locally advanced or metastatic GC or GEJ adenocarcinoma. 
•
Depending on the assigned treatment arm, the participant will receive BMS-986213 in 
combination with investigator’s choice chemotherapy or nivolumab in combination with 
investigator’s choice chemotherapy. 
•
One cycle of treatment is defined as 6 weeks. 
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Number of Participants: 
It is expected that approximately 420 participants will need to be enrolled in order to randomize 
250 participants; 40% of screened participants are expected to screen fail.
Approximately 250 participants are planned to be randomized to one of 2 treatment arms: 
1) BMS-986213 in combination with investigator’s choice chemotherapy
2) Nivolumab in combination with investigator’s choice chemotherapy 
The sample size is calculated in order to compare the ORR between participants with LAG-3 
positive expression randomized to receive BMS-986213 + Investigator’s choice Chemotherapy vs 
Nivolumab + Investigator’s choice Chemotherapy. 
 
Study Treatments:
Study Treatments for CA224060
Medication 
Potency 
Investigational Product 
(IP)/Non-IP 
BMS-986213
(Relatlimab 80 mg/
Nivolumab 240 mg)
16 mg/mL
IP
Nivolumab (BMS-936558-01)
Solution for Injection
10 mg/mL
IP
Oxaliplatin Concentrate for 
Solution for Infusion
5 mg/mL
IP
Capecitabine Tablet
150 mg and 500 mg tablets
IP
Fluorouracil Solution for 
Injection
50 mg/ mL
IP
Leucovorin (folinic acid) 
Solution for Injection
50 mg/mL
IP
S-1 
tegafur/gimeracil/oteracil 
Capsule
20 mg/5.8 mg/15.8 mg
IP
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Study Treatments for CA224060
Medication 
Potency 
Investigational Product 
(IP)/Non-IP 
S-1
tegafur/gimeracil/oteracil
Capsule
15 mg/4.35 mg/11.8 mg
IP
The study design schematic is presented below.
During the treatment phase, participants will receive BMS-986213 or nivolumab in combination 
with investigator’s choice of chemotherapy (XELOX, FOLFOX, or SOX):
•
Participants assigned to XELOX will receive BMS-986213 (relatlimab 120 mg/nivolumab 
360 mg) or nivolumab 360 mg, administered intravenously (IV) over 60 minutes or 30 minutes,
respectively, and oxaliplatin 130 mg/m2 administered IV on Days 1 and 22 of each treatment 
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
cycle every 6 weeks, and capecitabine 1000 mg/m2 administered orally twice daily (AM and 
PM dosing) on Days 1 to 14 and Days 22 to 35 of each treatment cycle every 6 weeks.
•
Participants assigned to FOLFOX will receive BMS-986213 (relatlimab 160 mg/nivolumab
480 mg) or nivolumab 480 mg administered IV over 60 minutes or 30 minutes, respectively, 
on Days 1 and 29 of every odd numbered 6-week treatment Cycle (Cycle 1, 3, 5, etc) and Day 
15 of every even numbered 6-week treatment Cycle (Cycle 2, 4, 6, etc). Oxaliplatin 85 mg/m2, 
leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 will be administered IV on Days 1, 15, 
and 29 of each treatment cycle every 6 weeks, and fluorouracil 1200 mg/m2 IV continuous 
infusion over 24 hours daily (or per local standard) on Days 1 & 2, 15 & 16, and 29 & 30 of 
each treatment cycle every 6 weeks. As a consequence of this dosing regimen, FOLFOX will 
be administered alone, without immunotherapy, on Day 15 of each odd numbered 6-week 
treatment cycle and Days 1 and 29 of each even numbered 6-week treatment cycle.
•
Participants assigned to SOX will receive BMS-986213 (relatlimab 120 mg/nivolumab 
360 mg), or nivolumab 360 mg, administered IV over 60 minutes or 30 minutes, respectively, 
and oxaliplatin 130 mg/m2 administered IV on Days 1 and 22 of each treatment cycle every 
6 weeks, and oral S-1 twice daily on Days 1 to 14 and Days 22 to 35 of each treatment cycle, 
every 6 weeks. S-1 (tegafur/gimeracil/oteracil) dose as calculated according to body surface 
area (BSA, mg/m2/dose): BSA <1.25 m2, 40 mg/dose; ≥1.25 and <1.5 m2, 50 mg/dose; 
≥1.5 m2, 60 mg/dose
No dose reductions of BMS-986213 or nivolumab are permitted, only dose delays are permitted. 
Dose modifications for Investigator’s choice chemotherapy are permitted. Treatment may be 
discontinued due to unacceptable toxicity, withdrawal of consent, disease progression, or 
termination of the study, whichever occurs first. Participants treated with BMS-986213 or 
nivolumab in combination with chemotherapy will be permitted to continue their treatment beyond 
initial RECIST 1.1-defined PD, assessed by the investigator, as long as they meet the appropriate
criteria and the investigator believes continuing treatment is in the patient’s best interests.
Data Monitoring Committee:  
A Data Monitoring Committee has been included and is detailed in Section 5.1.5.
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Assessments - All Participants (CA224060)
Procedure
Screening
Visit
Notes
All windows are based on calendar days.
Eligibility Assessments
Informed Consent
X
Informed consent must occur prior to any screening procedure and within 28 days of randomization. 
Contact interactive response technology (IRT) to obtain study subject number. Study allows for re-
enrollment of a participant that has discontinued the study as a pre-treatment failure. If re-enrolled, the 
participant must be re-consented and assigned a new subject number from IRT.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to randomization.
Medical History
X
Including concomitant medications and prior cancer therapy.
Tumor Tissue Samples
X
Recent sample or archival. Sufficient tumor tissue (either a formalin-fixed, paraffin-embedded [FFPE] 
tissue block or minimum 20 positively charged slides*) must be available within 3 months prior to 
randomization, with no intervening systemic therapy, and sent to a central laboratory for biomarker 
analysis. Tissue must be a core needle biopsy, excisional biopsy, or incisional biopsy. Fine needle 
biopsies are not considered adequate for biomarker review and randomization. Biopsies of bone 
lesions that do not have a soft tissue component or decalcified bone tumor samples are also not 
acceptable.
* If, despite best efforts, a minimum 20 slides are not obtainable, discuss with Sponsor.
In order to be randomized, the participant’s tumor-associated immune cells must have an evaluable
lymphocyte activation gene 3 (LAG-3) status (≥1% or < 1%; no indeterminate allowed) and must 
have a PD-L1 status (combined positive score [CPS] < 1 or indeterminate, CPS ≥1 to < 5, CPS ≥5). 
 
 
Safety Assessments
Physical Examination
X
Within 14 days prior to randomization.
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-1:
Screening Assessments - All Participants (CA224060)
Procedure
Screening
Visit
Notes
All windows are based on calendar days.
Physical Measurements
X
Include height, weight, and body surface area (BSA).
Within 14 days prior to randomization.
Performance Status (ECOG)
X
Within 14 days prior to randomization. See protocol Appendix 6.
Vital Signs 
X
Obtain vital signs at the screening visit and within 72 hours prior to first dose.
Including blood pressure (BP), heart rate, and temperature.
Assessment of Signs and Symptoms
X
Must be performed within 14 days prior to randomization.
Concomitant Medication Use
X
Within 28 days prior to randomization.
Serious Adverse Events Assessment
X
Serious Adverse Event collection from time of consent.
Laboratory Tests
X
Hematology, Serum Chemistry, and Urinalysis as outlined in Table 9.4.4-1 within 14 days prior to
randomization.
Serology as outlined in Table 9.4.4-1 within 28 days prior to randomization.
For HIV: testing at sites where locally mandated, see Appendix 7.
Troponin
X
Within 14 days prior to randomization.
Echocardiogram
X
Left ventricular ejection fraction (LVEF) assessment with documented LVEF ≥50% by either 
transthoracic echocardiogram (TTE) or multiple gated acquisition (MUGA) scan (TTE is preferred 
test) within 6 months prior to date of first study drug administration.
Electrocardiogram (ECG)
X
At rest. Within 14 days prior to randomization.
Pregnancy Test (WOCBP only)
X
Serum - (minimum sensitivity equivalent units 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]) to be done at screening visit and repeated within 24 hours prior to first dose of 
study treatment.
Follicle-stimulating Hormone 
X
If needed to document postmenopausal status as defined in Table 9.4.4-1.
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-1:
Screening Assessments - All Participants (CA224060)
Procedure
Screening
Visit
Notes
All windows are based on calendar days.
Efficacy Assessments
Body Imaging
X
See Section 9.1.1. Must be performed within 28 days prior to randomization.
Brain Imaging
X
See Section 9.1.1. magnetic resonance imaging (MRI) of the brain without and with contrast is 
required if participant is symptomatic or has history of brain metastasis and has not had brain imaging 
within 28 days prior to anticipated first study drug administration. Computed tomography (CT) of the 
brain (without and with contrast) can be performed if MRI is contraindicated.
Interactive Response Technology (IRT)
Contact IRT
X
The IRT must be contacted for subject number assignment at the time informed consent is obtained.
Abbreviations: ECOG = Eastern Cooperative Oncology Group; WOCBP = women of childbearing potential.
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-2:
On-treatment Assessments - Participants Assigned to Investigator’s Choice XELOX or SOX 
(CA224060)
Procedurea
Cycle 1 Day 1
(Cycle = 6 weeks)
Other Time Points Relative 
to Dosing Schedule
Notes
Safety Assessments
Targeted Physical Examination
X
See note
To be performed within 72 hours prior to dosing on Days 1 and 
22 of each cycle.
Vital Signs 
X
See note
Including BP, heart rate, and temperature to be performed 
within 72 hours prior to dosing on Days 1 and 22 of each cycle.
Weight and ECOG Performance 
Status
X
See note
To be performed within 72 hours prior to dosing on Days 1 and 
22 of each cycle.
See protocol Appendix 6 for ECOG Performance Status scale.
Adverse Event Assessment
Continuously
Assessed using National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v5.
Serious Adverse Event Assessment
Continuously
Assessed using NCI CTCAE v5.
Review of Concomitant 
Medications
Continuously
Laboratory Tests
X
See note
To be performed within 72 hours prior to dosing on Days 1 and 
22 of each cycle.
Includes Hematology, Serum Chemistry, and Urinalysis as 
outlined in Table 9.4.4-1.
All labs should be checked prior to dosing.
Troponin
See note
See note
Q2W or Q3W monitoring (depending on selected 
chemotherapy regimen) for the first 12 weeks. 
For immunotherapy dosing visits, test should be performed and 
evaluated within 72 hours prior to immunotherapy dosing.
Note: Symptom-based troponin testing may be performed as 
required.
Pregnancy Test (WOCBP only) 
X
See note
Serum or urine (minimum sensitivity equivalent units 25 IU/L 
or equivalent units of HCG) within 24 hours prior to 
administration of first dose of study treatment and then every 4 
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-2:
On-treatment Assessments - Participants Assigned to Investigator’s Choice XELOX or SOX 
(CA224060)
Procedurea
Cycle 1 Day 1
(Cycle = 6 weeks)
Other Time Points Relative 
to Dosing Schedule
Notes
weeks (± 7 days) regardless of dosing schedule. If collected 
with a dosing visit, then obtain within 24 hours prior to 
administration of study drug.
Home pregnancy test that meets the minimum sensitivity 
requirements can be used as necessary.
ECG
See note
See note
Cycle 1: Performed within 72 hours prior to dosing on Day 1 
and Day 22.
Cycles 2 to 4: Performed within 72 hours prior to dosing on 
Day 1.
Cycle 5 and Beyond: Performed within 72 hours prior to 
dosing every 12 weeks starting with C5D1.
Efficacy Assessments
Body Imaging
See Note
See Section 9.1.1. Tumor assessments should occur every 
6 weeks (± 7 days) starting from randomization up to and 
including Week 48, then every 12 weeks (± 7 days) regardless 
of treatment schedule until BICR-confirmed disease 
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-2:
On-treatment Assessments - Participants Assigned to Investigator’s Choice XELOX or SOX 
(CA224060)
Procedurea
Cycle 1 Day 1
(Cycle = 6 weeks)
Other Time Points Relative 
to Dosing Schedule
Notes
progression (PD) or the participant withdraws consent, 
whichever comes first. Participants who discontinue study 
treatment for reasons other than PD will continue to have 
tumor assessments until their disease progresses or they 
withdraw consent.
Use same imaging method as was used at screening/baseline.
Brain Imaging
See note
See Section 9.1.1. Participants with a history of brain 
metastases or symptoms should have surveillance MRI per 
standard of care (approximately every 12 weeks), or sooner if 
clinically indicated.
Study Treatment
Randomization
X
Contact IRT for randomization.
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-2:
On-treatment Assessments - Participants Assigned to Investigator’s Choice XELOX or SOX 
(CA224060)
Procedurea
Cycle 1 Day 1
(Cycle = 6 weeks)
Other Time Points Relative 
to Dosing Schedule
Notes
BMS-986213 or Nivolumab
X
See note
First dose of BMS-986213 or nivolumab and chemotherapy 
(XELOX or SOX) should be administered within 72 hours 
after randomization. BMS-986213 or nivolumab should be 
administered on the same day as the chemotherapy, unless
there is a dose delay or treatment is discontinued. BMS-
986213 or nivolumab must be administered within 3 days 
before or after the scheduled date. 
BMS-986213 should be administered in a single IV bag over 
60 minutes. Nivolumab should be administered over 30 
minutes.
XELOX or SOX and Dispense 
Drug Diary
X
See note
First dose to be administered within 72 hours after 
randomization. 
•
XELOX dose schedule: see Table 7.1.2-1. Subsequent 
XELOX doses may be administered within dosing 
windows per package insert or local standard.
•
SOX dose schedule: see Table 7.1.4-1. Subsequent SOX 
doses may be administered within dosing windows per 
package insert or local standard.
Review Drug Diary during each visit for compliance of twice 
daily administration of Capecitabine or S-1. Collect Drug 
Diary at the completion of each cycle.
Abbreviations: BICR = blinded independent central review; BP = blood pressure; C = cycle; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; 
 
 HCG = human chorionic gonadotropin; IV = 
intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; MRI = magnetic resonance imaging;
 
 
 SOX = S1 and oxaliplatin; WOCBP = women of childbearing potential; XELOX = capecitabine and oxaliplatin.
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs,
except for body imaging,
 and pregnancy testing.
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-3:
On-treatment Assessments - Participants Assigned to Investigator’s Choice FOLFOX (CA224060)
Procedurea
Cycle 1 Day 1
(Cycle = 6 weeks)
Other Time Points Relative
to Dosing Schedule
Notes
Safety Assessments
Targeted Physical Examination
X
See note
To be performed within 72 hours prior to dosing on Days 1, 15, 
and 29 of each cycle.
Vital Signs 
X
See note
Including BP, heart rate, and temperature to be performed 
within 72 hours prior to dosing on Days 1, 15, and 29.
Weight and ECOG Performance 
Status
X
See note
To be performed within 72 hours prior to dosing on Days 1, 15, 
and 29.
See protocol Appendix 6 for ECOG Performance Status scale.
Adverse Event Assessment
Continuously
Assessed using NCI CTCAE v5
SAE Assessment
Continuously
Assessed using NCI CTCAE v5
Review of Concomitant 
Medications
Continuously
Laboratory Tests
X
See note
To be performed within 72 hours prior to dosing on Days 1, 15, 
and 29. 
Includes Hematology, Serum Chemistry, and Urinalysis as 
outlined in Table 9.4.4-1.
All labs should be checked prior to dosing.
Troponin
See note
See note
Q2W or Q3W monitoring (depending on selected chemotherapy 
regimen) for the first 12 weeks.
For immunotherapy dosing visits, test should be performed and 
evaluated within 72 hours prior to immunotherapy dosing.
Note: Symptom-based troponin testing may be performed as 
required.
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-3:
On-treatment Assessments - Participants Assigned to Investigator’s Choice FOLFOX (CA224060)
Procedurea
Cycle 1 Day 1
(Cycle = 6 weeks)
Other Time Points Relative
to Dosing Schedule
Notes
Pregnancy Test (WOCBP only) 
X
See Note
Serum or urine (minimum sensitivity equivalent units 25 IU/L 
or equivalent units of HCG) within 24 hours prior to 
administration of first dose of study treatment and then every 4 
weeks (± 7 days) regardless of dosing schedule. If collected with 
a dosing visit, then obtain within 24 hours prior to 
administration of study drug.
Home pregnancy test that meets the minimum sensitivity 
requirements can be used as necessary.
ECG
See Note
See Note
Cycle 1: Performed within 72 hours prior to dosing on Days 1 
and 15
Cycles 2-4: Performed within 72 hours prior to dosing on Day 1.
Cycle 5 and Beyond: Performed within 72 hours prior to dosing 
every 12 weeks starting with C5D1
Efficacy Assessments
Body imaging
See Note
See Section 9.1.1. Tumor assessments should occur every 
6 weeks (± 7 days) starting from randomization up to and 
including Week 48, then every 12 weeks (± 7 days) regardless 
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-3:
On-treatment Assessments - Participants Assigned to Investigator’s Choice FOLFOX (CA224060)
Procedurea
Cycle 1 Day 1
(Cycle = 6 weeks)
Other Time Points Relative
to Dosing Schedule
Notes
of treatment schedule until BICR-confirmed PD or the 
participant withdraws consent, whichever comes first. 
Participants who discontinue study treatment for reasons other 
than PD will continue to have tumor assessments until their 
disease progresses or they withdraw consent.
Use same imaging method as was used at screening/baseline
Brain Imaging
See Note
See Section 9.1.1. Participants with a history of brain metastasis 
or symptoms should have surveillance MRI per standard of care 
(approximately every 12 weeks), or sooner if clinically indicated
Study Treatment
Randomization
X
Contact IRT for randomization
BMS-986213, or Nivolumab
X
See Note
First dose of BMS-986213 or nivolumab and FOLFOX should 
be administered within 72 hours after randomization. BMS-
986213 or nivolumab should be administered every 4-weeks 
on the same day as FOLFOX, unless there is a dose delay or 
treatment is discontinued. BMS-986213 or nivolumab may be 
administered within 3 days before or after the scheduled date if 
necessary.
BMS-986213 should be administered in a single IV bag over 60 
minutes. Nivolumab should be administered over 30 minutes.
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-3:
On-treatment Assessments - Participants Assigned to Investigator’s Choice FOLFOX (CA224060)
Procedurea
Cycle 1 Day 1
(Cycle = 6 weeks)
Other Time Points Relative
to Dosing Schedule
Notes
FOLFOX
X
See Note
First dose to be administered within 72 hours after 
randomization. 
FOLFOX dose schedule: see Table 7.1.3-1. Subsequent 
FOLFOX doses may be administered within dosing windows 
per package insert or local standard.
Abbreviations: BP = blood pressure; C = cycle; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
 
 
FOLFOX = oxaliplatin, leucovorin, and fluorouracil; FU = Follow-up; HCG = human 
chorionic gonadotropin; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; MRI = magnetic resonance 
imaging;
SAE = serious adverse event; concentration;
 WOCBP = women 
of childbearing potential
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs, 
except for body imaging, 
and pregnancy testing.
Revised Protocol No.: 03
Date: 24-Jun-2019
29
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-4:
Follow-up Assessments - All Participants (CA224060)
Procedure
Follow-Upa
Visits 1 and 2
Survival Follow-Up 
Visitsb
Notes
Safety Assessments
Targeted Physical Examination
X
Weight, BP, HR, and temperature. Targeted physical examination to 
be performed only as clinically indicated.
Serious Adverse Events Assessments
X
Assessed using NCI CTCAE v5
Adverse Events Assessment
X
Assessed using NCI CTCAE v5
Review of Subsequent Cancer Therapy
X
X
Laboratory Tests
See Note
For Follow-up Visit 1, including Hematology, Serum Chemistry, and 
Urinalysis as outlined in Table 9.4.4-1.
Repeat at Follow-up Visit 2 if study treatment related toxicity 
persists.
Pregnancy Test (WOCBP only)
See Note
Serum or urine pregnancy testing is only required at FU1 and FU2 
visits, unless increased frequency and duration is required per local 
regulations.
Revised Protocol No.: 03
Date: 24-Jun-2019
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Table 2-4:
Follow-up Assessments - All Participants (CA224060)
Procedure
Follow-Upa
Visits 1 and 2
Survival Follow-Up 
Visitsb
Notes
Efficacy Assessments
Body imaging
See Note
See Note
See Section 9.1.1. For participants who discontinue study drug for 
reasons other than PD, follow-up scans should be performed every 6 
weeks (± 7 days) up to and including Week 48, then every 12 weeks 
(± 7 days) until BICR confirmed PD, lost to follow-up, or 
withdrawal of consent.
Radiographic assessments should be Q12W in Follow-Up and not be 
delayed until follow-up visits 1 & 2.
Brain Imaging
See Note
See Note
See Section 9.1.1. Participants with a history of brain metastasis or 
symptoms should have surveillance MRI per standard of care 
(approximately every 12 weeks), or sooner if clinically indicated
Abbreviations:
 
 FU = Follow-up; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events;
 WOCBP = women of childbearing potential
a Follow-up visits occur as follows: Follow-up Visit 1 = 30 days from the last dose (± 7 days) or coincide with the date of discontinuation (± 7 days) if date of 
discontinuation is greater than 42 days after last dose. Follow-up Visit 2 = 100 days (± 7 days) from last dose of study treatment. Participants must be followed 
for at least 100 days after last dose of study treatment. Both Follow-up visits should be conducted in person.
b Survival follow-up visits may be conducted in clinic or by phone. The first survival follow-up visit will occur 3 months (± 14 Days) after Follow-up Visit 2, 
subsequent survival follow-up visits will occur every 3 months (± 14 days) thereafter. BMS may request that survival data be collected on all treated participants 
outside of the 3 month specified window. At the time of this request, each participant will be contacted to determine their survival status unless the participant 
has withdrawn consent for all contacts.
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BMS-986213
relatlimab-nivolumab FDC
3
INTRODUCTION
CA224060 is a Phase 2, randomized, open-label study of BMS-986213 (fixed-dose combination 
[FDC] relatlimab/nivolumab at a 1:3 ratio) in combination with investigator’s choice 
chemotherapy, versus nivolumab in combination with investigator’s choice chemotherapy, as first-
line (1L) treatment in participants with untreated, unresectable, and either locally advanced or 
metastatic gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. Relatlimab is 
a fully human lymphocyte activation gene 3 (LAG-3) specific antibody that was isolated following 
immunization of transgenic mice expressing human immunoglobulin (Ig) genes. Relatlimab binds 
to LAG-3 with high affinity and inhibits binding of this receptor to cells bearing its ligand, major 
histocompatibility complex (MHC) Class II, the peptide antigen presentation molecule recognized 
by CD4+ T cells. Relatlimab binding inhibits the negative regulatory function of LAG-3 in vitro. 
By blocking the normal downregulatory pathway, relatlimab enhances the antitumor immune 
response and, thus, has the potential to inhibit the growth of multiple malignancies when 
administered in combination with other therapeutic immuno-oncology (IO) monoclonal antibodies 
(mAbs).
Nivolumab is a human mAb (IgG4-S228P) that targets the programmed death-1 (PD-1) cluster of 
differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory 
molecule expressed by activated T and B lymphocytes. 1 Binding of PD-1 to its ligands, 
programmed death-ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte 
activation. Inhibition of the interaction between PD-1 and its ligands promotes immune responses 
and antigen-specific T-cell responses to both foreign antigens as well as self-antigens.
This Phase 2 study for BMS-986213 in GC and GEJ cancer will allow for direct comparison of 
the treatment effect of BMS-986213 in combination with investigator’s choice chemotherapy,
versus nivolumab in combination with investigator’s choice chemotherapy, as measured by 
objective response rate (ORR) and duration of response (DOR) in participants with untreated, 
unresectable, and either locally advanced or metastatic GC or GEJ adenocarcinoma. The study will 
enroll patients with LAG-3 (+) and LAG-3 (-) expression status (≥1% or < 1%; no indeterminate 
allowed). 
 
 
 
 This clinical equipoise 
is further supported by the fact that the relationship between the immunogenic effects of 
chemotherapy and the clinical efficacy of immunotherapy has not been well characterized. 
Accordingly, participants will have their LAG-3 status (≥1% or < 1%; no indeterminate allowed) 
determined prior to randomization, and enrollment into the 2 treatment arms for this study will be 
stratified based on LAG-3 expression status.
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3.2.1
Research Hypothesis
In participants with untreated, unresectable, and either locally advanced or metastatic GC or GEJ 
adenocarcinoma, the administration of relatlimab plus nivolumab, in combination with 
chemotherapy, will improve ORR compared to nivolumab in combination with chemotherapy in 
the LAG-3 positive population.
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3.3
Benefit-risk Assessment
Patients with advanced or metastatic GC and GEJ cancer present a significant unmet medical need. 
 
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The combination of relatlimab and nivolumab has been evaluated and appears to have a safety 
profile similar to nivolumab monotherapy. 
 
A pattern of immune-mediated adverse events (IMAEs) has been defined for treatment with 
nivolumab monotherapy and nivolumab in combination with other immune-targeting agents such 
as relatlimab. Management algorithms have been developed for these events and are provided in 
Appendix 8. Most high-grade immune-related adverse events are manageable with the use of 
corticosteroids or hormone replacement therapy (endocrinopathies) as detailed in these algorithms. 
Additional details on the safety profiles of relatlimab and nivolumab, including results from other 
clinical studies, are also available in the relatlimab, nivolumab, and BMS-986213
(relatlimab/nivolumab FDC) IBs.
The safety profile of nivolumab combined with oxaliplatin and fluoropyrimidine reflects the 
additive toxicity of nivolumab monotherapy and chemotherapy, and no new safety signal was 
identified. The ongoing internal and external studies of PD-L1 inhibitors in combination with 
chemotherapy in treatment-naïve advanced GC/GEJ participants suggest that this combination is 
tolerable and manageable, as no new safety signals have been detected.
To ensure an ongoing favorable risk/benefit assessment for participants enrolled in CA224060, an 
independent Data Monitoring Committee (DMC) will be utilized to evaluate the safety and 
efficacy of the treatments throughout the conduct of the trial.
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BMS-986213
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This study involves investigational (relatlimab) and approved (nivolumab) drugs whose effects on 
pregnancy are not yet known or fully defined. Contraception is therefore required for participants 
who are women of childbearing potential (WOCBP), males, and for female partners of male 
participants who are WOCBP. These contraception guidelines (see Appendix 4) apply to all female 
participants and partners of male participants who could be exposed to the drug and who could 
become pregnant both during treatment and during a defined period after study drug treatment.
The combination of relatlimab and nivolumab, or nivolumab in combination with chemotherapy,
has been tested in patients with GC, with promising preliminary data.
 
 
 
 
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objective
Endpoint
Primary
•
To compare ORR of BMS-986213 in combination 
with chemotherapy, with ORR of nivolumab in 
combination with chemotherapy, by BICR, in 
randomized 
participants 
with 
untreated, 
unresectable, and either locally advanced or 
metastatic 
LAG-3 
positive
GC 
or 
GEJ 
adenocarcinoma.
•
ORR in participants who are LAG-3 positive. ORR 
is defined as the number of participants with a BOR 
of CR or PR divided by the number of randomized 
participants in each arm. BOR is defined as the best 
response designation as determined by the BICR, 
recorded between the date of randomization and the 
date of objectively documented progression (per 
Response Evaluation Criteria in Solid Tumors 
[RECIST 1.1]), death due to any cause, or the date 
of subsequent anticancer therapy, whichever occurs 
first.
Secondary
•
To assess the overall safety and tolerability of BMS-
986213 in combination with chemotherapy vs. 
nivolumab in combination with chemotherapy in 
treated participants with advanced or metastatic GC 
or GEJ cancer.
•
The incidence of AEs, SAEs, AE leading to 
discontinuation,
deaths, 
and 
laboratory 
abnormalities in each arm.
•
To compare ORR of BMS-986213 in combination 
with chemotherapy, with ORR of nivolumab in 
combination with chemotherapy, as assessed by
investigator, in randomized participants with 
untreated, unresectable, and either locally advanced 
or metastatic LAG-3 positive
GC or GEJ 
adenocarcinoma.
•
ORR is defined as above, as the number of 
participants with a BOR of CR or PR as assessed by 
the investigator using RECIST 1.1, divided by the 
number of randomized participants in each 
Treatment Arm.
•
To compare ORR by BICR and by investigator of 
BMS-986213 in combination with chemotherapy 
with ORR of nivolumab in combination with 
chemotherapy in randomized participants with 
advanced or metastatic LAG-3 negative GC or GEJ 
adenocarcinoma, and overall (across
LAG-3 
negative and positive groups).
•
ORR in the LAG-3 negative group or overall is 
defined as above, as the number of participants in 
each population with a BOR of CR or PR divided by 
the number of randomized participants in each 
Treatment Arm, for that population.
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BMS-986213
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Table 4-1:
Objectives and Endpoints
Objective
Endpoint
•
To estimate DOR of BMS-986213 in combination 
with chemotherapy and DOR of nivolumab in 
combination with chemotherapy in randomized 
participants with advanced or metastatic LAG-3 
positive GC or GEJ adenocarcinoma, by BICR and 
by the investigator.
•
DOR (based on BICR and investigator) is defined as 
the time between the date of first documented 
response (CR or PR) to the date of the first PD, per 
RECIST 1.1, death due to any cause, or the date of 
subsequent anticancer therapy whichever occurs 
first.
•
To estimate DOR of BMS-986213 in combination 
with chemotherapy and DOR of nivolumab in 
combination with chemotherapy in randomized 
participants with advanced or metastatic LAG-3 
negative GC or GEJ adenocarcinoma, and in the 
overall population by BICR and by the investigator.
•
DOR in participants with advanced or metastatic 
LAG-3 negative GC or GEJ adenocarcinoma and 
for participants in the overall population (across the 
LAG-3 groups) is defined as above.
•
To assess the difference in the overall survival (OS)
of BMS-986213 in combination with chemotherapy 
and
OS of nivolumab in combination with 
chemotherapy in randomized participants with 
untreated, unresectable, and either locally advanced 
or metastatic GC or GEJ adenocarcinoma separately 
in the LAG-3 positive and LAG-3 negative groups 
and overall.
•
OS is defined as the time between the date of 
randomization and the date of death. For those 
without documentation of death, OS will be 
censored on the last date the participant was known 
to be alive. 
•
To assess the difference in the PFS of BMS-
986213 in combination with chemotherapy and 
PFS of nivolumab in combination with 
chemotherapy as assessed by BICR and 
investigator in randomized participants with 
untreated, unresectable, and either locally 
advanced or metastatic GC or GEJ adenocarcinoma
separately in the LAG-3 positive and LAG-3 
negative groups and overall.
•
PFS is defined as the time between the date of 
randomization and the date of the first documented 
PD per BICR or investigator or death due to any 
cause. Participants who die without a reported prior 
PD per BICR or investigator (and die without start 
of subsequent therapy) will be considered to have 
progressed on the date of death. Those who did not 
have documented PD per RECIST 1.1 criteria and 
who did not die, will be censored at the date of the 
last evaluable tumor assessment on or prior to 
initiation 
of 
subsequent 
anticancer 
therapy. 
Participants who did not have any on-study tumor 
assessments and did not die (or died after initiation 
of subsequent anticancer therapy) will be censored 
at the randomization date. Those who started any 
subsequent anticancer therapy without a prior 
reported PD will be censored at the last tumor 
assessment prior to or on the initiation of the 
subsequent 
anticancer 
therapy. 
Participants 
receiving treatment beyond progression must 
continue tumor assessments until such treatment has 
been discontinued.
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BMS-986213
relatlimab-nivolumab FDC
Table 4-1:
Objectives and Endpoints
Abbreviations: 
 AE = adverse event; BICR = blinded independent central review; BOR = 
best overall response; CR = complete response; 
 
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BMS-986213
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 DOR = duration of response; 
 
 
 GC = gastric cancer; GEJ = 
gastroesophageal junction; LAG-3 = lymphocyte activation gene 3; 
 ORR = objective 
response rate; OS = overall survival; 
PD = disease progression; PFS = progression-free 
survival; 
PR = partial response; 
 
RECIST = Response 
Evaluation Criteria in Solid Tumors; SAE = serious adverse event
.
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 2, randomized, open-label, 2-arm study of BMS-986213 or nivolumab in 
combination with investigator’s choice chemotherapy as L1 treatment in participants with
untreated, unresectable, and either locally advanced or metastatic GC or GEJ adenocarcinoma. 
Approximately 250 participants will be randomized in 2 treatment arms in this global clinical 
study. Nivolumab monotherapy will be administered IV as either 360 mg every 3 weeks (Q3W)
or 480 mg every 4 weeks (Q4W), depending on the assigned chemotherapy regimen. Relatlimab 
and nivolumab combination, as an FDC, will be administered as 120-mg relatlimab/360-mg 
nivolumab Q3W or 160-mg relatlimab/480-mg nivolumab Q4W, depending on the assigned 
chemotherapy regimen. 
After signing the informed consent form, participants will enter the Screening Phase. A pre-
treatment tumor sample is required to be submitted from all participants. Although this study will 
enroll participants regardless of their LAG-3 expression status (≥1% or < 1%; no indeterminate 
allowed), participants must have their LAG-3 status determined prior to completion of the 
remaining Screening procedures. Patients with an indeterminate LAG-3 expression status 
cannot be enrolled in the study. As deemed appropriate by the Investigator, participants may 
complete the remaining Screening procedures in parallel to the determination of the LAG-3 status 
in order to minimize the duration of the Screening Phase. 
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
5.1.1
Screening Phase
•
The Screening Phase begins by establishing the participant’s initial eligibility and signing of 
the informed consent form within 28 days of randomization.
•
Participants are enrolled using the Interactive Response Technology (IRT) system. 
•
A pre-treatment tumor sample is required to be submitted from all participants. The 
participant’s tumor-associated immune cells must have an evaluable LAG-3 status (≥1% or 
< 1%; no indeterminate allowed) and must have a PD-L1 status (combined positive score 
[CPS] < 1 or indeterminate, CPS ≥1 to < 5, CPS ≥5). LAG-3 expression status (LAG-3 [+]
or LAG-3 [-]) and PD-L1 expression status must be determined by the central lab prior to 
completion of the remaining screening procedures. As deemed appropriate by the 
investigator, participants may complete the remaining screening procedures in parallel to the 
determination of the LAG-3 and PD-L1 expression in order to minimize the duration of the 
Screening Phase. 
•
Sufficient tumor tissue (either a formalin-fixed, paraffin-embedded [FFPE] tissue block or 
minimum 20 positively charged slides [if 20 are not obtainable, discuss with Sponsor]) must 
be submitted for biomarker evaluation prior to randomization. If available, the pathology report 
should be submitted with the FFPE tissue block or unstained tumor tissue slides. The tumor 
tissue sample may be fresh or archival if obtained within 3 months prior to randomization, and 
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there cannot have been any systemic therapy given after the sample was obtained. Tissue must 
be a core needle biopsy, excisional or incisional biopsy. Fine needle biopsies are not considered 
adequate for biomarker review and randomization. Biopsies of bone lesions that do not have a 
soft tissue component or decalcified bone tumor samples are also not acceptable. If insufficient 
tumor tissue is provided for analysis, acquisition of additional tumor tissue (block and/or 
slides) for the biomarker analysis is required.
•
Participant is assessed for study eligibility according to the inclusion (Section 6.1) and 
exclusion (Section 6.2) criteria. The detailed procedures are described in Table 2-1.
5.1.2
Treatment Phase
•
The Treatment Phase begins after contacting the IRT system for randomization. The choice of 
chemotherapy regimen (XELOX, SOX, or FOLFOX) must be decided before contacting the 
IRT system for randomization.
•
Participants will be randomized to either the BMS-986213 or nivolumab arm. Each arm will 
be given in combination with investigator’s choice chemotherapy (XELOX, FOLFOX, or
SOX). 
•
The treatment will be given until disease progression (PD) (see Section 7.3.8), unacceptable 
toxicity, or participant withdrawal of consent, whichever comes first.
•
Stratification factors for this study are as follows: 
−
LAG-3 expression (≥1% or < 1%; no indeterminate allowed)
−
Region (Japan/Taiwan [J/T] vs rest of world [ROW])
−
PD-L1 expression status (CPS < 1 or indeterminate, CPS ≥1 to < 5, CPS ≥5).
•
Administration of study treatment is to begin within 3 calendar days of randomization. 
•
Each cycle will be 6 weeks in duration.
•
On the day of infusion, BMS-986213 or nivolumab is to be administered first, followed by 
chemotherapy. The administration procedures of chemotherapy will follow local standards. 
BMS-986213 or nivolumab and chemotherapy should be administered on the same day,
with the following exceptions:
−
BMS-986213 or nivolumab is allowed to be administered alone in cases where the 
chemotherapy has been delayed or discontinued due to toxicity. 
−
Chemotherapy alone is allowed to be administered in cases where BMS-986213 or 
nivolumab has been delayed or discontinued due to toxicity.
−
Participants assigned to FOLFOX will have only FOLFOX administered on Day 15 of the 
odd-numbered cycles (ie, Cycles 1, 3, 5, etc) and Day 1 and 29 of the even-numbered cycles 
(ie, Cycles 2, 4, 6, etc).
•
No cross-over is allowed between XELOX, SOX, and FOLFOX regimens.
•
The Treatment Phase ends when the participant is discontinued from study therapy (ie, PD, 
unacceptable toxicity, or participant withdrawal of consent). 
Study assessment data are to be collected as outlined in Table 2-2 and Table 2-3.
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CA224060
BMS-986213
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5.1.3
Follow-up Phase
•
The Follow-up Phase begins when the decision is made to discontinue a participant from study 
therapy.
•
Follow-up Visit 1 will be performed 30 days from the last dose (± 7 days) or coincide with the 
date of discontinuation (± 7 days) if date of discontinuation is greater than 42 days after last 
dose. Follow-up Visit 2 will be performed 100 days (± 7 days) from last dose of study 
treatment. Participants must be followed for at least 100 days after last dose of study treatment. 
Both follow-up visits should be conducted in person.
•
Survival visits - The first survival follow-up visit will be performed 3 months (± 14 days) after 
follow-up Visit 2. Subsequent survival follow-up visits will occur every 3 months (± 14 days)
thereafter. Survival follow-up visits may be conducted in clinic or by phone.
Study follow-up assessment data are to be collected as outlined in Table 2-4.
5.1.4
Blinded Independent Central Review
A Blinded Independent Central Review (BICR) will be utilized in this study for determination of 
BICR-assessed endpoints. The BICR will review all available tumor assessment scans for all 
treated participants. All investigator determinations of PD will be reviewed by the BICR (see 
Section 9.1.4). Details of BICR responsibilities and procedures will be specified in the BICR 
charter.
5.1.5
Data Monitoring Committee
A DMC will be established to provide oversight of safety and efficacy considerations in protocol 
CA224060 and to provide advice to the Sponsor regarding actions the committee deems necessary 
for the continued protection of participants enrolled in the study. The DMC will act in an advisory 
capacity to BMS and will monitor participant safety and evaluate the available safety and efficacy 
data for the study. The oncology therapeutic area of BMS has primary responsibility for design 
and conduct of the study. Additional details concerning DMC oversight are provided in the DMC
charter.
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
5.2
Number of Participants
It is expected that approximately 420 participants will need to be enrolled in order to randomize 
250 participants.
Approximately 250 participants are planned to be randomized 1:1 to 1 of 2 treatment arms: 
1) BMS-986213 in combination with investigator’s choice chemotherapy
2) Nivolumab in combination with investigator’s choice chemotherapy 
See Section 10.1 for sample size determination and associated assumptions.
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BMS-986213
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5.3
Study Definitions
The start of the trial is defined as the first visit for the first participant screened. The End of Trial 
for the primary endpoint of ORR is defined as the last visit or scheduled procedure shown in the 
Schedule of Activities for the last participant for the corresponding endpoint.
Study completion is defined as the final date on which data for the primary endpoint was or is 
expected to be collected, if this is not the same.
The duration of the study, from start of randomization to primary endpoint ORR analysis, is 
expected to be approximately 22 months, assuming 16 months accrual duration. Additional 
follow-up for progression-free survival (PFS) and overall survival (OS) may be conducted up to 
approximately 5 years for OS after the randomization of the last participant. The study will end 
once survival follow-up has concluded. Under some circumstances, participants may not be 
followed for 5 years for survival in this study (eg, the participants may be offered to enroll into a 
roll-over study, or the sponsor may terminate the study early).
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BMS-986213
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CA224060
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6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an institutional review board/independent ethics 
committee (IRB/IEC)-approved written informed consent form in accordance with 
regulatory and institutional guidelines. This must be obtained before the performance of 
any protocol-related procedures that are not part of normal patient care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) All participants must have histologically or cytologically confirmed diagnosis of 
unresectable and either locally advanced or metastatic GC or GEJ adenocarcinoma. The 
documentation of GC or GEJ involvement can include biopsy, endoscopy, or imaging.
b) Participant must be previously untreated with systemic treatment (including HER 2 
inhibitors) given as primary therapy for unresectable and either locally advanced or 
metastatic gastric or GEJ adenocarcinoma
c) Allowed Prior Therapies: Prior adjuvant or neoadjuvant chemotherapy, radiotherapy,
and/or chemoradiotherapy for GC or GEJ cancer are permitted, as long as the last 
administration of the last regimen (whichever was given last) occurred at least 6 months 
prior to randomization. Palliative radiotherapy is allowed and must be completed 2 weeks 
prior to randomization. Chinese traditional medicines with an approved indication of 
cancer treatment are permitted as long as the last administration occurred at least 2 weeks 
prior to randomization.
d) Participant must have at least 1 measurable lesion by CT or MRI per RECIST 1.1 criteria; 
radiographic tumor assessment should be performed within 28 days prior to randomization.
e) ECOG performance status score of 0 or 1 (Appendix 6).
f)
Tumor tissue must be provided for biomarker analyses. In order to be randomized, the 
participant’s tumor-associated immune cells must have an evaluable LAG-3 status (≥1% 
or < 1%; no indeterminate allowed) and must have a PD-L1 status (CPS < 1 or 
indeterminate, CPS ≥1 to < 5, CPS ≥5). Participants whose tumor-associated immune 
cells are LAG-3 indeterminate will not be randomized to a treatment arm. Either a FFPE 
tissue block or minimum 20 positively charged slides (if a minimum of 20 slides is not 
obtainable, discuss with Sponsor) must be submitted for biomarker evaluation prior to 
randomization. If available, the pathology report should be submitted with the FFPE tissue 
block or unstained tumor tissue slides. The tumor tissue sample may be fresh or archival if 
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BMS-986213
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obtained within 3 months prior to randomization, and there can have been no systemic 
therapy given after the sample was obtained. Tissue must be a core needle, excisional, or 
incisional biopsy. 
g) Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pretreatment failure (ie, participant has not been randomized). 
If re-enrolled, the participant must be re-consented.
3) Age and Reproductive Status
a) Males and females, ≥18 years of age or age of majority.
b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L 
or equivalent units of HCG) within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception (see Appendix 
4) for the duration of treatment with study treatment(s) plus 24 weeks after the last dose of 
study treatment (ie, 30 days [duration of ovulatory cycle] plus the time required for 
nivolumab and relatlimab to undergo approximately 5 half-lives).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (see Appendix 4) for the duration of treatment with study 
treatment(s) plus 33 weeks after the last dose of the study treatment (ie, 90 days [duration 
of sperm turnover] plus the time required for nivolumab and relatlimab to undergo 
approximately 5 half-lives). In addition, male participants must be willing to refrain from 
sperm donation during this time.
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception (Appendix 4)
that have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) HER2 positive status (IHC3+ or FISH positive [HER2:CEP17 ratio > 2] or IHC2+/FISH+).
b) Participants with untreated known central nervous system (CNS) metastases. Participants 
are eligible if CNS metastases have been adequately treated and participants have 
neurologically returned to baseline (except for residual signs or symptoms related to the 
CNS treatment) for at least 2 weeks prior to randomization. In addition, participants must 
be either off corticosteroids or on a stable or decreasing dose of ≤10 mg daily prednisone 
(or equivalent) for at least 2 weeks prior to randomization.
c) Prior malignancy active within the previous 3 years, except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.
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d) Participants with an active, known, or suspected autoimmune disease. Participants with 
type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll.
e) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 
14 days prior to first study drug administration. Inhaled or topical steroids, and adrenal 
replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of 
active autoimmune disease.
f)
All toxicities attributed to prior anticancer therapy other than hearing loss, alopecia, and 
fatigue must have resolved to Grade 1 (National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE] version 5) or baseline before administration of 
study drug.
g) Participants with > Grade 1 peripheral neuropathy.
h) Participants with ascites that cannot be controlled with appropriate interventions.
i)
Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following:
i)
Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months 
prior to consent
ii)
Uncontrolled angina within the 3 months prior to consent
iii)
Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes or poorly controlled atrial fibrillation)
iv)
QTc prolongation > 480 msec
v)
History of other clinically significant cardiovascular disease (ie, cardiomyopathy, 
congestive heart failure with New York Heart Association functional classification 
III-IV, pericarditis, significant pericardial effusion, significant coronary stent 
occlusion, poorly controlled venous thrombosis, etc)
vi)
Cardiovascular disease-related requirement for daily supplemental oxygen
vii)
History of 2 or more MIs OR 2 or more coronary revascularization procedures
viii) Participants with history of myocarditis, regardless of etiology
ix)
Left ventricular ejection fraction (LVEF) <50% by either transthoracic 
echocardiogram (TTE) or multiple gated acquisition (MUGA) scan (TTE is preferred 
test) within 6 months prior to date of first study drug administration.
j)
Participants with serious or uncontrolled medical disorders.
k) Participants must have recovered from the effects of major surgery requiring general 
anesthetic or significant traumatic injury at least 14 days prior to randomization.
2) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell costimulation or 
checkpoint pathways.
b) Prior treatment with relatlimab or any other LAG-3-targeted agents.
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c) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to randomization/treatment. Refer to Section 7.6.1 for prohibited therapies.
d) Participants who have received a live/attenuated vaccine within 30 days of first treatment.
3) Physical and Laboratory Test Findings
a) White blood cells < 2000/μL (SI: < 2.00 × 109/L)
b) Neutrophils < 1500/μL (SI: < 1.50 × 109/L)
c) Platelets < 100*103/μL (SI: < 100 × 109/L) (transfusions not permitted within 72 hours 
prior to qualifying laboratory value)
d) Hemoglobin < 9.0 g/dL (SI:< 90 g/L) (transfusions not permitted within 72 hours prior to 
qualifying laboratory value)
e) Serum creatinine > 1.5 × upper limit of normal (ULN) or calculated creatinine clearance 
< 50 mL/min (using the Cockcroft-Gault formula):
Female creatinine clearance (CrCl) = (140 - age in years) × weight in kg × 0.85
   72 × serum creatinine in mg/ dL
Male CrCl = (140 - age in years) × weight in kg × 1.00
       
72 × serum creatinine in mg/ dL
f)
AST or ALT: > 3.0 × ULN (or > 5.0 x ULN if liver metastases are present)
g) Total bilirubin > 1.5 × ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 × ULN)
h) Troponin T (TnT) or I (TnI) > 2 × institutional ULN. TnT or TnI levels between > 1 to 2 ×
ULN will be permitted to participate in the study if a repeat assessment remains within 
ULN or patient has no cardiac symptoms and participant undergoes a cardiac imaging 
evaluation found to have no significant myocardial disease or dysfunction. When repeat 
levels within 24 hours are not available, a repeat test should be conducted as soon as 
possible.
i)
Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus 
(eg, Hepatitis B surface antigen [Australia antigen] positive, or Hepatitis C virus antibody 
[anti-HCV] positive [except if HCV-ribonucleic acid (RNA) negative]).
j)
Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome. NOTE: Testing for HIV must be performed at sites 
where mandated locally.
k) Positive pregnancy test at enrollment or prior to administration of study medication.
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components.
b) Any contraindications to any of the study drugs of the chemotherapy regimen (XELOX, 
SOX, or FOLFOX) selected by the investigator. Investigators should refer to local 
package insert of the chemotherapy drugs.
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BMS-986213
relatlimab-nivolumab FDC
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances, a person who has been imprisoned may be included or permitted to 
continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is 
required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
No restrictions are required for BMS-986213 or nivolumab. 
Please also refer to the XELOX, SOX, and FOLFOX package inserts for possible restrictions. 
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. 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, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs.
6.4.1
Retesting During Screening or Lead-in Period
This study permits the re-enrollment of a participant that has discontinued the study as a pre-
treatment failure (ie, participant has not been randomized). If re-enrolled, the participant must be 
re-consented.
Retesting of laboratory parameters and/or other assessments within any single screening or lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current clinical state.
Laboratory parameters and/or assessments that are included in Screening Assessments - All 
screening tests for participants may be repeated in an effort to find all possible well-qualified 
participants. Consultation with the Medical Monitor may be needed to identify whether repeat 
testing of any particular parameter is clinically relevant (see Table 2-1).
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BMS-986213
relatlimab-nivolumab FDC
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), or medical 
device intended to be administered to a study participant according to the study randomization or 
treatment allocation.
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
•
relatlimab/nivolumab FDC solution for injection
•
nivolumab solution for injection
•
oxaliplatin concentrate for solution for infusion
•
capecitabine tablets
•
fluorouracil solution for injection
•
leucovorin (folinic acid) solution for injection
•
tegafur/gimeracil/oteracil capsule
An investigational product (IP; also known as investigational medicinal product in some regions) 
is defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventive, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
Investigational products used in this trial are provided in Table 7-1. There are no non-
investigational products in this study.
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Table 7-1:
Study Treatments for CA224060
Product Description/Class and 
Dosage Form
Potency
IP/
Non-IMP
Packaging/Appearance
Storage Conditions
(per label)
Nivolumab (BMS-936558-01)
Solution for Injectiona
10 mg/mL
IP
10-mL vial. Clear to opalescent, colorless to 
pale yellow liquid. May contain particles.
Refer to the label on container 
and/or pharmacy manual
BMS-986213
(Relatlimab 80 mg/
Nivolumab 240 mg)
Solution for Injectionb
16 mg/mL
IP
20-mL vial. Colorless to pale yellow liquid, 
clear to slightly opalescent, light (few) 
particulates (consistent in appearance to 
protein particulates) may be present.
Refer to the label on container 
and/or pharmacy manual
Oxaliplatin Concentrate for 
Solution for Infusionc
5 mg/mL
IP
Clear, colorless solution (20 mL/ vial), 
1 vial/carton
Refer to the label on container 
and/or pharmacy manual
Capecitabinec Tablet
150 mg and 500 mg 
IP
Wallet/blister card containing 10, 20, or 30 
tablets
Refer to the label on container 
and/or pharmacy manual
Fluorouracil Solution for 
Injectionc
50 mg/mL
IP
Clear, colorless, or almost colorless
solution. 50 mL/vial (1 vial/carton)
Refer to the label on container 
and/or pharmacy manual
Leucovorin (folinic acid) 
Solution for Injectionc
50 mg/mL
IP
8 mL/vial (1 or 4 vials/carton)
Refer to the label on container 
and/or pharmacy manual
S-1 
tegafur/gimeracil/oteracilc
Capsule
20 mg/5.8 mg/15.8 mg 
IP
PCTFE/PVC/Alopaque blisters containing 
14 capsules each. Each pack contains 
84 capsules.
Refer to the label on container 
and/or pharmacy manual
S-1
tegafur/gimeracil/oteracilc
Capsule
15 mg/4.35 mg/11.8 mg 
IP
PCTFE/PVC/Alopaque blisters containing 
14 capsules each. Each pack contains 
84 capsules.
Refer to the label on container 
and/or pharmacy manual
Abbreviations: IP = investigational product; N/A = not applicable; PCTFE = polychlorotrifluoroethylene; PVC = polyvinyl chloride.
a May be labeled as either “BMS-936558-01” or “Nivolumab.”
b Relatlimab/nivolumab combination is also referred to BMS-986213.
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c These products may be obtained by the investigational sites as local commercial products in certain countries if allowed by local regulations. In these cases, 
products may be in a different pack size/potency/pharmaceutical form than listed in the table. These products should be prepared/stored/administered in 
accordance with the package inserts or summaries of product characteristics.
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BMS-986213
relatlimab-nivolumab FDC
7.1
Treatments Administered
7.1.1
BMS-986213 or Nivolumab Dosing
BMS-986213 (prepared in normal saline for relatlimab 120 mg/nivolumab 360 mg or relatlimab 
160 mg/nivolumab 480 mg), nivolumab (360 or 480 mg) dosing is to be administered as an IV 
infusion through a 0.2-micron to 1.2-micron pore-size, low-protein binding in-line filter at the 
protocol-specified doses. It is not to be administered as an IV push or bolus injection. Instructions 
for dilution and infusion of BMS-986213 and nivolumab injection will be provided in the 
Pharmacy Manual. Care must be taken to assure sterility of the prepared solution as the product 
does not contain any antimicrobial preservative or bacteriostatic agent.
Participants should receive BMS-986213 or nivolumab as a 1-hour infusion or 30-minute infusion, 
respectively, on the days outlined in Table 7.1.2-1, Table 7.1.3-1, and Table 7.1.4-1 based on the
specific chemotherapy regimen. Treatment will be given until PD, unacceptable toxicity, 
withdrawal of consent, or the study ends, whichever occurs first. Participants should begin study 
treatment within 3 calendar days of randomization. 
There will be no dose escalations or reductions of BMS-986213 or nivolumab. Participants may 
be dosed within a ± 3 day window. Premedication for potential infusion reaction is not 
recommended for the first dose of either treatment.
Participants should be carefully monitored for infusion reactions during administration. If an acute 
infusion reaction is noted, participants should be managed according to Section 7.3.10.
Doses of BMS-986213 or nivolumab may be interrupted, delayed, or discontinued depending on 
how well the participant tolerates the treatment. Resumption of treatment should be at the next 
scheduled time point. Dosing visits are not skipped, only delayed.
Infusions are compatible with PVC or polyolefin containers and infusion sets and glass bottles.
For details on prepared drug storage, preparation, and administration, please refer to the IBs and/or 
Pharmacy Manual.
When BMS-986213 or nivolumab are to be administered on the same day as the chemotherapy, 
BMS-986213 or nivolumab are to be administered first. BMS-986213 or nivolumab infusion must 
be promptly followed by a diluent flush to clear the line of IP before starting the chemotherapy 
infusion(s). The second infusion will always be the chemotherapy study drug(s) and will start after 
the infusion line has been flushed, filters changed, and the participant has been observed to ensure 
no infusion reaction has occurred. The time between immunotherapy and chemotherapy infusions 
is expected to be approximately 30 minutes, but may be more or less depending on the situation.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2).
7.1.2
Dose Schedule for BMS-986213 or Nivolumab Plus XELOX
Participants assigned to XELOX will receive BMS-986213 (relatlimab 120 mg/nivolumab
360 mg) or nivolumab 360 mg, administered IV over 60 minutes or 30 minutes, respectively,
oxaliplatin 130 mg/m2 administered IV on Days 1 and 22 of each 6-week treatment cycle, and 
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capecitabine 1000 mg/m2 administered orally twice daily (ie, 1000 mg/m2 in the morning and 
1000 mg/m2 in the evening) on Days 1 to 14 and Days 22 to 35 of each 6-week treatment cycle
(see Table 7.1.2-1). Immunotherapy treatment should be administered first, prior to chemotherapy 
treatment. Dosing windows for subsequent XELOX doses should adhere to recommendations in
the prescribing information or local standards, where indicated.
Premedication for potential infusion reaction is not recommended for the first dose of either 
treatment. Premedication maybe administered for nausea and vomiting prophylaxis, after the 
completion of the immunotherapy treatment or, in the absence of preceding immunotherapy, before 
chemotherapy administration, as clinical presentation warrants and per local standard.
Capecitabine should be taken with food.
Participants should be provided with drug diaries at each visit and instructed to record intake of 
capecitabine in the diary after each twice daily administration.
Table 7.1.2-1:
Dose Schedule for BMS-986213 or Nivolumab Plus XELOX
Treatment 
Group
Drug Name
Cycle 1 
(Week 1)
Cycle 2 
(Week 7)
Cycle 3 
(Week 13)
Cycle 4 
(Week 19)
Cycle 5 
(Week 25) 
until EOT
(Every 6
weeks)
BMS-986213 
or nivolumab 
in combination 
with XELOX
BMS-986213
(relatlimab 120 
mg/nivolumab 360 mg), 
nivolumab 360 mg
Days 1 and 
22
Days 1 and 
22
Days 1 and 
22
Days 1 and 
22
Days 1 and 
22
Oxaliplatin 130 mg/m2
Days 1 and 
22
Days 1 and 
22
Days 1 and 
22
Days 1 and 
22
Days 1 and 
22
Capecitabine 
1000 mg/m2 twice daily 
(ie, 1000 mg/m2 in the 
morning and 1000 
mg/m2 in the evening)
Days 1 to 
14
and
Days 22 to 
35
Days 1 to 
14
and
Days 22 to 
35
Days 1 to 
14
and
Days 22 to 
35
Days 1 to 
14
and
Days 22 to 
35
Days 1 to 
14
and
Days 22 to 
35
7.1.3
Dose Schedule for BMS-986213 or Nivolumab Plus FOLFOX
•
Participants assigned to FOLFOX will receive BMS-986213 (relatlimab 160 mg/nivolumab
480 mg) or nivolumab 480 mg, administered IV over 60 minutes or 30 minutes, respectively, 
on Days 1 and 29 of every odd-numbered 6-week treatment cycle (Cycle 1, 3, 5, etc) and Day 
15 of every even numbered 6-week treatment cycle (Cycle 2, 4, 6, etc). Oxaliplatin 85 mg/m2, 
leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 will be administered IV on Days 1, 15, and 
29 of each 6-week treatment cycle, and fluorouracil 1200 mg/m2 IV continuous infusion over 
24 hours daily (or per local standard) on Days 1 and 2, 15 and 16, and 29 and 30 of each 6-
week treatment cycle (see Table 7.1.3-1). As a consequence of this dosing regimen, FOLFOX 
will be administered alone, without immunotherapy, on Day 15 of each odd numbered 6-week 
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relatlimab-nivolumab FDC
treatment cycle and Days 1 and 29 of each even numbered 6-week treatment cycle.
Immunotherapy treatment should be administered first, prior to chemotherapy treatment. 
Dosing windows for subsequent FOLFOX doses should adhere to recommendations in the 
prescribing information or local standards, where indicated.
Premedication for potential infusion reaction is not recommended for the first dose of either 
treatment. Premedication maybe administered for nausea and vomiting prophylaxis, after the 
completion of the immunotherapy treatment or, in the absence of preceding immunotherapy, 
before chemotherapy administration, as clinical presentation warrants and per local standard.
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BMS-986213
relatlimab-nivolumab FDC
Table 7.1.3-1:
Dose Schedule for BMS-986213 or Nivolumab Plus FOLFOX
Treatment 
Group
Drug Name
Cycle 1 
(Week 1)
Cycle 2
(Week 7)
Cycle 3
(Week `13)
Cycle 4
(Week 19)
Odd Cycles
Starting at 
Cycle 5 (Week 
25) until EOT
Even Cycles
Starting at 
Cycle 6 
(Week 31) 
until EOT
BMS-986213 or 
nivolumab in 
combination 
with FOLFOX
BMS-986213
(relatlimab 160
mg/nivolumab
480 mg), or 
nivolumab 480 mg, 
Days 1 and 29
Day 15
Days 1 and 29
Day 15
Days 1 and 29
Day 15
Oxaliplatin 
85 mg/m2
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15,
29
Leucovorin
400 mg/m2
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 
29
Fluorouracil 
400 mg/m2
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 29
Days 1, 15, 
29
Fluorouracil 
1200 mg/m2
Days 1 & 2, 15 
& 16, 29 & 30
Days 1 & 2, 15 & 
16, 29 & 30
Days 1 & 2, 15 
& 16, 29 & 30
Days 1 & 2, 15 
& 16, 29 & 30
Days 1 & 2, 15 
& 16, 29 & 30
Days 1 & 2, 
15 & 16, 29 
& 30
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BMS-986213
relatlimab-nivolumab FDC
7.1.4
Dose Schedule for BMS-986213 or Nivolumab Plus SOX
Participants assigned to SOX will receive BMS-986213 (relatlimab 120 mg/nivolumab 360 mg)
or nivolumab 360 mg, administered IV over 60 or 30 minutes, respectively, and oxaliplatin 
130 mg/m2 administered IV on Days 1 and 22 of each 6-week treatment cycle, and oral S-1 twice 
daily (ie, 1 dose in the morning and 1 dose in the evening) on Days 1 to 14 and Days 22 to 35 of 
each 6-week treatment cycle. S-1 (tegafur/gimeracil/oteracil) dose should be administered as 
calculated according to body surface area (BSA, mg/m2/dose): BSA < 1.25 m2, 40 mg/dose; ≥1.25 
and < 1.5 m2, 50 mg/dose; ≥1.5 m2, 60 mg/dose (see Table 7.1.4-1). Immunotherapy treatment 
should be administered first, prior to chemotherapy treatment. Dosing windows for subsequent 
SOX doses should adhere to recommendations in the prescribing information or local standards, 
where indicated.
Premedication for potential infusion reaction is not recommended for the first dose of either 
treatment.  Premedication maybe administered for nausea and vomiting prophylaxis, after the 
completion of the immunotherapy treatment or, in the absence of preceding immunotherapy, 
before chemotherapy administration, as clinical presentation warrants and per local standard.
Participants should be provided with drug diaries at each visit and instructed to record intake of S-
1 in the diary after each twice daily administration.
Table 7.1.4-1
Dose Schedule for BMS-986213 or Nivolumab Plus SOX
Treatment 
Group
Drug Name
Cycle 1 
(Week 1)
Cycle 2 
(Week 7)
Cycle 3 
(Week 13)
Cycle 4 
(Week 19)
Cycle 5 
(Week 25) 
until EOT
(Every 6
weeks)
BMS-
986213 or 
nivolumab 
in 
combination 
with SOX
BMS-986213 
(relatlimab 120 
mg/nivolumab
360 mg) or
nivolumab 
360 mg
Day 1 and 
22
Day 1 and 
22
Day 1 and 
22
Day 1 and 
22
Day 1 and 
22
Oxaliplatin 
130 mg/m2
Days 1 and 
22
Days 1 and 
22
Days 1 and 
22
Days 1 and 
22
Days 1 and 
22
S-1
(tegafur/gimeracil
/oteracil)
(ie, 1 dose in the 
morning and 
1 dose in the 
evening)
Days 1 to 14 
and 
Days 22 to 
35
Days 1 to 14
and 
Days 22 to 
35
Days 1 to 14 
and 
Days 22 to 
35
Days 1 to 14
and 
Days 22 to 
35
Days 1 to 14 
and 
Days 22 to 
35
7.1.5
Crossover for Investigator’s Choice Chemotherapy
No crossover will be allowed among the XELOX, FOLFOX and SOX regimens in this study.
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BMS-986213
relatlimab-nivolumab FDC
7.2
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log in information and directions on how to 
access the IRT. After the participant’s initial eligibility is established and informed consent has 
been obtained, the participant must be enrolled into the study by using IRT to obtain the subject 
number. Every participant who signs the informed consent form must be assigned a subject number
in IRT. The investigator or designee will register the participant for enrollment by following the 
enrollment procedures established by BMS. The following information is required for enrollment:
•
Date that informed consent was obtained
•
Year of birth
•
Gender at birth
After enrollment in the IRT, participants who have met all eligibility criteria will be randomized 
through the IRT. The following information is required for participant randomization:
•
Subject number
•
Year of birth 
•
LAG-3 status (≥1% or < 1%; no indeterminate allowed) provided by the central lab directly 
to the IRT system
•
PD-L1 status (CPS < 1 or indeterminate, CPS ≥1 to < 5, CPS ≥5) provided by the central lab 
directly to the IRT system
•
Anatomical location (gastric vs GEJ)
•
Region (Japan/Taiwan vs ROW)
•
The choice of chemotherapy regimen - XELOX, SOX, or FOLFOX
The randomization procedures will be stratified by the following factors: LAG-3 expression (≥1% 
or < 1%; no indeterminate allowed), Region (Japan/Taiwan vs ROW), and PD-L1 expression status
(CPS < 1 and indeterminate, CPS ≥1 to < 5, or CPS ≥5). The exact procedures for using the IRT 
will be detailed in the IRT manual.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
All participants will be enrolled using the IRT and will be designated a subject number after 
signing the Pre-Screen informed consent form (ICF). Per the ICF, information that identifies the 
participant, such as name, will be replaced with a unique code. The Sponsor refers to this coded 
information as Study Data. Personal information is coded to protect the participants’ privacy. The 
participant’s name and identifying information will remain with the study site and will remain 
confidential at all times.
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7.3
Dosage Modification
7.3.1
Dose Modification Criteria for BMS-986213 or Nivolumab Plus
Chemotherapy
If AEs are considered to be related to study treatment (BMS-986213 or nivolumab OR 
chemotherapy), every attempt must be made to attribute the individual study treatment to the AE, 
if possible, or to the combination regimen.
•
For AEs that are deemed to be related to BMS-986213 or nivolumab ONLY by the treating 
physician, dose delays are permitted (see Section 7.3.5). Dose reductions are not permitted (see 
Section 7.3.2). The chemotherapy should continue as scheduled.
•
For AEs that are deemed to be related to the chemotherapy ONLY by the treating physician, 
dose modifications are permitted according to local standard or local package insert (see 
Sections 7.3.3.2 for XELOX, 7.3.3.3 for FOLFOX, and 7.3.3.4 for SOX). BMS-986213 or 
nivolumab administration should continue as scheduled.
•
For AEs that are possibly related to the combination regimen (BMS-986213 or nivolumab 
PLUS chemotherapy), the most conservative toxicity management guidelines must be 
followed.
•
If there is a delay in administration of study drug(s) due to toxicity, treatment with the other 
study agent(s) should continue as scheduled. Resumption of treatment should be at the next 
scheduled time point if criteria to resume treatment are met.
7.3.2
Dose Modification Criteria for BMS-986213 or Nivolumab
No dose reduction for BMS-986213 or nivolumab is permitted.
7.3.3
Dose Modification Criteria for Oxaliplatin-Plus-Fluoropyrimidine 
Treatment
Dose modifications of oxaliplatin, capecitabine, leucovorin, fluorouracil, and tegafur-gimeracil-
oteracil are permitted according to local standards or local package inserts.
7.3.3.1
General Guidance for Dose Modification of Chemotherapy 
•
Treatment for the first cycle should only commence if all the inclusion criteria are met and the 
participant has been randomized. For subsequent cycles, dose delay/modification is permitted 
per local standard or as described in Sections 7.3.3.2, 7.3.3.3, and 7.3.3.4. 
•
Doses of any study drug omitted for toxicity are not replaced or restored. Instead, the patient 
should resume the planned treatment cycles. Supportive care (for example, colony-stimulating 
factors [CSFs], blood and blood products, etc) can be administered in accordance with the latest 
American Society of Clinical Oncology or other equivalent guidelines. 
•
Dose modification, for nonserious and nonlife-threatening toxicities like alopecia, altered taste,
or nail changes, may not be required and the final decision is left to the discretion of the treating 
investigator. 
•
In situations where concomitant toxicities of varying severity exist, dose modification will be 
tailored for the toxicity with highest CTCAE v5 grading. 
•
If there is a delay or modification in administration of one of the drugs in the chemotherapy 
regimen due to toxicity, treatment with the other drug(s) in the regimen should continue as 
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scheduled. If clinically appropriate, the investigator can delay all treatment components up to a 
maximum of 7 days to allow synchronized administration of all agents. 
If toxicity related to any component of chemotherapy does not resolve in the same treatment cycle, 
the administration of that component can be delayed up to 6 weeks. If the toxicity does not resolve 
within 6 weeks, that component will be discontinued, unless it is determined by the treating 
investigator that the patient might benefit from continuation of the component.
7.3.3.2
Dose Modification Criteria for XELOX
Capecitabine
Toxicity due to capecitabine administration may be managed by symptomatic treatment and/or 
treatment interruption or dose reduction. Dose modifications of capecitabine are presented in Table 
7.3.3.2-1. Once the dose has been reduced, it should not be increased at a later time. For those 
toxicities considered by the treating physician to be unlikely to become serious or life threatening
(eg, alopecia, altered taste, or nail changes), treatment can be continued at the same dose without 
reduction or interruption. Participants taking capecitabine should be informed of the need to 
interrupt treatment immediately if moderate or severe toxicity occurs. Doses of capecitabine 
omitted for toxicity are not replaced.
Table 7.3.3.2-1:
Recommended Dose Modifications of Capecitabine
Toxicitya
During a Course of Therapy
Dose Adjustment for Next Treatments 
(% of starting dose)
Grade 1
Maintain dose level
Maintain dose level
Grade 2
1st appearance
Interrupt until resolved to Grade 0 to 1
100% (1000 mg/m2)
2nd appearance
75% (750 mg/m2)
3rd appearance
50% (500 mg/m2)
4th appearance
Discontinue treatment permanently
-
Grade 3
1st appearance
Interrupt until resolved to Grade 0 to 1
75% (750 mg/m2)
2nd appearance
50% (500 mg/m2)
3rd appearance
Discontinue treatment permanently
-
Grade 4
1st appearance
Discontinue treatment permanently or, if 
physician deems it to be in the participant’s 
best interest to continue, interrupt until 
resolved to Grade 0 to 1
50% (500 mg/m2)
a According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria 
(version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation 
Program, US National Cancer Institute, version 4.0.
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Oxaliplatin
Dose Modifications for Neurotoxicity
•
For Grade 2 peripheral sensory neuropathy (moderate paresthesia or dysesthesia), or limiting 
instrumental activities of daily living, skip oxaliplatin. When toxicity resolves to ≤Grade 1, 
resume oxaliplatin at 75% of initial dose. If oxaliplatin is skipped for 4 weeks (2 consecutive 
doses) for neurologic toxicity, discontinue oxaliplatin.
•
For Grade 3 or greater peripheral sensory neuropathy (severe paresthesia or dysesthesia), or 
limiting self-care activities of daily living, discontinue oxaliplatin.
Dose Modifications for Participants with Renal Impairment
•
For normal renal function or mild to moderate renal impairment (CrCl > 50 mL/min), the full 
dose of oxaliplatin can be administered.
•
For severe renal impairment, the oxaliplatin dose should be reduced to 75% of the initial dose.
Dose Modifications for Participants with Hematological Toxicity
•
For Grade 2 or Grade 3 thrombocytopenia, oxaliplatin should be reduced to 75% of the initial 
dose. For Grade 4 thrombocytopenia, the dose should be reduced to 50% of the initial dose.
•
For Grade 3 or Grade 4 neutropenia or febrile neutropenia, the oxaliplatin dose should be 
reduced to 75% of the initial dose.
7.3.3.3
Dose Modification Criteria for FOLFOX
Recommended dose modifications of FOLFOX are provided in Table 7.3.3.3-1 and criteria for 
dose modification of FOLFOX are provided in Table 7.3.3.3-2.
Table 7.3.3.3-1:
Recommended Dose Modifications of FOLFOX
Drug
Starting Dose
Dose Modification
Dose Level - 1
Dose Level - 2
Oxaliplatin
85 mg/m2
70 mg/m2
50 mg/m2
5-FU
Bolus 5-FU: 400 mg/m2
Leucovorin: 400 mg/m2 
Infusion 5-FU: 
2400 mg/m2/48 hours
Bolus 5-FU: 300 mg/m2
Leucovorin: 300 mg/m2 
Infusion 5-FU:
2000 mg/m2/48 hours
Bolus 5-FU: 200 mg/m2
Leucovorin: 200 mg/m2
Infusion 5-FU:
1600 mg/m2/48 hours
Abbreviation: 5-FU: 5-fluorouracil.
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Table 7.3.3.3-2:
Criteria for Dose Modifications of FOLFOX
Toxicity
Definition
During a course of 
therapy
Dose adjustments for next 
treatments
Neutropenia
Grade 3 or greater
Interrupt until resolved to 
Grade 2
Dose level -1
*If treatment delayed for 4 
consecutive weeks, discontinue all 
treatment
Thrombocytopenia
Grade 2
Interrupt until resolved to
Grade 1
Dose level -1
*If Grade 2 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Grade 3
Interrupt until resolved to
Grade 1
Dose level -1
*If Grade 3 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Grade 4
Interrupt until resolved to
Grade 1
Dose level -1
*If Grade 4 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Neurologic toxicity
Grade 2 peripheral 
sensory neuropathy
Interrupt until resolved to
Grade 1
Oxaliplatin dose -1
Continue 5-FU and leucovorin 
*If oxaliplatin delayed for 
neurologic toxicity for 4 
consecutive weeks, discontinue 
oxaliplatin, continue 5-FU and 
leucovorin
Grade 3 or greater 
peripheral sensory 
neuropathy
Discontinue oxaliplatin
Continue 5-FU and leucovorin
Gastrointestinal 
toxicities
Grade 2 or greater 
diarrhea
Interrupt until resolved to 
Grade 1
Dose level -1
If dose delayed for diarrhea for 4 
consecutive weeks, discontinue all 
treatment
For toxicities not listed above, dose modifications are permitted per local standards. Participants 
may also discontinue oxaliplatin following multiple cycles if, in the investigator’s judgment, 
cumulative toxicity is likely to increase over time and become problematic.
7.3.3.4
Dose Modification Criteria for SOX Including Initiation and Continuation
The dosage and the necessity of treatment interruption should be checked for each participant
before the start of each administration in accordance with the following criteria for starting 
treatment. Decisions on dose interruption and dose reduction should be made on the basis of the 
latest data available at the time.
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Criteria for Starting SOX Therapy
Prior to starting SOX therapy, it must be confirmed whether the participant fulfills the criteria in 
Table 7.3.3.4-1. If the participant does not meet all of the criteria, the study treatment could be 
postponed until all of the criteria are met. Note that, even if a participant does not meet 1 or more 
of the following criteria, SOX therapy may be administered if treatment is expected to lead to 
clinical benefit, SOX therapy is not contraindicated and can be safely administered to the 
participant. If any of the criteria for starting SOX therapy are not met at subsequent doses, the dose 
should be reduced by 1 level, and the acceptability of the administration and the need for 
postponement will be determined according to the criteria for starting treatment at postreduction 
doses.
Table 7.3.3.4-1:
Criteria for Starting SOX Therapy
Parameter
Criteria
White blood cells
≥3000/mm3 (only for dose of 130 mg/m2 oxaliplatin)
Neutrophils
≥1500/mm3
Platelets
≥100000/mm3 (only for dose of 130 mg/m2 oxaliplatin)
≥75000/mm3
AST/ALT
≤ULN × 2.5 (or ≤ULN × 5.0 in the presence of liver metastasis)
Serum creatinine
≤ULN × 1.2
Infection
No fever ≥38°C suggesting infection
Diarrhea, stomatitis, 
Hand-Foot syndrome
Grade ≤1
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.
Criteria for Interruption of SOX Therapy
If any of the criteria in Table 7.3.3.4-2 are met after starting tegafur-gimeracil-oteracil, tegafur-
gimeracil-oteracil potassium should be interrupted then resumed after the criteria are met. Doses 
of tegafur-gimeracil-oteracil potassium omitted for toxicity are not replaced. 
Table 7.3.3.4-2:
Criteria of Interruption of Tegafur-Gimeracil-Oteracil Potassium
Parameter
Criteria of Interruption of Tegafur-Gimeracil-Oteracil Potassium (Within the 
Same Treatment Period)
Neutrophils
< 1000/mm3 (Grade ≥3)
Platelets
< 50000/mm3 (Grade ≥3)
AST/ALT
> ULN × 2.5 (or > ULN × 5.0 in the presence of liver metastasis)
Serum creatinine
> ULN × 1.2
Infection
Fever ≥38°C suggesting infection
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Table 7.3.3.4-2:
Criteria of Interruption of Tegafur-Gimeracil-Oteracil Potassium
Parameter
Criteria of Interruption of Tegafur-Gimeracil-Oteracil Potassium (Within the 
Same Treatment Period)
Diarrhea, stomatitis, 
Hand-Foot syndrome
Grade ≥2
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.
Criteria for Dose Reduction of SOX Therapy
On the planned day of administering SOX therapy, it must be confirmed whether the participant
fulfills the criteria in Table 7.3.3.4-3. If the participant meets any of the criteria at any time during 
the last dose and start of subsequent dose, 1 or both agents must be reduced according to Table 
7.3.3.4-4 and be continued. Once the dose has been reduced, it should not be increased at a later 
time.
Table 7.3.3.4-3:
Criteria for Dose Reduction of SOX Therapy
Adverse Events
Next Doses
Parameter
Criteria
Oxaliplatin
Tegafur-Gimeracil-
Oteracil Potassium
Decreased platelet count
(only for dose of 130 mg/m2 
oxaliplatin)
Not met ≥ 100000/mm3 within
7 days of planned date of
dosing
1-level reduction
-
Not met ≥75000/mm3 (Grade 
≤1) within 7 days of planned 
date of dosing
(only for dose of 50 mg/m2
oxaliplatin)
Not met ≥ 75000/mm3
(Grade ≤ 1) within 7 days of
planned date of dosing
-
1-level reduction
< 25000/mm3 (Grade 4)
1-level reduction
1-level reduction
Decreased neutrophil 
count
< 500/mm3 (Grade 4)
1-level reduction
1-level reduction
Febrile neutropenia
Neutrophil count < 1000/mm3
with fever ≥38°C (axillary 
temperature)
1-level reduction
1-level reduction
Diarrhea, stomatitis,
Hand-Foot syndrome
Grade ≥  3
1-level reduction
1-level reduction
Allergic
reaction/hypersensitivity
suspected to be due to
Grade ≥  3
Discontinued
-
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Table 7.3.3.4-3:
Criteria for Dose Reduction of SOX Therapy
Adverse Events
Next Doses
Parameter
Criteria
Oxaliplatin
Tegafur-Gimeracil-
Oteracil Potassium
administration of
oxaliplatin
Peripheral neuropathy
Grade 2
1-level reduction
-
Grade 3
Skip dosinga
-
Grade 4
Discontinued
-
a Resume dosing from 1-level reduction after recovering Grade 2 or less.
Table 7.3.3.4-4:
Doses of SOX Therapy for Dose Reduction
Dose Reduction
Level
Oxaliplatin
(mg/m2)
Tegafur-Gimeracil-Oteracil Potassium (mg/dose)
< 1.25 m2
≥1.25 m2
to < 1.5 m2
≥1.5 m2
Initial dose
130
40
50
60
1-level reduction
100
25
40
50
2-level reduction
75
20
25
40
3-level reduction
50
Discontinueda
4-level reduction
Discontinued
-
a If tegafur-gimeracil-oteracil potassium combination drug is discontinued, oxaliplatin should also be discontinued.
7.3.4
Criteria for Oxaliplatin-Plus-Fluoropyrimidine Discontinuation
Except where specified below, both medications in the oxaliplatin-plus-fluropyrimidine 
chemotherapy regimen should be discontinued for any of the following reasons:
•
Any Grade ≥  4 peripheral neuropathy requires discontinuation of oxaliplatin.
•
In case of persistent Grade 3 paraesthesia, oxaliplatin should be discontinued.
•
Any Grade ≥  3 mucocutaneous reaction possibly attributable to capecitabine, leucovorin, or 
tegafur-gimeracil-oteracil requires permanent discontinuation.
•
Grade ≥  3 drug-related thrombocytopenia associated with clinically significant bleeding.
•
Any drug-related liver function test abnormality that meets the following criteria requires 
discontinuation:
−
AST or ALT > 5 to 10 × ULN for > 2 weeks
−
AST or ALT > 10 × ULN
−
Total bilirubin > 5 × ULN
−
Concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 ×
ULN and total bilirubin > 2 × ULN
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•
Any oxaliplatin-related decrease in creatinine clearance to < 30 mL/min (using the Cockcroft
Gault formula) requires discontinuation of oxaliplatin.
•
Any drug-related AE that recurs after 2 prior dose reductions for the same drug-related AE 
requires discontinuation of the drug(s) that was/were previously dose reduced.
•
Any Grade ≥3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) felt to be causing the reaction. The drug not felt to be related to 
the hypersensitivity reaction or infusion reaction may be continued.
•
Any Grade 4 drug-related AE that the investigator deems is inappropriate to be managed by 
dose reduction(s) requires discontinuation of the drug(s) felt to be causing the event. The drug 
not felt to be related to the event may be continued.
•
If any toxicity does not resolve within 42 days, that component will be discontinued unless it 
is determined by the treating investigator that the participant might benefit from continuation 
of the component.
For toxicities that are not listed above, the treating investigators can decide to discontinue any 
individual chemotherapy agent, or all chemotherapy agents, if it is not the best interest in the 
participant per the local standards. If the fluoropyrimidine has to be discontinued completely, the 
benefit of continuing oxaliplatin should be carefully weighed against toxicity by the treating 
investigator per local standards. 
Post-treatment study follow-up is critically important and is essential to preserving participant
safety and the integrity of the study. Participants who discontinue study treatment will continue to 
be followed for collection of tumor surveillance assessments, safety
 as per protocol. 
7.3.5
Dose Delay Criteria for BMS-986213 or Nivolumab
BMS-986213 or nivolumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or total bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, total bilirubin will require dose discontinuation (see Section 7.3.7)
•
All troponin elevations require a dose delay to allow for prompt cardiac evaluation
•
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, warrants delaying the dose of study medication
Participants who require delay of BMS-986213 or nivolumab should be re-evaluated weekly or 
more frequently if clinically indicated and resume BMS-986213 or nivolumab dosing when the
re-treatment criteria are met (see Section 7.3.6). If there is a delay in administration of study 
drug(s) due to toxicity, treatment with the other study agent(s) should continue as scheduled.
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7.3.6
Criteria to Resume BMS-986213 or Nivolumab Treatment
Participants may resume study treatments when the drug-related AE(s) resolve to Grade ≤1 or 
baseline value, with the following exceptions: 
•
Participants may resume treatment in the presence of Grade 2 fatigue 
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity 
•
For participants with Grade 2 AST, ALT, and/or total bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete. 
Note: Participants with combined Grade 2 AST and/or ALT AND total bilirubin values 
meeting discontinuation parameters (Section 7.3.7) should have treatment permanently 
discontinued. 
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor/designee. 
•
Participants with drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement, may resume treatment after consultation with the BMS Medical 
Monitor/designee. Adrenal insufficiency requires discontinuation regardless of control with 
hormone replacement. 
•
Troponin elevations will require the participant to undergo a cardiac evaluation. Following this 
evaluation, determination of further treatment will be based on the discussion with the BMS 
Medical Monitor/designee. 
If the criteria to resume treatment are met, the participant should restart treatment at the next 
scheduled time point per protocol. 
7.3.7
Criteria for BMS-986213 or Nivolumab Discontinuation
BMS-986213 or nivolumab should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment.
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation.
−
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation, regardless of control with hormone replacement.
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−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
o
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation
o
Grade ≥3 drug-related AST, ALT, or total bilirubin requires discontinuation*
o
Concurrent AST or ALT > 3 × ULN AND total bilirubin > 2 × ULN requires 
discontinuation
*In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit-risk ratio that 
warrants continuation of study drug(s), a discussion between the investigator and the
BMS Medical Monitor/designee must occur.
•
Grade 3 or higher myocarditis
•
Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or total bilirubin), except for the following events that do not require 
discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy AEs, such as, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor
•
Any event that leads to delay in dosing lasting > 8 weeks in the BMS-986213 or nivolumab 
PLUS FOLFOX treatment (or > 6 weeks in the BMS-986213 or nivolumab PLUS either 
XELOX or SOX treatment) from the previous dose requires discontinuation, with the 
following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are
allowed.
−
Dosing delays lasting > 8 weeks in the BMS-986213 or nivolumab PLUS FOLFOX 
treatment (or > 6 weeks in the BMS-986213 or nivolumab PLUS either XELOX or SOX 
treatment) from the previous dose that occur for nondrug-related reasons may be allowed 
if approved by the BMS medical monitor.
•
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the
Investigator, presents a substantial clinical risk to the participant with continued BMS-986213 
or nivolumab dosing.
Prior to reinitiating treatment in a participant with a dosing delay lasting > 8 weeks in the BMS-
986213 or nivolumab PLUS FOLFOX treatment (or > 6 weeks in the BMS-986213 or nivolumab 
PLUS either XELOX or SOX treatment) from the previous dose, the BMS Medical Monitor must 
be consulted. Tumor assessments should continue as per protocol even if dosing is delayed.
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Periodic study visits to assess safety and laboratory studies should also continue every 6 weeks or 
more frequently if clinically indicated during such dosing delays.
7.3.8
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.46 Participants treated with BMS-986213 or 
nivolumab in combination with chemotherapy will be permitted to continue their treatment beyond 
initial RECIST 1.1-defined PD, assessed by the investigator, as long as they meet the following 
criteria:
•
Investigator-assessed clinical benefit
•
Tolerance of study drug
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of PD (eg, CNS metastases)
•
Participant provides written informed consent prior to receiving additional BMS-986213 or 
nivolumab treatment (alone or in combination with chemotherapy). All other elements of the 
main consent including description of reasonably foreseeable risks or discomforts or other 
alternative treatment options will still apply.
A radiographic assessment/scan should be performed within 6 weeks of initial investigator-
assessed progression to determine whether there has been a decrease in the tumor size or continued 
PD. The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
participant is clinically deteriorating and unlikely to receive any benefit from continued treatment 
with BMS-986213 or nivolumab.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive study evaluations 
according to Table 2-2 and Table 2-3. For the participants who continue treatment beyond 
progression, further progression is defined as an additional 10% increase in tumor burden with a 
minimum 5 mm absolute increase from time of initial PD. This includes an increase in the sum of 
diameters of all target lesions and/or the diameters of new measurable lesions compared to the 
time of initial PD. Investigational treatment should be discontinued permanently upon 
documentation of further progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm). Any new lesion considered nonmeasurable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions that become measurable, these new lesions must demonstrate an absolute increase of 
at least 5 mm.
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7.3.9
Management Algorithms for Immuno-Oncology Agents
IO agents are associated with AEs that can differ in severity and duration than AEs caused by other 
therapeutic classes. Relatlimab and nivolumab are considered IO- agents in this protocol. Early 
recognition and management of AEs associated with IO agents may mitigate severe toxicity. 
Management algorithms have been developed to assist investigators in assessing and managing 
the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary (note for participants with dyspnea, CBC should be measured)
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
•
Myocarditis
The above algorithms are found in Appendix 8 of this protocol.
7.3.10
Treatment of BMS-986213 and Nivolumab Infusion-related Reactions
Because both BMS-986213 (FDC relatlimab/nivolumab) and nivolumab contain only human Ig 
protein sequences, they are unlikely to be immunogenic and induce infusion or hypersensitivity 
reactions. However, if such a reaction were to occur, it might manifest with fever, chills, rigors, 
headache, rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-
like reactions. All Grade 3 or 4 infusion reactions should be reported within 24 hours to the study 
Medical Monitor/designee and reported as an SAE if it meets the criteria. Infusion reactions should 
be graded according to NCI CTCAE (Version 5) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional BMS-986213 or nivolumab administrations
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, nonsteroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for ≤24 
hours):
•
Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the 
participant 
with 
diphenhydramine 
50 mg
IV 
(or 
equivalent) 
and/or 
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acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor participant 
closely. If symptoms recur, then no further study treatment will be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg
should be administered at least 30 minutes before infusion. If necessary, corticosteroids (up to 
25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]; Grade 4: life-threatening; pressor or ventilatory support indicated):
•
Immediately discontinue infusion of study treatment. Begin an IV infusion of normal saline 
and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg
IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Study treatment will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.4
Preparation/Handling/Storage/Accountability of IP
For nivolumab, refer to the current version of the IB and/or Pharmacy Manual for complete 
storage, handling, dispensing, and infusion information.
Similarly, for BMS-986213, refer to the current version of the IB and/or Pharmacy Manual for 
complete storage, handling, and dispensing information.
The IPs should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IPs are only dispensed to study participants. The IPs must be 
dispensed only from official study sites by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatments are stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatments arise, do not dispense the 
study treatment and contact BMS immediately.
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Study treatment not supplied by BMS will be stored in accordance with the package insert.
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration, and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
Further guidance and information for final disposition of unused study treatments are provided in 
Appendix 2.
7.4.1
Retained Samples for Bioavailability/Bioequivalence
Not applicable.
7.5
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability, as well as by 
recording capecitabine or S-1 administration in the participant drug diary (as applicable) , medical 
records, and electronic case report forms (eCRF). Participants should bring all drug (capecitabine 
or S-1) containers to each study visit for drug reconciliation. The drug diary should be submitted 
and reviewed at each clinic visit at the end of each cycle, as applicable. Drug accountability should 
be reviewed by the site study staff at each visit to confirm treatment compliance.
7.6
Concomitant Therapy
Concomitant medications are recorded at baseline and throughout the treatment phase of the study 
in the appropriate section of the eCRF. All medications (prescriptions or over-the-counter 
medications) continued at the start of the study or started during the study and different from the 
study treatment must be documented in the concomitant therapy section of the eCRF.
7.6.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.6.3)
•
Any concurrent antineoplastic therapy (ie, chemotherapy [except those allowed per protocol], 
hormonal therapy, immunotherapy, extensive, nonpalliative radiation therapy, or standard or 
investigational agents for treatment of GC/GEJ cancer)
•
Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.
•
Refer to the local institutional guidelines and/or the XELOX, SOX, and FOLFOX package 
inserts for possible prohibited and/or restricted treatments. 
•
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose.
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7.6.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
Participants who need anticoagulation treatment due to concomitant cardiovascular disease should 
be monitored closely; a maintenance of international normalized ratio (INR) > 2 is recommended.
Participants who are administered concomitantly fluoropyrimidine and oral coumadin-derivative 
anticoagulant therapy, such as warfarin, should have their anticoagulant response (INR or 
prothrombin time) monitored frequently in order to adjust the anticoagulant dose. Participants who 
are administered capecitabine and other sensitive cytochrome p-450 (CYP) 2C9 substrate, or a 
CYP2C9 substrate with narrow therapeutic index, should be closely monitored for toxicity.
7.6.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of nonautoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted.
7.6.4
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each participant. Imaging contraindications and contrast risks should be considered in 
this assessment. Participants with renal insufficiency should be assessed as to whether or not they 
should receive contrast and, if so, what type and dose of contrast is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie, estimated glomerular filtration rate [eGFR]
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this participant population. In addition, participants may be excluded from MRI if 
they have tattoos, metallic implants, pacemakers, etc. Gentle hydration before and after IV contrast 
should follow local standard of care. The ultimate decision to perform MRI in an individual 
participant in this study rests with the site radiologist, the investigator, and the standard set by the 
local Ethics Committee.
7.7
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment. Study treatment will be provided via an 
extension of the study, a rollover study requiring approval by responsible health authority and 
ethics committee or through another mechanism at the discretion of BMS.
BMS reserves the right to terminate access to BMS-supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of BMS-986213 is 
terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
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study objectives; c) the participant can obtain medication from a government sponsored or private 
health program. In all cases, BMS will follow local regulations
7.8
Blinding
This is a randomized, open-label study. Access to treatment codes will be restricted from all 
participants, and site and BMS personnel prior to primary database lock, with exceptions as 
specified below.
Treatment information is recorded on the CRF page and thus is accessible to all BMS personnel 
with access to the clinical database, as well as site staff and participants. This access will be used 
by Sponsor personnel such as GPVE, the MST, and the Medical Monitor to monitor safety of this 
novel combination in an unblinded manner as the study is ongoing, but not to perform unplanned 
efficacy analyses. Sponsor personnel may additionally receive access to randomization codes as 
assigned by IRT for purposes of interim analyses prescribed in the SAP or DMC charter. The 
unblinded access will not impact the integrity of the study as no early efficacy decisions will be 
made.
 
 
 A bioanalytical scientist in the Bioanalytical Sciences department of Bristol-
Myers Squibb Research & Development (or a designee in the external central bioanalytical 
laboratory) may obtain the randomized treatment assignments in order to minimize unnecessary 
bioanalytical analysis of samples.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue IP (and non-IP at the discretion of the investigator) for any of the 
following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
Any clinical AE, laboratory abnormality, or intercurrent illness that, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
•
Documented radiographic PD per RECIST criteria, unless the participant meets criteria for 
treatment beyond progression
•
Criteria listed in Sections 7.3.3.2, 7.3.3.3, 7.3.3.4, 7.3.4, and 7.3.7
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Discontinuation of the study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets 1 of the conditions outlined in Section 9.2.7 or if the 
investigator believes that it is in the best interest of the participant.
Refer to the Schedule of Activities (Section 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Refer to Section 9.2.5, Pregnancy.
All participants who discontinue study treatment should comply with protocol-specified follow-
up procedures as outlined in Section 2. The only exception to this requirement is when a participant
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.1.1
Poststudy Treatment Study Follow-up
In this study, ORR is the primary endpoint of the study. Poststudy follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study drug must continue to be followed for collection of outcome 
and/or survival follow-up data as required and in line with Section 5 until death or the conclusion 
of the study.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol-defined window (see Section 5). At the time of this request, each participant will be 
contacted to determine their survival status unless the participant has withdrawn consent for all 
contacts or is lost to follow-up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
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•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of 3
documented phone calls, faxes, or emails as well as lack of response by participant to 1 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining the participant’s
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. 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 informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
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Additional measures, including nonstudy required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study treatment-related toxicities resolve, return to baseline, or are deemed 
irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, cough, 
and fever) consistent with possible pulmonary adverse events, the participant should be 
immediately evaluated to rule out pulmonary toxicity, according to the suspected pulmonary 
toxicity management algorithm in Appendix 8.
For those participants receiving on-going treatment with BMS-986213 or nivolumab, troponin 
elevations will require the participant to undergo a cardiac evaluation. Following this evaluation, 
determination of further treatment will be based on the discussion with the BMS Medical Monitor 
or designee.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
9.1.1
Imaging Assessment for the Study
Images will be submitted to an imaging core lab for BICR. Sites should be qualified prior to 
scanning the first participant and understand the image acquisition guidelines and submission 
process as outlined in the CA224060 Imaging Manual to be provided by the imaging core lab. 
Screening images should be acquired as outlined in Table 2-1. On study images should be acquired 
as outlined in Table 2-2, Table 2-3, and Table 2-4 from the date of randomization until participant 
has confirmed progression by BICR, subsequent therapy is started, withdraw of consent, or 
participant is lost to follow up.
Every attempt should be made to image each participant using an identical acquisition protocol on 
the same scanner for all imaging time points.
Tumor assessments at other time points may be performed if clinically indicated and should be 
submitted to the central imaging vendor. 
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled time points and/or at an outside institution) should be collected for 
RECIST 1.1 tumor assessment and submitted to the BICR.
9.1.2
Methods of Measurement
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known/suspected sites of 
disease should be performed for tumor assessments. Images should be acquired with slice 
thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should be made to 
image each participant using an identical acquisition protocol on the same scanner for all imaging 
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time points. Tumor measurements should be made by the same investigator or radiologist for each 
assessment whenever possible. Change in tumor measurements and tumor response to guide 
ongoing study treatment decisions will be assessed by the Investigator using the RECIST 1.1 
criteria.
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained. 
Should a participant have contraindication for both MRI and CT intravenous contrasts, a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable.
Use of CT component of a positron emission tomography (PET)-CT scanner: Combined modality 
scanning such as with PET-CT is increasingly used in clinical care, and is a modality/technology 
that is in rapid evolution; therefore, the recommendations outlined here may change rather quickly 
with time. At present, low dose or attenuation correction CT portions of a combined PET-CT are 
of limited use in anatomically-based efficacy assessments. It is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for anatomically-
based RECIST 1.1 measurements. However, if a site can document that the CT performed as part 
of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST 1.1 measurements. Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed
Bone scan or PET scan is not adequate for assessment of RECIST 1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain non-
target organs, those non-target organs may be evaluated less frequently. For example, bone scans 
may need to be repeated only when CR is identified in target disease or when progression in bone 
is suspected.
MRI of brain without and with contrast should be acquired as outlined in Table 2-1, Table 2-2, 
Table 2-3, and Table 2-4. CT of the brain (without and with contrast) can be performed if MRI is 
contraindicated.
Bone scans may be collected per local standards, as clinically indicated. 
9.1.3
Imaging and Clinical Assessment
Assessments of PR and CR must be confirmed at least 4 weeks (28 days) after initial response.
Changes in tumor measurements and tumor responses will be assessed by the investigator per study 
design using RECIST 1.1 criteria. Investigators will also report the number and size of new lesions 
that appear while on study. The time point of tumor assessments will be reported on the eCRF 
based on the investigator’s assessment using RECIST 1.1 criteria. (See Appendix 5 for specifics 
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of RECIST 1.1 criteria to be utilized in this study.) A Best Overall Response of SD requires a 
minimum of 35 days on study from randomization to the date of the first imaging assessment.
Tumor assessments for all participants should continue as per protocol even if dosing is delayed 
or discontinued. Tumor measurements should be made by the same investigator or radiologist for 
each assessment whenever possible. Change in tumor measurements and tumor response to guide 
ongoing study treatment decisions will be assessed by the Investigator using the RECIST 1.1 
criteria.
9.1.4
BICR Confirmation of Progression
Sites should submit all scans to the imaging core lab on a rolling basis, preferably within 7 days 
of scan acquisition, throughout the duration of the study. BICR of scans will occur on a rolling 
basis, blinded to treatment arm, clinical data, and investigator assessment of submitted scans. 
When progression per RECIST 1.1 criteria is assessed by the investigator, the site will inform the 
imaging core lab, so that the BICR assessment of progression can be performed. The BICR review 
will be completed and the results provided to the site within 5 days of receipt of the scans, provided 
there are no pending imaging queries to the site. 
Participants whose progression is not confirmed by the BICR will be required to continue tumor 
assessments (if clinically feasible) according to the protocol-specified schedule, or sooner if 
clinically indicated. Also, if participants discontinue treatment without radiographic progression, 
tumor assessments will continue according to the protocol specified schedule, as noted in 
Section 2, until progression has been confirmed by BICR.
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment. The BICR assessment of progression is only relevant for determining 
when tumor assessments for a given participant are no longer required to be submitted to the 
imaging vendor.
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9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
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IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component 
for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. 
IMAEs can include events with an alternate etiology which were exacerbated by the induction of 
autoimmunity. Information supporting the assessment will be collected on the participant’s case 
report form.
Contacts for SAE reporting are specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until the 
time points specified in the Schedule of Activities (Section 2). Nonserious AE information should 
also be collected from the start of a placebo lead-in period or other observational period intended 
to establish a baseline status for the participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochures (IBs) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 100 days of discontinuation of dosing.
For participants randomized/assigned to treatment and never treated with study drug, SAEs should 
be collected for 30 days from the date of randomization.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure, (e.g. a follow-up skin biopsy).
All nonserious AEs must be collected at the start of study treatment until the time points specified 
in the Schedule of Activities (Section 2).
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF module.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor or designee within 24 hours 
of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs 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 reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
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collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known adverse events, when appropriate for the program or protocol.
All nonserious AEs (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment. 
Every AE must be assessed by the investigator with regard to whether it is considered immune-
mediated. For events which are potentially immune-mediated, additional information will be 
collected on the participant’s case report form.
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2) will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A suspected, unexpected serious adverse 
reaction is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
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5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
Per Section 8.1, in most cases, the study treatment will be permanently discontinued in an
appropriate manner (eg, dose tapering if necessary for participant safety). If the investigator 
determines a possible favorable benefit-risk ratio that warrants continuation of study treatment, or 
reinitiation of study treatment, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur. If, for whatever reason, pregnancy has ended, confirmed by negative 
serum pregnancy test, treatment may be resumed (at least 3 weeks and not greater than 6 weeks 
after the pregnancy has ended), following approvals of participant/sponsor/ IRB/EC, as applicable.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information, must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and if any sexual activity (e.g. vaginal, anal, oral) has occurred between a male 
participant and a pregnant WOCBP partner(s), the information should be reported to the Sponsor 
or designee, even if the male participant has undergone a successful vasectomy. In order for 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the female partner(s) must sign an informed consent form for disclosure of this information. 
Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
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9.2.7
Potential Drug-induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences 
of potential DILIs, meeting the defined criteria, must be reported as SAEs (see Section 9.2 and 
Appendix 3 for reporting details).
Potential DILI is defined as: 
1) ALT or AST elevation > 3 × upper limit of normal (ULN)
AND 
2) Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, preexisting chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, or any other potential safety assessment required or not required by protocol, should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. 
For this study, any dose of BMS-986213 or nivolumab greater than 160 mg/480 mg or 480 mg
Q4W, or any dose of BMS-986213 or nivolumab greater than 120 mg/360 mg or 360 mg Q3W, 
respectively, within a 24 hour time period will be considered an overdose.
In the event of an overdose the investigator should:
1) Contact the Medical Monitor immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities 
3) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities. Safety 
assessments include AEs, physical examinations, vital signs, performance status, assessment of 
signs and symptoms, laboratory tests, and pregnancy tests as outlined in the Schedule of Activities.
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9.4.1
Physical Examinations
Refer to Schedule of Activities (see Section 2).
9.4.2
Vital Signs
Refer to Schedule of Activities (see Section 2).
9.4.3
Electrocardiograms
Refer to Schedule of Activities (see Section 2).
9.4.4
Clinical Safety Laboratory Assessments
Laboratory assessments are listed in Table 9.4.4-1.
•
Investigators must document their review of each laboratory safety report
•
All clinical safety laboratory assessments will be performed locally per the Schedule of 
Activities (Section 2)
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Table 9.4.4-1:
Laboratory Assessment Panels
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase
Alanine aminotransferase
Total bilirubin
Alkaline phosphatase
Gamma-glutamyl transferase only when alkaline 
phosphatase is ≥Grade 2
Creatinine
Blood urea nitrogen or serum urea level
Glucose 
Direct bilirubin
Lactate dehydrogenase 
Uric acid
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
TSH, free T3 and free T4 - screening only
TSH, with reflexive free T3 and free T4 if TSH is 
abnormal - on treatment
Creatinine clearance - screening only
FSH (if needed to document postmenopausal status as 
defined in Appendix 4) - screening only
Troponin (local standard to be used/allowed)
Urinalysis 
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
Ph
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive on the dipstick
Serology (at screening)
hepatitis C antibody (if Hepatitis C antibody is positive reflex to hepatitis C RNA) or hepatitis C RNA, hepatitis 
B surface antigen, , HIV antibodies. (Testing for HIV must be performed at sites where mandated by local 
requirements, see Appendix 7)
Other Analyses
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG).
Follicle stimulating hormone (FSH) screening only; required to confirm menopause in women < age 55)
Abbreviations: HIV = human immunodeficiency virus; RNA = ribonucleic acid; T3 = triiodothyronine; T4 = 
thyroxine; TSH = thyroid stimulating hormone; WOCBP = women of childbearing potential
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9.4.5
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
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10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The sample size of the study is based on the primary objective, ie, on the comparison of the ORR 
of participants who were randomized to receive BMS-986213 in combination with chemotherapy 
versus those randomized to receive nivolumab and chemotherapy and with LAG-3 positive 
expression. A total of approximately 250 participants are expected to be randomized in a 1:1 ratio 
to the relatlimab+nivolumab+chemotherapy, or nivolumab+chemotherapy arms.
 
 
In order to ensure 
sufficient follow-up to achieve objective response and to assess the durability of response, the last 
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patient last visit for the ORR analysis will occur after the last (response evaluable) patient 
randomized had the chance to proceed with the Week 24 tumor assessment.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined below:
Population
Description
Enrolled 
All participants who sign an informed consent form. This is the dataset for 
disposition (and select safety)
Randomized participants
All participants who are randomized to any treatment. This is the dataset for 
baseline demographics and select efficacy analyses.
LAG-3 positive participants
All randomized participants in the LAG-3 positive group. This is the dataset for 
baseline demographics and primary efficacy analyses.
Response evaluable participants
All randomized participants who had measurable lesions at baseline
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Population
Description
Treated participants
All randomized participants who take at least 1 dose of study treatment. This is 
the dataset for safety analyses.
10.3
Statistical Analyses
A description of the participant population will be included in the statistical output reported, 
including subgroup of age, gender, and race.
10.3.1
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment arm as randomized 
overall and by LAG-3 expression group using descriptive statistics.
10.3.2
Efficacy Analyses
Primary Endpoint
Statistical Analysis Methods
•
Objective response rate (ORR) as assessed by 
BICR in participants who are LAG-3 positive 
is defined as the number of participants with a 
best overall response (BOR) of CR or PR 
divided by the number of randomized 
participants who are LAG-3 positive in each 
arm. BOR is defined as the best response 
designation based on the BICR, recorded 
between the date of randomization and the 
date of objectively documented progression 
(per RECIST 1.1 as determined by the 
investigator)
or death,
or the date of 
subsequent anti-cancer therapy, whichever 
occurs first.
•
ORR as assessed by BICR in participants who are LAG-
3 positive will be compared between the BMS-986213 in 
combination with chemotherapy and nivolumab in 
combination with chemotherapy using a two-sided 
Cochran-Mantel-Haenszel test stratified by region (J/T or 
ROW) and PD-L1 status (CPS < 1 or indeterminate, CPS 
≥1 to <5, CPS ≥5) as recorded in the IRT. Associated 
70% CIs for ORR difference will be calculated. 
Additionally, ORR along with the exact 95% CI for each 
arm will be calculated using the Clopper-Pearson 
method.52
Secondary
•
Objective Response Rate (ORR) as assessed 
by investigator in participants who are LAG-
3 positive is defined as the number of 
participants with a best overall response 
(BOR) of CR or PR divided by the number of 
randomized participants who are LAG-3 
positive in each arm. BOR is defined as the 
best response designation based on the 
investigator, recorded between the date of 
randomization and the date of objectively 
documented progression (per RECIST 1.1) or 
the date of subsequent anti-cancer therapy, 
whichever occurs first.
•
ORR based on investigator in LAG-3 positive population
will be compared between the BMS-986213 in 
combination with chemotherapy vs Nivolumab in 
combination with chemotherapy using a two-sided 
Cochran-Mantel-Haenszel test stratified by region (J/T
ROW) and PD-L1 status as recorded in the IRT. 
Additionally, ORR along with the exact 95% CI for each 
arm will be calculated using the Clopper-Pearson 
method.52
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Primary Endpoint
Statistical Analysis Methods
•
Duration of Response (DOR) (as assessed by 
BICR and as assessed by investigator) in 
participants who are LAG-3 positive, is 
defined as the time between the date of first 
documented response (CR or PR) to the date 
of the first PD, per RECIST 1.1 or death due 
to any cause, whichever occurs first. 
Participants who die without a reported prior 
PD per BICR (and die without start of 
subsequent therapy) will be considered to 
have progressed on the date of death.
•
Summary of DOR with median (95% CI) and range 
(minimum, maximum) by K-M method. Participants who 
did not have documented PD per BICR or investigator 
per RECIST 1.1 criteria and who did not die, will be 
censored at the date of the last evaluable tumor 
assessment on or prior to initiation of subsequent anti-
cancer therapy. Participants who did not have any on-
study tumor assessments and did not die (or died after 
initiation of subsequent anti-cancer therapy) will be 
censored at the randomization date. Those who started 
any subsequent anti-cancer therapy without a prior 
reported PD per BICR or investigator will be censored at 
the last tumor assessment prior to or on the initiation of 
the subsequent anti-cancer therapy
•
ORR in participants who are LAG-3 negative
and in the population overall (as assessed by 
BICR and by investigator) is defined as the 
number of participants with a best overall 
response (BOR) of CR or PR divided by the 
number of randomized participants with 
LAG-3 negative cancers or participants in the 
overall population in each arm 
•
ORR in participants who are LAG-3 negative and in the 
population overall as assessed by BICR and investigator 
will be compared between the BMS-986213 in 
combination with chemotherapy and Nivolumab in 
combination with chemotherapy arms using a two-sided 
Cochran-Mantel-Haenszel test stratified by region (J/T or 
ROW) and PD-L1 status (CPS < 1 or indeterminate, CPS 
≥1 to <5, CPS ≥5) as recorded in the IRT. Additionally, 
ORR along with the exact 95% CI for each arm will be 
calculated using the Clopper-Pearson method.52
•
DOR in participants who are LAG-3 negative
and DOR in the overall population (as 
assessed by BICR and as assessed by 
investigator) is defined as the time between 
the date of first documented response (CR or 
PR) to the date of the first PD, per RECIST 
1.1 or death due to any cause, whichever 
occurs first. 
•
Summary of DOR in the LAG-3 negative and in the 
overall populations with median (95% CI) and range 
(minimum, maximum) by K-M method. Participants who 
die without a reported prior PD per BICR (and die 
without start of subsequent therapy) will be considered to 
have progressed on the date of death. In addition the 
censoring rules apply as in the LAG-3 positive group, 
described above.
•
Overall survival time (OS) in participants who 
are LAG-3 positive or
LAG-3 negative 
separately and overall, is defined as the time 
between the date of randomization and the 
date of death due to any cause. For those 
without documentation of death, OS will be 
censored on the last date the participant was 
known to be alive.
•
OS: The difference in the distribution of OS will be 
assessed between BMS-986213 in combination with 
chemotherapy vs nivolumab in combination with 
chemotherapy separately in participants who are LAG-3
positive and LAG-3 negative using a two-sided log rank 
test and a significance level of 15% one-sided (30% 2-
sided), stratified by region (Japan/Taiwan [J/T] or Rest of 
World [ROW]) and PD-L1 expression status as recorded 
in the IRT. For this comparison, the HR with its 
associated two-sided 70% confidence intervals (CI) will 
be estimated via a stratified Cox model with randomized 
treatment arm as the only covariate in the model. OS for 
each treatment arm will be estimated and plotted using 
the Kaplan-Meier (K-M) product-limit method. Median 
survival time along with 95% CI will be constructed 
based on a log-log transformed CI for the survival 
function. The analysis will be repeated to assess OS 
differences between the 2 arms across all participants, 
using the same methods as above with an additional 
stratification factor of LAG-3 expression
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Primary Endpoint
Statistical Analysis Methods
•
PFS in participants who are LAG-3-positive, 
LAG-3 negative, and overall, as assessed by a 
Blinded Independent Central Review (BICR), 
using RECIST 1.1. PFS is defined as the time 
between the date of randomization and the 
first date of documented progression, or death 
due to any cause, whichever occurs first. 
Participants who die without a reported prior 
PD per BICR (and die without start of 
subsequent therapy) will be considered to 
have progressed on the date of death. 
•
PFS: The difference in the distribution of PFS between 
BMS-986213 in combination with chemotherapy vs 
Nivolumab in combination with chemotherapy will be 
assessed separately in participants who are LAG-3
positive and LAG-3 negative via a two-sided, log-rank 
test and a significance level of 15% one-sided (30% 2-
sided), stratified by the same factors as above. The hazard 
ratio and the corresponding 70% CI will be estimated in 
a stratified Cox proportional hazards model using 
randomized arm as a single covariate. The PFS curves for 
each randomized arm will be estimated and plotted using 
the K-M product limit method. Median PFS along with 
95% CI will be constructed based on a log-log 
transformed CI for PFS. The above analysis will be 
repeated to assess PFS differences between the 2 arms 
across all participants, using the same methods as above 
with an additional stratification factor of LAG-3 
expression. The same censoring rules apply as for DOR.
Abbreviations: BICR = blinded independent central review; BOR = best overall response; CI = confidence interval; 
CR = complete response; DOR = duration of response; 
 GC = gastric cancer; GEJ = 
gastroesophageal junction; J = Japan; K = Korea; K-M = Kaplan-Meier; ORR = objective response rate; OS = overall 
survival; 
 PD = disease progression; PD-L1 = programmed death-ligand 1; PFS = 
progression-free survival; 
 PR = partial response; RECIST = Response 
Evaluation Criteria in Solid Tumors; ROW = rest of world; T = Taiwan.
10.3.3
Safety Analyses
All safety analyses will be performed on the Safety Sample.
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Endpoint
Statistical Analysis Methods
Secondary
•
The Safety and tolerability objective will be 
measured by the incidence of adverse events
(AEs), serious adverse events (SAEs), adverse 
events leading to discontinuation, deaths, and 
laboratory abnormalities in each arm by LAG-
3 group and overall
•
Safety analyses will be performed in all treated 
participants. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 by treatment group. All on-study 
AEs, treatment-related AEs, SAEs, and treatment-
related SAEs will be tabulated using worst grade per 
NCI CTCAE v 5.0 criteria by system organ class and 
preferred term. On-study lab parameters including 
hematology, chemistry, liver function, and renal 
function will be summarized using worst grade NCI 
CTCAE v 5.0 criteria.
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10.3.9
Interim Analyses 
There are no official planned interim analyses. Approximately after at least 24 weeks since the last 
participants has been randomized, or after all randomized participants had an opportunity to 
complete at least 24-week scans, the ORR analysis will be performed. Additional analyses that 
allow for longer follow-up to estimate the DOR and other time to event endpoints will also be 
performed, after at least 9 months since the last participant has been randomized. In addition 
planned analyses will be produced for DMC evaluation of risk/benefit, as per the DMC charter.
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REFERENCES
1
Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nat Immunol 2007;8(3):239-45.
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46 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20.
52 Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26:404-13.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
1L
first-line
5-FU
5-fluorouracil
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BICR
blinded independent central review
BMI
body mass index
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BSA
body surface area
C
Celsius or Cycle
CFR
Code of Federal Regulations 
CI
confidence interval
cm
centimeter
CNS
central nervous system
CPS
combined positive score
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CT
computed tomography
CTLA 4
cytotoxic t-lymphocyte-associated antigen 4
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Term
Definition
CYP
cytochrome p-450
D
day
DCR
disease Control Rate
DILI
drug induced liver injury
DLT
dose limiting toxicity
DMC
Data Monitoring Committee
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eg
exempli gratia (for example)
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FDA
Food and Drug Administration
FDC
fixed dose combination
FFPE
formalin-fixed, paraffin-embedded 
FOLFOX
oxaliplatin, leucovorin, and fluorouracil
FSH
follicle stimulating hormone
FU
follow-up
GEJ
gastroesophageal junction
GC
gastric cancer
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Term
Definition
HCG
human chorionic gonadotrophin
HCV
hepatitis C virus
HCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
hazard ratio
IA
interim analysis
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
Ig
immunoglobulin
IMAE
immune-mediated adverse events 
INR
international normalized ratio
IO
immuno-oncology
IP
investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
J
Japan
K
Korea
kg
kilogram
K-M
Kaplan-Meier
L
liter
LAG-3
lymphocyte activation gene 3
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Cli nical Pr ot oc ol
C A 2 2 4 0 6 0
B M S- 9 8 6 2 1 3 
relatli ma b- ni v ol u ma b F D C
Ter m
Defi niti o n
m g
milli gra m
M H C
maj or hist oc o m pati bilit y c o m ple x
mi n
mi n ute
m L
milliliter
m A bs
m o n ocl o nal a nti b o dies
MI
m y ocar dial i nfarcti o n 
M RI
ma g netic res o na nce i ma gi n g
g
micr o gra m
N/ A
n ot a p plica ble
N CI C T C A E
Nati o nal Ca ncer I nstit ut e C o m m o n Ter mi n ol o g y  Crit eria f or 
A d verse E ve nts
O R R
o bjecti ve res p o nse rate
O S
o verall s ur vi val
P D
pr o gressi ve disease
P D- 1
pr o gra m me d deat h- 1
P D- L 1 
pr o gra m me d deat h-li ga n d 1
P D- L 2
pr o gra m me d deat h-li ga n d 2
P E T
p ositr o n e missi o n t o m o gra p h y
P F S
pr o gressi o n-free s ur vi val
Re vise d Pr ot oc ol N o.: 0 3
Date: 2 4-J u n- 2 0 1 9
1 2 3
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Term
Definition
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
ROW
rest of world
SAE
serious adverse event
SD
stable disease
SI
International System of Units
SOX
S1 and oxaliplatin
T
Taiwan
T3
triiodothyronine
T4
thyroxine
TnI
troponin I 
TnT
troponin T
ULN
upper limit of normal
US
United States
VAS
visual analogue scale
WOCBP
women of childbearing potential
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Term
Definition
XELOX
capecitabine and oxaliplatin
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the CRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following:  (1) the physical, safety or mental 
integrity of 1 or more participants; (2) the scientific value of the trial (eg, reliability and robustness 
of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or Trial 
protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to participants and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
participants currently enrolled in the study if they are affected by the amendment; and (3) the new 
form must be used to obtain consent from new participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
In situations where consent cannot be given to participants, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the participants, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participants’ signed 
ICF and, in the US, the participants’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study participants are the most important considerations 
and should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
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When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (e.g., lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, 
if applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form.
Sourced by site, and not supplied by 
BMS or its vendors (examples include IP 
sourced 
from 
the 
sites 
stock or 
commercial supply, or a specialty 
pharmacy)
The investigator or designee accepts responsibility 
for documenting traceability and study treatment
integrity in accordance with requirements applicable 
under law and the SOPs/standards of the sourcing 
pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does
not have an established system that meets these requirements.
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CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
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RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS or its vendors) such as full or partially 
used study treatment containers, vials, syringes cannot be destroyed on-site.
It is however, the investigator’s or designee’s responsibility to arrange for disposal of all empty 
study treatment containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local, and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. The return of full or partially used study 
treatments supplied by BMS or its vendors will be arranged by the responsible Study Monitor.
CLINICAL STUDY REPORT 
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
Study Steering Committee chair or their designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Other criteria (as determined by the study team)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
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principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work.
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
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).
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.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as 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)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see Section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
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 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 Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
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 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 24 weeks after the end of study 
treatment.*
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
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Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb
•
Intrauterine device (IUD)c
•
Intrauterine hormone-releasing system (IUS)c
•
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 drug. 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.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
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Unacceptable Methods of Contraception*
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 33 weeks after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 33 weeks after the end of 
treatment in the male participant.
•
Male participants 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 
during the treatment and until 33 weeks after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 33 weeks after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 5
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) 
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline 
.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ≥2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
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default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
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unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
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date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
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Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study). If the subject is not on-study for 
at least this amount of time, any tumor assessment indicating stable disease before this time period 
will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a 
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCE
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
Revised Protocol No.: 03
Date: 24-Jun-2019
147
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v
Approved
1.0
v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
APPENDIX 6
ECOG STATUS SCALE
PERFORMANCE STATUS CRITERIA: ECOG Score 
ECOG (Zubrod) 
Score 
Description
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 alight or 
sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self care but unable to carry out any work activities; up and about more 
than 50% of waking hours.
3
Capable of only limited self care; confined to bed or chair more than 50% of waking hours.
4
Completely disabled; cannot carry on any self care; totally confined to bed or chair.
Revised Protocol No.: 03
Date: 24-Jun-2019
148
Approved
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Approved
1.0
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
APPENDIX 7
COUNTRY SPECIFIC REQUIREMENTS
Argentina, Czech Republic, France, Germany, Italy, Spain, Peru and Any Other Countries 
Where Exclusion of HIV Positive Participants Is Locally Mandated
Country-specific language
Section 2 Flow Chart/Time and Events
Schedule, Table 2-1: Screening
Assessments- LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion Criteria,
Exclusion criterion 3j
“Known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiency syndrome (AIDS)”to be 
replaced with “Positive test for HIV”.
Revised Protocol No.: 03
Date: 24-Jun-2019
149
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
APPENDIX 8
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
Revised Protocol No.: 03
Date: 24-Jun-2019
150
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CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
151
Approved
4.0
v
Approved
1.0
v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
152
Approved
4.0
v
Approved
1.0
v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
153
Approved
4.0
v
Approved
1.0
v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
154
Approved
4.0
v
Approved
1.0
v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
155
Approved
4.0
v
Approved
1.0
v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
156
Approved
4.0
v
Approved
1.0
v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
157
Approved
4.0
v
Approved
1.0
v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Revised Protocol No.: 03
Date: 24-Jun-2019
158
Approved
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v
Approved
1.0
v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
APPENDIX 9
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 02, 16-Nov-2018
To 
 include updates to reflect current data 
and protocol standards, and make administrative corrections. 
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Added text reflecting addition of 
Data Monitoring Committee.
BMS development decision
Table 2-1 Screening 
Assessments - All 
Participants (CA224060)
Added language providing for the 
optional collection of tumor tissue 
older than 3 month
Revision to Translational 
Medicine scope of 
investigation
3.3 Benefit/Risk 
Assessment
Revised text and added text 
reflecting addition of updated 
safety data and Data Monitoring 
Committee.
Reflects updated data
5.1.1 Screening Phase
Removed language requiring an 
associated pathology report to 
accompany FFPE tissue block or 
unstained tumor tissue section for 
biomarker evaluation prior to 
randomization; pathology report is 
optional.
Added language providing for the
optional collection of tumor tissue 
older than 3 months
Administrative correction
Revision to Translational 
Medicine scope of 
investigation
5.1.5 Data Monitoring 
Committee
Added section defining use of 
Data Monitoring Committee.
BMS development decision
6.1 Inclusion Criteria
Removed language requiring an 
associated pathology report to 
accompany FFPE tissue block or 
Administrative correction
Revised Protocol No.: 03
Date: 24-Jun-2019
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CA224060
BMS-986213
relatlimab-nivolumab FDC
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
unstained tumor tissue section for 
biomarker evaluation prior to 
randomization; pathology report is 
optional.
6.2 Exclusion Criteria
Revised language excluding 
participants who received 
live/attenuated vaccines within 30 
days of first treatment
Removed exclusion of 
recombinant human erythropoietin 
within 3 weeks of first study drug 
administration
Reflects new required 
content
Administrative correction
7.2 Method of Treatment 
Assignment
Added text regarding treatment 
access rules
Procedural clarification
7.3.9 Management 
Algorithms for Immuno-
Oncology Agents
Added “Myocarditis” to list of 
available algorithms for guidance 
on management and treatment of 
myocarditis
To meet current standards
7.6.1 Prohibited and/or 
Restricted Treatments
Added prohibition of any 
live/attenuated vaccine during 
treatment up to 100 days post 
treatment
To meet current standards
9.2.1 Time Period and 
Frequency for Collecting 
AE and SAE Information
Removal of prescreening consent 
option
Administrative correction
Revised Protocol No.: 03
Date: 24-Jun-2019
160
Approved
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Approved
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Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
10.3.9 Interim Analyses
Revised text to incorporate 
analyses for DMC evaluation of 
risk/benefit
BMS development decision
Appendix 3
Updated definitions and
procedures for recording, 
evaluating, follow-up and 
reporting AEs and SAEs
To meet current standards
Appendix 8
Added “Myocarditis” to list of 
available algorithms for guidance 
on management and treatment of 
myocarditis
To meet current standards
All
Minor formatting and
typographical corrections
Minor, therefore have not 
been summarized
Overall Rationale for the Revised Protocol 01, 29-Jun-2018
The primary purpose for this revision was to update Appendix 4, WOCBP to current standards, 
and to modify the PD-L1 stratification levels.
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
All
Modified PD-L1 stratification 
levels for statistical analyses
Due to a change in 
methodology and evolving 
understanding of the relevant 
cutoffs for the gastric 
population
Revised Protocol No.: 03
Date: 24-Jun-2019
161
Approved
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v
Approved
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v


Clinical Protocol
CA224060
BMS-986213
relatlimab-nivolumab FDC
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Section 6.2 Exclusion 
Criteria
Additional exclusion criterion 
added
Section 8.1 
Discontinuation from 
Study Treatment
Modified text to include 
consideration by the investigator 
of abnormal liver tests for 
participant discontinuation, and 
revision of procedures to follow in 
case of pregnancy
To meet current standards
Section 9.2.1 Time 
Period and Frequency for 
Collecting AE and SAE 
Information
Modified text regarding collection 
of AE and SAE information
To meet current standards
Appendix 4
Updated appendix for WOCBP
To meet current standards
All
Updated CTCAE to version 5
To meet current standards
All
Minor formatting and 
typographical corrections
Minor, therefore have not 
been summarized
Revised Protocol No.: 03
Date: 24-Jun-2019
162
Approved
4.0
v
Approved
1.0
v

SAP_001.pdf: 
Official Title of Study: 
A Randomized, Open-label, Phase II Clinical Trial of Relatlimab (anti-LAG-3) and Nivolumab in 
Combination with Chemotherapy Versus Nivolumab in Combination with Chemotherapy as First- 
Line Treatment in Patients with Gastric or Gastroesophageal Junction Adenocarcinoma 
 
NCT Number: NCT03662659 
Document Date (Date in which document was last revised): Jul 27, 2020 


CSR STATISTICAL ANALYSIS PLAN
AN OPEN LABEL STUDY OF RELATLIMAB AND NIVOLUMAB WITH 
CHEMOTHERAPY VERSUS NIVOLUMAB WITH CHEMOTHERAPY IN PATIENTS
WITH GASTRIC OR GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA
Protocol CA224060
VERSION # 2.0
DATE: 27-JUL-2020
Approved
2.0
v
Approved
1.0
v


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4.1.1
Objective Response Rate.........................................................................................17
4.1.2
Duration of Response .............................................................................................17
4.1.3
Progression-Free Survival......................................................................................18
4.1.3.1
Primary Definition of Progression-Free Survival (Accounting for Subsequent 
Therapy).................................................................................................................18
4.1.3.2
Secondary Definition of Progression Free Survival (Irrespective of 
Subsequent Therapy) ..............................................................................................20
4.1.4
Overall Survival .....................................................................................................22
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7.1.1
Adverse Events, Serious Adverse Events, Multiple Events, Select Adverse 
Events, Other Events of Special Interest and Immune-Mediated Adverse 
Events.....................................................................................................................32
7.1.1.1
Select Adverse Events (EU/ROW Submissions) .......................................................33
7.1.1.2
Other Events of Special Interest..............................................................................33
7.1.1.3
Immune-Mediated Adverse Events (US Submission)................................................34
7.1.2
Laboratory Tests.....................................................................................................34
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7.3.1
Subject Disposition.................................................................................................35
7.3.2
Demographics and Other Baseline Disease Characteristics....................................36
7.3.3
Medical History......................................................................................................37
7.3.4
Prior Therapy Agents .............................................................................................37
7.3.5
Physical Examinations............................................................................................38
7.3.6
Baseline Physical Measurements ............................................................................38
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7.4.1
Administration of Study Therapy.............................................................................38
7.4.2
Modifications of Study Therapy ..............................................................................42
7.4.2.1
Dose Delays ...........................................................................................................42
7.4.2.2
Dose Interruptions..................................................................................................42
7.4.2.3
IV Rate Reductions .................................................................................................42
7.4.2.4
Dose Escalations ....................................................................................................43
7.4.2.5
Dose Reductions.....................................................................................................43
7.4.2.6
Dose Omissions ......................................................................................................43
7.4.3
Concomitant Medications.......................................................................................43
7.4.3.1
Immune Modulating Medication .............................................................................43
7.4.3.2
Subsequent Cancer Therapy ...................................................................................44
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7.5.1
Analysis of Objective Response Rate (ORR)............................................................45
7.5.3
Time to Response and Duration of Response...........................................................47
7.5.4
Analysis of Progression-Free-Survival....................................................................47
7.5.7
Analysis of Overall Survival....................................................................................50
7.5.8
Current Status of PFS and OS Follow-up................................................................51
7.5.9
Interim analysis of Overall Survival........................................................................52
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7.6.1
Deaths ....................................................................................................................52
7.6.2
Serious Adverse Events...........................................................................................52
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................52
7.6.4
Adverse Events Leading to Dose Modification........................................................53
7.6.5
Adverse Events .......................................................................................................53
7.6.6
Select Adverse Events (EU/ROW Submissions) .......................................................53
Approved
2.0
v
Approved
1.0
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Incidence of Select AE ............................................................................................53
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Time-to Onset of Select AE .....................................................................................54
7.6.6.3
Time-to Resolution of Select AE..............................................................................54
7.6.7
Immune-Mediated Adverse Events (US Submission)................................................55
7.6.8
Other Events of Special Interest..............................................................................55
7.6.9
Multiple Events.......................................................................................................55
7.6.10
Laboratory Parameters...........................................................................................56
7.6.10.1
Hematology ............................................................................................................56
7.6.10.2
Serum Chemistry ....................................................................................................56
7.6.10.3
Electrolytes.............................................................................................................56
7.6.10.4
Additional Analyses................................................................................................56
7.6.11
Vital Signs ..............................................................................................................57
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Approved
2.0
v
Approved
1.0
v


CSR Statistical Analysis Plan
CA224060
BMS-986213
relatlimab+nivolumab
6
1
BACKGROUND 
CA224060 is a Phase 2, randomized, open-label study of BMS-986213 (fixed-dose combination
[FDC] relatlimab/nivolumab at a 1:3 ratio) in combination with investigator̓s choice
chemotherapy, versus nivolumab in combination with investigator̓s choice chemotherapy, as 
first line (1L) treatment in subjects with unresectable, untreated, locally advanced or metastatic
gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. Relatlimab is a fully
human lymphocyte activation gene 3 (LAG-3) specific antibody that was isolated following
immunization of transgenic mice expressing human immunoglobulin (Ig) genes. Relatlimab binds
to LAG-3 with high affinity and inhibits binding of this receptor to cells bearing its ligand, major
histocompatibility complex (MHC) Class II, the peptide antigen presentation molecule recognized
by CD4+ T cells. Relatlimab binding inhibits the negative regulatory function of LAG-3 in vitro.
By blocking the normal downregulatory pathway, relatlimab enhances the anti-tumor immune
response and, thus, has the potential to inhibit the growth of multiple malignancies when
administered in combination with other therapeutic immuno-oncology (IO) monoclonal antibodies
(mAbs).
Research Hypothesis:  
In subjects with untreated, unresectable, locally advanced or metastatic gastric cancer (GC) or
gastroesophageal junction (GEJ) adenocarcinoma, the administration of relatlimab plus
nivolumab, in combination with chemotherapy, will improve ORR compared to nivolumab in
combination with chemotherapy in the LAG-3 positive population.
Approved
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Approved
1.0
v


CSR Statistical Analysis Plan
CA224060
BMS-986213
relatlimab+nivolumab
7
Schedule of Analyses:
ORR is the primary endpoint for this study.  The primary ORR analysis will be performed once all 
randomized subjects have had the potential for 6 months of follow-up. Additional analyses will be 
performed to evaluate the duration of response e.g. once everyone has 9 months of follow-up.
An independent Data Monitoring Committee (DMC) will monitor periodic interim safety and 
efficacy reports to allow for a risk/benefit assessment. An initial safety evaluation will be 
conducted (by the DMC) when the first 20 subjects randomized in the study have received at least 
one dose and have a minimum of 6 weeks follow-up.  
2
STUDY DESCRIPTION
2.1
Study Design
This is a Phase 2, randomized, open-label, two-arm study of BMS-986213 or nivolumab in 
combination with investigator’s choice chemotherapy as first-line treatment in subjects with 
unresectable, untreated, locally advanced or metastatic GC or GEJ adenocarcinoma. 
Approximately 250 subjects will be randomized in two treatment arms in this global clinical study. 
Nivolumab monotherapy will be administered IV as either 360 mg Q3W or 480 mg Q4W, 
depending on the assigned chemotherapy regimen. Relatlimab and nivolumab combination, as a 
fixed dose combination, will be administered as 120 mg relatlimab/360 mg nivolumab every 
3 weeks (Q3W) or 160 mg relatlimab/480 mg nivolumab every 4 weeks (Q4W), depending on the 
assigned chemotherapy regimen. 
Approved
2.0
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Approved
1.0
v


CSR Statistical Analysis Plan
CA224060
BMS-986213
relatlimab+nivolumab
8
Figure 2.1-1:
Study Design Schematic
Screening Phase
•
The Screening Phase begins by establishing the participant’s initial eligibility and signing of 
the informed consent form.
•
Subjects are enrolled using the Interactive Response Technology (IRT) system. 
•
A pre-treatment tumor sample is required to be submitted from all subjects. The participant’s 
tumor associated immune cells must have an evaluable LAG-3 status (≥1% or <1%; no 
indeterminate allowed) and must have an evaluable PD-L1 status ((CPS ≥5%, CPS ≥ 1 to <5,
or CPS < 1% (including indeterminate)). LAG-3 expression status and PD-L1 CPS must be 
determined by the central lab prior to completion of the remaining screening procedures. 
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, 
with an associated pathology report, must be submitted for biomarker evaluation prior to 
randomization
Treatment Phase
•
The Treatment Phase begins after contacting the IRT system for randomization. The choice of 
chemotherapy regimen (XELOX, SOX, or FOLFOX) must be decided before contacting the 
IRT system for randomization
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CSR Statistical Analysis Plan
CA224060
BMS-986213
relatlimab+nivolumab
9
•
Subjects will be randomized to either the BMS-986213 or nivolumab arm. Each arm will be 
given in combination with investigator’s choice chemotherapy (XELOX, FOLFOX, or SOX)
•
The treatment will be given until disease progression (PD), unacceptable toxicity, or 
participant withdrawal of consent, whichever comes first
•
Stratification factors for this study are: 
−
LAG-3 expression (≥1% or <1%; no indeterminate allowed)
−
PD-L1 CPS expression status (≥5%, ≥ 1 to <5, or < 1% (including indeterminate))
 
 
Note: region (Japan/Taiwan [J/T] vs Rest of world [ROW]) was originally a stratification factor 
for the study and is in the IRT system, but no one from Japan/Taiwan enrolled in the study.  
Therefore, although it is still in the system as a stratification factor for the study, it will not be 
analyzed nor used as such.
•
Administration of study treatment is to begin within 3 calendar days of randomization
•
Each cycle will be 6 weeks in duration
•
On the day of infusion, BMS-986213 or nivolumab is to be administered first, followed by 
chemotherapy. The administration procedures of chemotherapy will follow local standards. 
BMS-986213 or nivolumab and chemotherapy should be administered on the same day, with 
the exceptions identified in the protocol:
−
BMS-986213 or nivolumab is allowed to be administrated alone in cases where the 
chemotherapy has been delayed or discontinued due to toxicity
−
Chemotherapy alone is allowed to be administered in cases where BMS-986213 or 
nivolumab has been delayed or discontinued due to toxicity
−
Subjects assigned to FOLFOX will have only FOLFOX administered on Day 15 of the odd 
numbered cycles (i.e. Cycles 1, 3, 5, etc.) and Day 1 and 29 of the even numbered cycles 
(i.e. Cycles 2, 4, 6, etc.)
•
No cross-over is allowed between XELOX, SOX, and FOLFOX regimens.
•
The Treatment Phase ends when the participant is discontinued from study therapy (i.e., PD, 
unacceptable toxicity, or participant withdrawal of consent)
Approved
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CSR Statistical Analysis Plan
CA224060
BMS-986213
relatlimab+nivolumab
10
Follow-up Phase
•
The Follow-up Phase begins when the decision is made to discontinue a participant from study 
therapy
•
Follow-up Visit 1 will be performed 30 days from the last dose (±7 days) or coincide with the 
date of discontinuation (±7days) if date of discontinuation is greater than 42 days after last 
dose. Follow-up Visit 2 will be performed 100 days ±7 days) from last dose of study treatment. 
Participants must be followed for at least 100 days after last dose of study treatment. Both 
follow-up visits should be conducted in person.
•
Survival visits - The first survival follow-up visit will be performed 3 months (±14 days) after 
follow-up Visit 2. Subsequent survival follow-up visits will occur every 3 months (±14 days) 
thereafter. Survival follow-up visits may be conducted in clinic or by phone.
Any additional follow-up data collected up to 135 days since last dosing (in select sites) will be 
presented in listings.
2.2
Treatment Assignment
After the participant’s initial eligibility is established and informed consent has been obtained, the 
participant must be enrolled into the study by using IRT to obtain the subject number. Every 
participant who signs the informed consent form must be assigned a subject number in IRT. The 
investigator or designee will register the participant for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:
•
Date that informed consent was obtained
•
Year of birth
•
Gender at birth
After enrollment in the IRT, subjects who have met all eligibility criteria will be randomized 
through the IRT. The following information is required for participant randomization:
•
Subject number
•
Year of birth 
•
LAG-3 status (≥1% or < 1%; no indeterminate allowed) provided by the central lab directly 
to the IRT system
•
PD-L1 status ((CPS ≥5%, CPS ≥ 1 to <5, or CPS < 1% or including indeterminate) provided
by the central lab directly to the IRT system
•
Anatomical location (gastric vs GEJ)
•
The choice of chemotherapy regimen - XELOX, SOX, or FOLFOX
Approved
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v


CSR Statistical Analysis Plan
CA224060
BMS-986213
relatlimab+nivolumab
11
•
The randomization procedures will be stratified by the following factors: LAG-3 expression 
(≥1% or < 1%; no indeterminate allowed) and PD-L1
•
CPS expression status ((≥5%, ≥ 1 to <5, or < 1% (including indeterminate)). The exact 
procedures for using the IRT will be detailed in the IRT manual.
Note: region (Japan/Taiwan [J/T] vs rest of world [ROW]) was originally a stratification factor 
for the study, but no one from Japan/Taiwan enrolled in the study.  Therefore, although it is 
still in the system as a stratification factor for the study, it will not be analyzed nor used as 
such.
During the treatment phase, subjects will receive BMS-986213 or nivolumab in combination with 
investigator̓s choice of chemotherapy (XELOX, FOLFOX, or SOX):
•
Subjects assigned to XELOX will receive BMS-986213 (relatlimab 120 mg/nivolumab 360 
mg) or nivolumab 360 mg, administered intravenously (IV) over 60 minutes or 30 minutes,
respectively, and oxaliplatin 130 mg/m2 administered IV on Days 1 and 22 of each treatment
cycle every 6 weeks, and capecitabine 1000 mg/m2 administered orally twice daily (AM and
PM dosing) on Days 1 to 14 and Days 22 to 35 of each treatment cycle every 6 weeks.
•
Subjects assigned to FOLFOX will receive BMS-986213 (relatlimab 160 mg/nivolumab 480 
mg) or nivolumab 480 mg administered IV over 60 minutes or 30 minutes, respectively, on 
Days 1 and 29 of every odd numbered Cycle (Cycle 1, 3, 5, etc.) and Day 15 of every even
numbered Cycle (Cycle 2, 4, 6, etc.). Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and
fluorouracil 400 mg/m2 will be administered IV on Days 1, 15, and 29 of each treatment cycle
every 6 weeks, and fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily (or 
per local standard) on Days 1 & 2, 15 & 16, and 29 & 30 of each treatment cycle every 6 
weeks.
•
Subjects assigned to SOX will receive BMS-986213 (relatlimab 120 mg/nivolumab 360 mg), 
or nivolumab 360 mg, administered IV over 60 minutes or 30 minutes, respectively, and 
oxaliplatin 130 mg/m2 administered IV on Days 1 and 22 of each treatment cycle every 6 
weeks, and oral S-1 twice daily on Days 1 to 14 and Days 22 to 35 of each treatment cycle,
every 6 weeks. S-1 (tegafur/gimeracil/oteracil) dose as calculated according to body surface
area (BSA, mg/m2/dose): BSA <1.25 m2, 40 mg/dose; Ӌ1.25 and <1.5 m2, 50 mg/dose; Ӌ1.5
m2, 60 mg/dose.
2.3
Blinding and Unblinding
This is a randomized, open-label study.  Treatment information is recorded on the CRF page and 
thus is accessible to all BMS personnel with access to the clinical database, as well as site staff 
and subjects. This access will be used by Sponsor personnel such as GPVE, the MST, and the 
Medical Monitor to monitor safety of this novel combination in an unblinded manner as the 
study is ongoing, but not to perform unplanned efficacy analyses. Sponsor personnel may 
additionally receive access to randomization codes as assigned by IRT for purposes of interim 
Approved
2.0
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Approved
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v


CSR Statistical Analysis Plan
CA224060
BMS-986213
relatlimab+nivolumab
12
analyses prescribed in the SAP or DMC charter. The unblinded access will not impact the 
integrity of the study as no early efficacy decisions will be made.
 
 
 A bioanalytical scientist in the Bioanalytical 
Sciences department of Bristol-Myers Squibb Research & Development (or a designee in the 
external central bioanalytical laboratory) will be unblinded to (may obtain) the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples.
2.4
Protocol Amendments
Below are listed the global protocol amendments and their impact on the statistical analysis plan.
Table 2.4-1:
Changes to Protocol that Affect the Analyses
Document
Date of Issue
Summary of Change
Revised Protocol 03
24JUN2019
No changes with statistical implications.
Revised Protocol 02
16NOV2018
-Added a Data Monitoring Committee
-Added text regarding treatment access rules: although open label, 
no summary analyses will be performed by treatment arm unless a 
planned interim analysis.
Revised Protocol 01
29JUN2018
-Modified PD-L1 stratification levels to 3 categories:
(CPS ≥5%, CPS ≥ 1 to <5, or CPS < 1% (including indeterminate))
-Revised time period and frequency for collecting AE and SAE 
information extended to 135 days after last dose for all safety 
listings.
-Updated CTCAE to version 5
Original Protocol
02APR2018
-Not applicable
2.5
Blinded Independent Review Committee
A Blinded Independent Central Review (BICR) will be utilized in this study for determination of 
BICR-assessed endpoints. The BICR will review all available tumor assessment scans for all 
treated participants. All investigator determinations of disease progression will be reviewed by the 
BICR. Details of BICR responsibilities and procedures will be specified in the BICR charter.
2.6
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be utilized. A DMC will be established 
to provide oversight of safety and efficacy considerations. Additionally, the DMC will provide 
advice to the sponsor regarding actions the committee deems necessary for the continuing 
protection of subjects enrolled in the study. The DMC will be charged with assessing such actions 
in light of an acceptable benefit/risk profile for BMS-986213, or nivolumab, plus chemotherapy. 
Approved
2.0
v
Approved
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v


CSR Statistical Analysis Plan
CA224060
BMS-986213
relatlimab+nivolumab
13
The DMC will act in an advisory capacity to BMS and will monitor subject safety and evaluate 
the available efficacy data for the study. 
3
OBJECTIVES
Table 3-1:
Objectives and Endpoints
Objectives
Endpoints
Primary Objective:
To compare ORR of BMS-986213 in
combination with chemotherapy, with ORR of
nivolumab in combination with
chemotherapy, by BICR, in randomized
subjects with untreated, unresectable, and 
either locally advanced, or metastatic LAG-3
positive GC or GEJ adenocarcinoma.
ORR in subjects who are LAG-3 positive.
ORR is defined as the number of subjects with
a BOR of CR or PR divided by the number of
randomized subjects in each arm. BOR is
defined as the best response designation as
determined by the BICR, recorded between
the date of randomization and the date of
objectively documented progression (per
Response Evaluation Criteria in Solid
Tumors [RECIST 1.1]), death due to any
cause, or the date of subsequent anticancer
therapy, whichever occurs first.
Secondary Objectives:
To assess the overall safety and tolerability of
BMS-986213 in combination with
chemotherapy vs. nivolumab in combination
with chemotherapy in treated subjects with
advanced or metastatic GC or GEJ cancer.
The incidence of AEs, SAEs, AE leading to
discontinuation, deaths, and laboratory
abnormalities in each arm.
.
To compare ORR of BMS-986213 in
combination with chemotherapy, with ORR of
nivolumab in combination with
chemotherapy, as assessed by investigator, in
randomized subjects with untreated,
unresectable, and either locally advanced, or
metastatic LAG-3 positive GC or GEJ 
adenocarcinoma.
ORR is defined as above, as the number of
subjects with a BOR of CR or PR as assessed
by the investigator using RECIST 1.1,
divided by the number of randomized
subjects in each Treatment Arm.
To compare ORR by BICR and by
investigator of BMS-986213 in combination
with chemotherapy with ORR of nivolumab
in combination with chemotherapy in
randomized subjects with advanced or 
metastatic LAG-3 negative GC or GEJ
ORR in the LAG-3 negative group or
overall is defined as above, as the number of
subjects in each population with a BOR of CR
or PR divided by the number of randomized
Approved
2.0
v
Approved
1.0
v


CSR Statistical Analysis Plan
CA224060
BMS-986213
relatlimab+nivolumab
14
Table 3-1:
Objectives and Endpoints
Objectives
Endpoints
adenocarcinoma, and overall (across LAG-3
negative and positive groups).
subjects in each Treatment Arm, for that
population
To estimate duration of response (DOR)
of BMS-986213 in combination with
chemotherapy and DOR of nivolumab in
combination with chemotherapy in
randomized subjects with advanced or
metastatic LAG-3 positive GC or GEJ
adenocarcinoma, by BICR and by the
investigator.
DOR (based on BICR and investigator) is
defined as the time between the date of first
documented response (CR or PR) to the date
of the first PD, per RECIST 1.1, death due to
any cause, or the date of subsequent
anticancer therapy whichever occurs first.
To estimate DOR of BMS-986213 in
combination with chemotherapy and DOR
of nivolumab in combination with
chemotherapy in randomized subjects with
advanced or metastatic LAG-3 negative GC
or GEJ adenocarcinoma, and in the overall
population by BICR and by the investigator.
DOR in subjects with advanced or
metastatic LAG-3 negative GC or GEJ
adenocarcinoma and for subjects in the 
overall population (across the LAG-3
groups) is defined as above.
To assess the difference in the overall 
survival (OS) of BMS-986213 in
combination with chemotherapy and OS of
nivolumab in combination with
chemotherapy in randomized subjects with
untreated, unresectable, and either locally
advanced, or metastatic GC or GEJ
adenocarcinoma separately in the LAG-3
positive and LAG-3 negative groups and
overall.
OS is defined as the time between the date
of randomization and the date of death. For
those without documentation of death, OS
will be censored on the last date the 
participant was known to be alive.
To assess the difference in the PFS of BMS-
986213 in combination with chemotherapy 
and PFS of nivolumab in combination with
chemotherapy as assessed by BICR and
investigator in randomized subjects with
untreated, unresectable, and either locally
advanced or metastatic GC or GEJ
adenocarcinoma separately in the LAG-3
positive and LAG-3 negative groups and
overall.
PFS is defined as the time between the date
of randomization and the date of the first 
documented PD per BICR or investigator or
death due to any cause. Subjects who die 
without a reported prior PD per BICR or
investigator (and die without start of
subsequent therapy) will be considered to
have progressed on the date of death. Those 
who did not have documented PD per
RECIST1.1 criteria and who did not die, will
be censored at the date of the last evaluable
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Table 3-1:
Objectives and Endpoints
Objectives
Endpoints
tumor assessment on or prior to initiation of
subsequent anticancer therapy. Subjects who
did not have any on-study tumor assessments
and did not die (or died after initiation of
subsequent anticancer therapy) will be
censored at the randomization date. Those
who started any subsequent anticancer
therapy without a prior reported PD will be
censored at the last tumor assessment prior to
or on the initiation of the subsequent
anticancer therapy. Subjects receiving
treatment beyond progression must continue
tumor assessments until such treatment has
been discontinued.
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Table 3-1:
Objectives and Endpoints
Objectives
Endpoints
Abbreviations:
AE = adverse event; BICR = blinded independent central review; BOR =
best overall response; CR = complete response;
DOR = duration of response;
 
GC = gastric cancer; GEJ = gastroesophageal
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junction; LAG-3 = lymphocyte activation gene 3;
ORR = objective response rate; OS 
= overall survival;
PD = disease progression; PFS = progression-free survival;
PR = partial response;
RECIST = Response Evaluation 
Criteria in Solid Tumors; SAE = serious adverse event
.
4
ENDPOINTS
4.1
Efficacy Endpoints
Below are the detailed definitions of the efficacy endpoints.  
4.1.1
Objective Response Rate
Objective Response Rate (ORR) is defined as the number of randomized subjects who achieve a 
best response of confirmed complete response (CR) or confirmed partial response (PR) based on 
BICR assessments (using RECIST v1.1 criteria) divided by the number of all randomized subjects.  
If the objective is for a particular population (LAG3 positive, LAG3 negative), only that population
is selected. Best Overall Response (BOR) is defined as the best response, as determined by the 
BICR, recorded between the date of randomization and the date of objectively documented 
progression per RECIST v1.1 criteria or the date of subsequent therapy (including tumor-directed 
radiotherapy and tumor-directed surgery), whichever occurs first. For subjects without 
documented progression or subsequent therapy, all available response designations will contribute 
to the BOR determination. Confirmation of response is required at least 4 weeks after the initial 
response.  
When the objective is specific to the investigator assessment, the above definition is altered to 
exchange BICR for investigator assessment in the derivation of the endpoint.
Time to Response
Time to Response (TTR) is defined as the time from randomization to the date of the first 
confirmed documented response (CR or PR), as assessed by the BICR. TTR will be evaluated for 
responders (confirmed CR or PR) only.
When the objective is specific to the investigator assessment, the above definition is altered to 
exchange BICR for investigator assessment in the derivation of the endpoint.
4.1.2
Duration of Response
Duration of Response (DOR) is defined as the time between the date of first confirmed documented 
response (CR or PR) to the date of the first documented tumor progression as determined by the 
BICR (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. Subjects who 
start subsequent therapy without a prior reported progression will be censored at the last evaluable 
tumor assessments prior to initiation of the subsequent anticancer therapy. Subjects who die 
without a reported prior progression will be considered to have progressed on the date of their 
death. Subjects who neither progress nor die, DOR will be censored on the date of their last 
evaluable tumor assessment. DOR will be evaluated for responders (confirmed CR or PR) only.  
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When the objective is specific to the investigator assessment, the above definition is altered to 
exchange BICR for investigator assessment in the derivation of the endpoint.
4.1.3
Progression-Free Survival
Two definitions are used for analysis of Progression-Free Survival (PFS). The primary definition 
accounts for subsequent therapy by censoring at the last evaluable tumor assessment on or prior to 
the date of subsequent therapy. The secondary definition is irrespective of subsequent therapy and 
does not account for subsequent therapy. 
Clinical deterioration in the absence of unequivocal evidence of progression (per RECIST v1.1 
criteria) is not considered progression for purposes of determining PFS.
The first on-study tumor assessment is scheduled to be conducted at 12 weeks (± 1 week) following 
randomization. Subsequent tumor assessments are scheduled every 6 weeks (± 1 week) up to 
13 months, then every 12 weeks until disease progression.
When the objective is specific to the investigator assessment, the above definition is altered to 
exchange BICR for investigator assessment in the derivation of the endpoint.
4.1.3.1
Primary Definition of Progression-Free Survival (Accounting for 
Subsequent Therapy)
The primary definition of PFS (PFS truncated at subsequent therapy) is defined as the time between 
the date of randomization and the date of first documented tumor progression, based on BICR 
assessments (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. 
Subjects who die without a reported progression will be considered to have progressed on the date 
of their death. The following censoring rules will be applied for the primary definition of PFS:
•
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment.
•
Subjects who did not have any on study tumor assessments and did not die will be censored on 
their date of randomization.
•
Subjects who receive subsequent anti-cancer therapy prior to documented progression will be 
censored at the date of the last evaluable tumor assessment conducted on or prior to the date 
of initiation of the subsequent anti-cancer therapy.
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•
Subjects who did not have a documented progression and received subsequent anti-cancer 
therapy will be censored at the date of the last evaluable tumor assessment conducted on or 
prior to the initiation of the subsequent anti-cancer therapy.
Censoring rules for the primary definition of PFS (PFS truncated at subsequent therapy) are 
presented as follows and in Table 4.1.3.1-1.
Figure 4.1.3.1-1:
PFS Primary Definition
Table 4.1.3.1-1:
Censoring Scheme used in Primary Definition of PFS
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments*
Date of randomization 
Censored 
No on study tumor assessments and 
no death*
Date of randomization
Censored
Subsequent anti-cancer therapy 
started without death or progression 
per RECIST v1.1 reported prior or 
on the same day
Date of last evaluable tumor 
assessment prior to or on the date of 
initiation of the subsequent anti-
cancer therapy
Censored 
Documented progression per 
RECIST v1.1 and no new anti-
cancer started before
Date of the first documented 
progression per RECIST v1.1 
(excludes clinical progression)
Progressed 
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Table 4.1.3.1-1:
Censoring Scheme used in Primary Definition of PFS
Situation 
Date of Progression or Censoring 
Outcome 
No progression and no death, and 
no new anti-cancer therapy started
Date of last evaluable tumor 
assessment 
Censored 
Death without progression per 
RECIST v1.1 and no new anti-
cancer started before
Date of death 
Progressed
* Tumor assessments and death if any, occurring after start of subsequent anti-cancer therapy are not considered.
When the objective is specific to the investigator assessment, the above definition is altered to 
exchange BICR for investigator assessment in the derivation of the endpoint.
4.1.3.2
Secondary Definition of Progression Free Survival (Irrespective of 
Subsequent Therapy)
The secondary definition of PFS (ITT definition) is defined as the time between the date of 
randomization and the date of first documented tumor progression, based on BICR assessments 
(per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. 
Subjects who die without a reported progression will be considered to have progressed on the date 
of their death. The following censoring rules will be applied for the secondary definition of PFS:
•
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment.
•
Subjects who did not have any on study tumor assessments and did not die will be censored on 
their date of randomization.
Censoring rules for the secondary definition of PFS (ITT definition) are presented as follows and 
in Table 4.1.3.2-1.
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Figure 4.1.3.2-1:
PFS Secondary Definition
Table 4.1.3.2-1:
Censoring Scheme for Secondary definition of PFS
Situation
Date of Progression of Censoring
Outcome
No baseline tumor assessment
Date of randomization
Censored
No on-study tumor assessments and 
no death
Date of randomization
Censored
Documented progression per 
RECIST v1.1 
Date of first documented 
progression per RECIST v1.1 
criteria (excludes clinical 
progression)
Progressed
No progression and no death
Date of last evaluable tumor 
assessment
Censored
Death without progression per 
RECIST v1.1
Date of death
Progressed
When the objective is specific to the investigator assessment, the above definition is altered to 
exchange BICR for investigator assessment in the derivation of the endpoint.
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4.1.4
Overall Survival
Overall survival (OS) is defined as the time from randomization to the date of death from any 
cause. For subjects that are alive, their survival time will be censored at the date of last contact 
date (or “last known alive date”). Overall survival will be censored at the date of randomization 
for subjects who were randomized but had no follow-up.
Survival follow-up will be conducted every 3 months after subject’s off-treatment date.
4.2
Safety Endpoints
The assessment of safety will be based on the incidence of adverse events (AEs), serious adverse 
events (SAEs), adverse events leading to discontinuation, adverse events leading to dose 
modification, select adverse events (select AEs) for EU/ROW Submissions, immune-mediated 
AEs (IMAEs) for US Submission, other events of special interest (OEOSI), and deaths. The use 
of immune modulating concomitant medication will be also summarized. In addition clinical 
laboratory tests
will be analyzed.
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5
SAMPLE SIZE AND POWER
The sample size of the study is based on the primary objective, i.e., on the comparison of the ORR 
of subjects who were randomized to receive BMS-986213 in combination with chemotherapy 
versus those randomized to receive nivolumab and chemotherapy and with LAG-3 positive 
expression. 
A total of approximately 250 subjects are expected to be randomized in a 1:1 ratio to the BMS-
986213+chemotherapy or nivolumab+chemotherapy arms. 
In order to ensure sufficient follow-up to achieve 
objective response and to assess the durability of response, the last patient last visit for the ORR 
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analysis will occur after the last (response evaluable) patient randomized had the chance to proceed 
with the Week 24 tumor assessment.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
•
Baseline period:
−
Baseline evaluations or events will be defined as evaluations or events that occur before 
the date and time of the first dose of study treatment. Evaluations (laboratory tests and vital 
signs) on the same date and time of the first dose of study treatment will be considered as 
baseline evaluations. Events (AEs) on the same date and time of the first dose of study 
treatment will not be considered as pre-treatment events.
−
In cases where the time (onset time of event or evaluation time and dosing time) is missing 
or not collected, the following definitions will apply:
♦Pre-treatment AEs will be defined as AEs with an onset date prior to but not including 
the day of the first dose of study treatment;
♦Baseline evaluations (laboratory tests and vital signs) will be defined as evaluations 
with a date on or prior to the day of first dose of study treatment.
−
If there are multiple valid assessments on or prior to the first dose of study treatment:
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♦For laboratory tests, the latest non missing lab value on or before first dose date (and 
time if collected) will be used as the baseline in the analyses. For 'LIPASE' and 
'GLUCOSE', for treated subjects only, the last predose assessment with non-missing 
toxicity grade will be considered as baseline. If multiple assessments exist with the 
same collection date (and time if collected) and entry date and time, then the first 
observation is used as baseline.
♦For Eastern Cooperative Oncology Group (ECOG) performance status (PS), the latest 
ECOG PS value prior to or on the first dose date (and time if collected) will be used as 
the baseline in the analyses. If multiple records fall on the last date then the record with 
the highest value of ECOG PS will be considered as baseline.
♦For LAG-3, among the records prior to or on first dose date, the latest record will be 
used as the baseline in the analyses. If there is more than one record for the latest date, 
then choose the one with the greatest specimen ID.
♦For PD-L1, among the records prior to or on first dose date (and time if collected), 
identify first those with quantifiable test result. If there are no records with quantifiable 
test result, then select those with indeterminate result (“INDETERMINATE”). If there 
are no records with indeterminate test result, then select those with unavailable result 
(“NOT EVALUABLE). If there are no records with unavailable test result, then select 
those with not reported or not available result (all other records). The latest record will 
be used as the baseline in the analyses. If there is more than one record for the latest 
date, then choose the one with the greatest specimen ID.
•
Post baseline period:
−
On-treatment AEs will be defined as AEs with an onset date and time on or after the date 
and time of the first dose of study treatment (or with an onset date on or after the day of 
first dose of study treatment if time is not collected or is missing). For subjects who are off 
study treatment, AEs will be included if event occurred within a safety window of 30 days 
(or 100 days depending on the analysis) after the last dose of study treatment. No 
“subtracting rule” will be applied when an AE occurs both pre-treatment and post-
treatment with the same preferred term and grade.
−
On-treatment evaluations (laboratory tests and vital signs) will be defined as evaluations 
taken after the day (and time, if collected and not missing) of first dose of study treatment. 
For subjects who are off study treatment, evaluations should be within a safety window of 
30 days (or 100 days depending on the analysis) after the last dose of study treatment.
•
Late-emergent drug-related AEs will be defined as drug-related AEs with an onset date greater 
than 100 days after the last dose of study treatment in subjects who are off study treatment.
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•
In addition, data collected within an extended follow-up window of 135 days based on specific 
EU country requests, will be presented in listings.
6.2
Treatment Regimens
The treatment group “as randomized” corresponds to the treatment group assigned by the
Interactive Response Technology (IRT) system.
Arm 1 in the IRT system: BMS-986213 Plus Chemotherapy
Arm 2 in the IRT system: Nivolumab Plus Chemotherapy
The treatment group “as treated” will be same as the treatment group “as randomized” by IRT
unless a subject received the incorrect study treatment for the entire period of treatment, in which 
case the subject’s treatment group “as treated” will be defined as the incorrect study treatment.
Unless otherwise specified, the safety analysis will be based on the treatment group “as treated”.
Unless otherwise specified, the efficacy analysis will be based on the treatment group “as 
randomized”.
6.2.1
Stratification
The randomization will be stratified by the following factors:
•
LAG-3 expression (≥1% or <1%; no indeterminate allowed)
•
PD-L1 expression status (CPS ≥5, CPS ≥1 to < 5, CPS < 1 or indeterminate).
Note: region (Japan/Taiwan [J/T] vs Rest of world [ROW]) was originally a stratification factor
for the study, but no one from Japan/Taiwan enrolled in the study.  Therefore, although it is still
in the system as a stratification factor for the study, it will not be analyzed nor used as such.
6.3
Populations for Analyses
•
Enrolled subjects: All subjects who signed the informed consent form and obtained a subject
number.
•
Randomized subjects: All subjects who were randomized through the IRT.
•
Treated subjects: All randomized subjects who received at least one dose of any study 
treatment.
Unless otherwise specified, the safety analyses will include all treated subjects.
Unless otherwise specified, the efficacy analyses will include all randomized subjects.
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All analyses will be performed using the treatment arm as randomized (intent to treat), with the 
exception of dosing and safety, for which the treatment arm as received will be used. For purposes
of analysis, the following populations are defined in Table 6.3-1. 
Specific to this study, subjects may receive three types of chemotherapy regimen (as per 
investigator’s choice): XELOX, FOLFOX, or SOX. Chemotherapy regimen “as randomized” 
(referred to as “planned chemotherapy regimen”) will be retrieved from the IRT system. 
Chemotherapy regimen “as treated” will be, in general, the same as the planned chemotherapy 
regimen. However, if a subject received the other chemotherapy regimen for the entire period of 
treatment, the subject’s chemotherapy regimen will be defined as the regimen the subject actually 
received.
Table 6.3-1:
Populations for Analyses
Population
Description
All Enrolled Subjects
All subjects who sign informed consent and were registered into the IRT.
All Randomized Subjects 
All subjects who were randomized to either treatment arm.  This population 
will be used for analyses of demography, protocol deviations, baseline 
characteristics, efficacy, and clinical outcomes assessments (must have 
baseline and on-study assessment).
All Treated Subjects
All subjects who received at least one dose of any study medication. This is 
the primary population for exposure and safety analyses.
All Treated LAG-3 Positive 
Subjects
All treated subjects in the LAG-3 positive (>= 1%) group.  This is used for 
select disposition, exposure, and safety analyses.
All Treated LAG-3 Negative
Subjects
All treated subjects in the LAG-3 negative (<1%) group. This is used for 
select disposition, exposure, and safety analyses.
All Randomized LAG-3 
Positive Subjects
All randomized subjects in the LAG-3 positive (>= 1%) group. This is the 
dataset for primary efficacy analyses.
All Randomized LAG-3 
Negative Subjects
All randomized subjects in the LAG-3 negative (<1%) group. This is the 
dataset for select efficacy analyses.
All Randomized Response 
Evaluable Subjects
All randomized subjects who had measurable lesions at baseline and one on 
study scan
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7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, discrete variables will be tabulated by the frequency and proportion of 
subjects falling into each category, grouped by treatment. Percentages given in these tables will be 
rounded to the first decimal and, therefore, may not always sum to 100%. Percentages less than 
0.1 will be indicated as ‘< 0.1’. Continuous variables will be summarized by treatment group using 
the mean, standard deviation, median, minimum, and maximum values.
Time-to-event variables (e.g., time-to resolution) will be analyzed using the Kaplan-Meier 
technique. When specified, the median will be reported along with 95% CI using Brookmeyer and 
Crowley method8 (using log-log transformation for constructing the confidence intervals9).
The conventions to be used for imputing missing and partial dates for analyses requiring dates are 
described in Section 8.
7.1.1
Adverse Events, Serious Adverse Events, Multiple Events, Select 
Adverse Events, Other Events of Special Interest and Immune-Mediated 
Adverse Events
Drug-related AEs are those events with relationship to study drug “Related”, as recorded on the 
CRF. If the relationship to study drug is missing, the AE will be considered as drug-related. 
Serious adverse events consist of AEs deemed serious by the Investigator and flagged accordingly 
in the CRF and clinical database.
Adverse events leading to study drug discontinuation are AEs with action taken regarding study 
drug(s) = “Drug was discontinued”. 
Adverse events leading to dose delay are AEs with action taken regarding study drug(s) = “Drug
was delayed”.
Adverse events leading to dose reduction are AEs with action taken regarding study drug(s) = 
“Dose was reduced”.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and the most recent version of the dictionary at the time of the database lock will be used. Adverse 
event results will be graded for severity using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) and the version of the criteria specified in the protocol will be used.
In the AE summary tables, unless otherwise specified, subjects will be counted only once at the 
Preferred Term (PT), only once at the System Organ Class (SOC), and only once at subject level 
for the counting of total number of subjects with an AE. The AE tables will be sorted by the SOCs 
and then PTs. SOC will be ordered by descending frequency overall and then alphabetically. PTs 
will be ordered within SOC by descending frequency overall and then alphabetically. The sorting 
will be done based on the ‘Any Grade’ column of the experimental arm when arms are presented 
side-by-side.
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Unless otherwise specified, the AE summary tables will be restricted to on-treatment events 
regardless of the causality.
Analyses that take into account the multiple occurrences of a given adverse event will be conducted 
(see Section 7.6.9). To prepare these analyses, the CRF data will be processed according to 
standard BMS algorithms10 in order to collapse adverse event records into unique records based 
on the preferred term. These data will be presented as the rate per 100 person-years of exposure. 
These analyses will take into account all on-treatment events (allowing more than 1 event per 
subject) and the total exposure time. The person-year exposure will be computed as the sum over 
the subjects’ exposure expressed in years where the exposure time is defined as 
•
(Date of last dose of study treatment - date of first dose of study treatment + 31 days 
(or 101 days, depending on the analysis))/365.25, for subject who are off study treatment and 
were followed for at least 30 days (or 100 days, depending on the analysis) after last dose of 
study treatment.
•
(Last known alive date - date of first dose of study treatment +1)/365.25, for subjects who are 
still on-treatment or who are off study treatment and were followed less than 30 days 
(or 100 days depending on the analysis) after last dose of study treatment.
7.1.1.1
Select Adverse Events (EU/ROW Submissions)
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (e.g., pulmonary events, gastrointestinal events categories, etc.). AEs that may differ from 
or be more severe than AEs caused by non-immunotherapies and AEs whose early recognition and 
management may mitigate severe toxicity are included as select AEs. Categories of select AEs 
may include subcategories (e.g., adrenal disorders, diabetes, pituitary disorders, and thyroid 
disorders are subcategories of the endocrine event category). 
The list of MedDRA preferred terms used to identify select adverse events is revisited quarterly 
and updated accordingly. The preferred terms used for the selection at the time of the database 
lock will be provided by categories/subcategories.
In addition to the frequency and worst severity of select AEs, time-to onset, time-to resolution, 
and time-to resolution where immune modulating medication was initiated will be analyzed for 
each specific category/subcategory of drug-related select AEs when applicable.
Further details on the definitions time-to onset and time-to resolution are described in APPENDIX 
1.
7.1.1.2
Other Events of Special Interest
Other events of special interest (OEOSI) consist of a list of preferred terms grouped by specific 
category 
 
 
 
 The list of MedDRA preferred terms used to identify OEOSI is revisited quarterly and 
updated accordingly. The preferred terms used for the selection at the time of the database lock by 
categories will be provided.
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7.1.1.3
Immune-Mediated Adverse Events (US Submission)
In order to further characterize AEs of special clinical interest, analysis of immune-mediated AEs 
(IMAE) will be conducted. IMAEs are specific events (or groups of PTs describing specific events) 
that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, endocrine 
(adrenal insufficiency, hypothyroidism/thyroiditis, hypothyroidism, thyroiditis, hyperthyroidism, 
diabetes mellitus, and hypophysitis), and other specific events, considered as potential immune-
mediated events by investigator that meet the definition summarized below: 
•
those occurring within 100 days of the last dose, 
•
regardless of causality,
•
treated with immune-modulating medication (of note, endocrine AEs such as adrenal 
insufficiency, hypothyroidism/thyroiditis, hypothyroidism, thyroiditis, hyperthyroidism, 
diabetes mellitus, and hypophysitis are considered IMAEs regardless of immune-modulating 
medication use, since endocrine drug reactions are often managed without immune-modulating 
medication).
•
with no clear alternate etiology based on investigator assessment, or with an immune-mediated 
component 
The list of MedDRA preferred terms used to identify IMAEs is revisited quarterly and updated 
accordingly. The preferred terms used for the selection at the time of the database lock by 
categories will be provided.
7.1.2
Laboratory Tests
Clinical laboratory parameters (hematology, serum chemistry and electrolytes) will be evaluated.
Laboratory tests will be graded using the NCI Common Terminology Criteria, and the most recent 
version of the criteria at the time of the database lock will be used.
Clinical laboratory data will be first analyzed using International System of Units (SI). Analyses 
will be repeated using US conventional units.
In the laboratory summary tables, unless otherwise specified, subjects will be counted only once 
for each lab parameter according to their worst on treatment CTC grade (worst being the highest 
CTC grade). The laboratory tables and listings will be sorted by laboratory category, laboratory 
subcategory and laboratory test code sequence number.
7.2
Study Conduct
Enrollment by country and site, and enrollment by month will be summarized and listed for all 
enrolled subjects.
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A by-subject listing of batch numbers for all treated subjects will be provided.
7.2.1
Relevant Protocol Deviations
The following programmable deviations will be considered as relevant protocol deviations and
summarized and listed based on the all randomized subjects, by treatment group and overall. In 
addition, this analysis will be performed using the All Randomized LAG-3 Positive Subjects. Non-
programmable relevant eligibility and on-treatment protocoldeviations, as well as significant (both
programmable and non-programmable) eligibility and on-treatment protocol deviations will be
reported through 
listings.
At entrance deviations:
•
Subject with baseline ECOG > 1
•
Subject who received prior systemic anti-cancer therapy (adjuvant and neoadjuvant are 
allowed)  
•
Subject without histologically or cytologically confirmed diagnosis
•
Subjects without measureable disease at baseline
•
Subjects without PDL1 results (indeterminates are not deviations) prior to randomization
•
Subjects without LAG3 results (indeterminates are deviations) prior to randomization
•
Subjects with HER2 positive status (ihc3+ or fish positive ((her2:cep17 ratio >2) or 
(ihc2+/fish+))
On-treatment deviations
•
Subjects who received anti-cancer therapy 
•
Subjects treated differently as randomized
7.3
Study Population
Analyses in this section will be tabulated for all randomized subjects by treatment group as 
randomized, unless otherwise specified.
7.3.1
Subject Disposition
The total number of subjects enrolled (randomized or not randomized) will be presented along 
with the reason for not being randomized. This analysis will be performed on the all enrolled 
subjects population only.
Number of subjects randomized but not treated along with the reason for not being treated will be 
tabulated by treatment group as randomized.
This analysis will be performed on the All 
Randomized LAG-3 Positive Subjects, All Randomized LAG-3 Negative Subjects, and All 
Randomized Subjects.
Number of subjects who discontinued study treatment along with corresponding reason will be 
tabulated by treatment group as treated. Reason for discontinuation will be derived from subject 
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status CRF page. This analysis will be performed on the All Treated LAG-3 Positive Subjects, All 
Treated LAG-3 Negative Subjects, and All Treated Subjects.
A by-subject listing for all treated subjects will be provided showing the subject’s off treatment 
date and whether the subject continue in the study along with the reason for going off treatment 
period. A by-subject listing for all enrolled subjects will also be provided, showing whether the 
subject was randomized along with the reason for not being randomized.
Accrual will also be summarized by stratification factor, as stratified at IRT.
7.3.2
Demographics and Other Baseline Disease Characteristics
The following baseline characteristics will be summarized by treatment arm as randomized. All 
baseline presentations identify subjects with missing measurements. This analysis will be 
performed on the All Randomized LAG-3 Positive Subjects, All Randomized LAG-3 Negative 
Subjects, and All Randomized Subjects.
Listings will also be provided.
•
Age (continuous)
•
Age category (< 65, ≥ 65 and < 75, ≥ 75 and < 85, ≥ 85; ≥ 75, ≥ 65)
•
Sex (male, female)
•
Ethnicity (Hispanic/Latino and Not Hispanic/Latino)
•
Race (White, Black or African American, Asian, Other)
•
Region (Europe, North America, Rest of World, Asia)
•
Country
•
Time from Initial Disease Diagnosis to Randomization (1 year, >=1 year) (< 6months, 6months 
-< 1 year, 1-< 2 year, 2 - < 3 year, 3 -< 4 year, 4 - < 5 year, ≥ 5 year)
•
ECOG performance status (0, 1)
•
LAG-3 expression (LAG-3 expression  (≥1%, <1%); no indeterminate allowed)
•
PD-L1 expression (per IRT) (PD-L1 CPS ≥5, PD-L1 CPS ≥1 to < 5, PD-L1 CPS < 1 or 
indeterminate,)
•
PD-L1 expression (per IRT) (PD-L1 CPS ≥1, PD-L1 CPS < 1 or indeterminate,)
•
PD-L1 expression (per IRT) (PD-L1 CPS ≥5, PD-L1 CPS < 5 or indeterminate)
•
Primary tumor location at initial diagnosis (GC, GEJ cancer)
•
Disease stage at initial diagnosis (Stage I, Stage II, Stage III, Stage IV)
•
Disease status (locally recurrent, metastatic, locally advanced)
•
Lauren classification (intestinal type, diffuse type, mixed, unknown)
•
Siewert-Stein classification (Type I, Type II, Type III)
•
WHO histologic classification (adenosquamous carcinoma, mucinous adenocarcinoma, 
papillary serous adenocarcinoma, signet ring cell, tubular adenocarcinoma, other)
•
TNM classification:
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−
Tumor (Tx, T0, Tis, T1, T2, T3, T4, unknown)
−
Nodes (Nx, N0, N1, N2, N3, unknown)
−
Metastasis (Mx, M0, M1, unknown)
•
Smoking status (current/former, never smoker, unknown)
•
CNS metastases (yes/no)
•
Liver metastases (yes/no)
•
Peritoneal metastases (yes/no) 
•
HER-2 status at study entry (negative, positive, unknown)
•
EBV status (positive, negative, unknown)
•
H.pylori (no, yes, unknown)
•
Baseline hemoglobin (<10 g/dL; ≥ 10 g/dL)
•
Baseline albumin (< LLN, ≥ LLN)
•
Number of organs with baseline lesion (target or non-target; ӊ 1, >= 2) outside primary location 
(gastric, gastroesophageal junction and esophagus)
•
All lesions at Baseline (Investigator and BICR): sites of disease, number of disease sites per 
subject, number of subjects with no measurable lesion
•
Target Lesions (Investigator and BICR): Presence of target lesions, site of target lesion, sum 
of diameters of target lesions
Summary tables (cross-tabulations) by treatment group for stratification factor will be provided to 
show any discrepancies between what was reported through IRT vs. other data sources at baseline.  
This summary will be performed on the relevant populations based on all randomized subjects.
•
PD-L1 expression level (CPS ≥5, CPS ≥1 to < 5, CPS < 1 or indeterminate) (IRT vs. clinical 
database)
•
LAG-3 expression (<1%; ≥1%)
A listing of randomization scheme presenting randomized treatment group and as treated treatment 
group will be provided for all randomized subjects.
7.3.3
Medical History
A by-subject listing of general medical history for all randomized subjects will be provided.
7.3.4
Prior Therapy Agents
Prior therapy will be summarized for the relevant populations based on all randomized subjects.
Prior anti-cancer therapy:
•
Setting of prior systemic therapy regimen received (adjuvant, metastatic disease, neo-adjuvant)
•
Time from completion of prior adjuvant/neo-adjuvant therapy to treatment (for subjects who 
received prior adjuvant/neo-adjuvant therapy), (< 6 months, 6 -< 12month, ≥ 12 months)
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•
Prior surgery related to current cancer (yes or no)
•
Prior radiotherapy (yes or no)
•
Prior systemic therapy classified by therapeutic class and generic name
Other Prior therapy:
•
Prior/current non-study medication classified by anatomic and therapeutic classes
Agents and medication will be reported using the generic name. A listing by subject will also be
provided.
7.3.5
Physical Examinations
Subjects with abnormal baseline physical examination will be listed by subject.
7.3.6
Baseline Physical Measurements
Baseline physical measurements will be listed by subject.
7.4
Extent of Exposure
Listings will include all available exposure data. Analyses will be performed on the relevant 
populations by treatment group “as treated” in all treated subjects, unless otherwise specified.
7.4.1
Administration of Study Therapy 
The following parameters will be summarized (descriptive statistics) by treatment group.  These 
analyses will be performed on the All Treated LAG-3 Positive Subjects, All Treated LAG-3 
Negative Subjects, and All Treated Subjects.
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 90
- < 110%; ≥ 110%
•
Number of doses/cycles received (summary statistics)
•
Cumulative dose
•
Duration of treatment
−
using a KM curve whereby the last dose date will be the event date for those subjects who
are off study therapy. Subjects who are still on study therapy will be censored on their last
dose date. Median duration of treatment and associated 95% CI will be provided.
A by-subject listing of dosing of study medication (record of study medication, infusion details, 
dose change) and a listing of batch number will be also provided.
Key parameters used to characterize dosing data are found in Table 7.4.1-1, 7.4.1-2, and 7.4.1-3.  
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Table 7.4.1-1:
Administration of Study Therapy for Subjects Treated with XELOX
BMS-986213 or Nivolumab
Oxaliplatin
Capecitabine
Dosing schedule 
per protocol
Rela 120mg + Nivo 360mg (BMS-986213)
Q3WK, IV
or
Nivo 360mg Q3WK, IV
130mg/m2 Q3WK, IV
1000mg/m2 Q3WK, oral
Dose*
Dose is defined as Total Dose administered (mg). 
Dose administered in mg at each dosing date are 
collected on the CRF
Total dose administered (mg) / most 
recent BSA
Total dose administered (mg) / most recent 
BSA
Cumulative Dose
The sum of all doses (mg) administered to a 
subject during the treatment period
The sum of all doses (mg/m2) 
administered to a subject during the 
treatment period
The sum of all doses (mg/m2)
administered to a subject during the 
treatment period
Relative Dose 
Intensity (%)
Cumulative dose (mg) / [Last rela dose date – rela
Start dose date + 21) x 120/21]
Cumulative dose (mg) / [Last nivolumab dose 
date – nivolumab Start dose date + 21) x 360/21]
Cumulative dose (mg/m2) / [Last 
oxaliplatin dose date – oxaliplatin Start 
dose date + 21) x 130/21]
Cumulative dose (mg/m2) / [First dose of 
capecitabine in the last cycle –
capecitabine Start dose date + 21) x 
2000/21]
Duration of 
Treatment
Last dose date (of the last administered study therapy) - Start dose date (of the first administered study therapy) + 1
* Dose administered in mg at each dosing date and BSA (computed using recent weight and baseline height) are collected on the CRF.
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Table 7.4.1-2:
Administration of Study Therapy for Subjects Treated with FOLFOX
BMS-986213 or 
Nivolumab
Oxaliplatin
Leucovorin
Fluorouracil
Dosing schedule 
per protocol
Rela 160mg + Nivo 
480mg (BMS-986213)
Q4WK, IV
or
Nivo 480mg Q4WK, IV
85mg/m2 Q2WK
400mg/m2 Q2WK
Bolus 5-FU: 400mg/m2 Q2WK, IV on Day 1 of the 
cycle
Continuous 5-FU: 1200mg/m2 Q2WK, IV 
continuous infusion on Day1-2 of the cycle
Dose*
Dose is defined as Total 
Dose administered (mg). 
Dose administered in mg
at each dosing date are 
collected on the CRF
Total dose administered 
(mg) / most recent BSA
Total dose administered 
(mg) / most recent BSA
Total dose administered (mg) / most recent BSA
Cumulative 
Dose
The sum of all doses 
(mg) administered to a 
subject during the 
treatment period
The sum of all doses 
(mg/m2) administered to 
a subject during the 
treatment period
The sum of all doses 
(mg/m2) administered to 
a subject during the 
treatment period
The sum of all doses (mg/m2) administered to a 
subject during the treatment period
Relative Dose 
Intensity (%)
Cumulative dose (mg) / 
[Last rela dose date – rela
Start dose date + 28) x 
160/28]
Cumulative dose (mg) / 
[Last nivolumab dose 
date – nivolumab Start 
dose date + 28) x 480/28]
Cumulative dose 
(mg/m2) / [Last 
oxaliplatin dose date –
oxaliplatin Start dose 
date + 14) x 85/14]
Cumulative dose 
(mg/m2) / [Last 
leucovorin dose date –
leucovorin Start dose 
date + 14) x 400/14]
Bolus 5-FU: Cumulative dose (mg/m2) / [First dose 
of fluorouracil in the last cycle – fluorouracil Start 
dose date + 14) x 400/14]
Continuous 5-FU: Cumulative dose (mg/m2) / [First 
dose of continuous fluorouracil in the last cycle –
continuous fluorouracil Start dose date + 14) x 
1200/14]
Duration of 
Treatment
Last dose date (of the last administered study therapy) - Start dose date (of the first administered study therapy) + 1
* Dose administered in mg at each dosing date and BSA (computed using recent weight and baseline height) are collected on the CRF.
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Table 7.4.1-3:
Administration of Study Therapy for Subjects Treated with SOX
BMS-986213 or Nivolumab
Oxaliplatin
S-1 (tegafur/gimeracil/oteracil)
Dosing schedule per 
protocol
Rela 120mg + Nivo 360mg (BMS-986213)
Q3WK, IV
or
Nivo 360mg Q3WK, IV
130mg/m2 Q3WK, IV
S-1 (tegafur/gimeracil/oteracil)
BID, oral (administered as calculated 
according to body surface area (BSA, 
mg/m2/dose): BSA < 1.25 m2, 40 
mg/dose; ≥1.25 and < 1.5 m2, 50 mg/dose; 
≥1.5 m2, 60 mg/dose)
Dose*
Dose is defined as Total Dose administered (mg). 
Dose administered in mg at each dosing date are 
collected on the CRF
Total dose administered (mg) / 
most recent BSA
Total dose administered (mg) / most recent 
BSA
Cumulative Dose
The sum of all doses (mg) administered to a 
subject during the treatment period
The sum of all doses (mg/m2) 
administered to a subject during 
the treatment period
The sum of all doses (mg/m2) 
administered to a subject during the 
treatment period
Relative Dose 
Intensity (%)
Cumulative dose (mg) / [Last rela dose date – rela
Start dose date + 21) x 120/21]
Cumulative dose (mg) / [Last nivolumab dose date 
– nivolumab Start dose date + 21) x 360/21]
Cumulative dose (mg/m2) / [Last 
oxaliplatin dose date – oxaliplatin 
Start dose date + 21) x 130/21]
BSA <1.25m2:
Cumulative dose (mg/m2) / [First dose of 
S-1 in the last cycle – S-1 Start dose date + 
14) x 1,120/14]
BSA ≥1.25 and < 1.5 m2:
Cumulative dose (mg/m2) / [First dose of 
S-1 in the last cycle – S-1 Start dose date + 
14) x 1,400/14]
BSA ≥1.5 m2:
Cumulative dose (mg/m2) / [First dose of 
S-1 in the last cycle – S-1 Start dose date + 
14) x 1,680/14]
Duration of 
Treatment
Last dose date (of the last administered study therapy) - Start dose date (of the first administered study therapy) + 1
* Dose administered in mg at each dosing date and BSA (computed using recent weight and baseline height) are collected on the CRF.
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7.4.2
Modifications of Study Therapy
7.4.2.1
Dose Delays
Table 7.4.2.1-1:
Dose Delays
Q4W BMS-
986213 or 
Nivolumab
Q3W BMS-
986213 or 
Nivolumab
XELOX
FOLFOX
SOX
Specifications per Protocol
Dose 
considered as 
actually 
delayed
If the delay is 
exceeding 3 
days
If the delay is 
exceeding 3 
days
Per package 
insert or local 
standard
Per package 
insert or local 
standard
Per package 
insert or local 
standard
Maximum 
delay allowed 
between doses
42 days
42 days
Not specified
Not specified
Not specified
Definitions for the Analysis
Dose Delay
duration of 
preceding cycle 
in days – 28
duration of 
preceding cycle 
in days – 21
duration of 
preceding cycle 
in days – 21
duration of 
preceding cycle 
in days – 14
duration of 
preceding cycle 
in days – 14
Categories of 
dose delays
on-time, 4 - 7 
days, 8 - 14 
days, 15 - 42 
days, > 42 days
on-time, 4 - 7 
days, 8 - 14 
days, 15 - 42 
days, > 42 days
on-time, 4 - 7 
days, 8 - 14 
days, 15 - 42 
days, > 42 days
on-time, 3 – 4, 5 
- 7 days, 8 - 14 
days, 15 - 42 
days, > 42 days
on-time, 4 - 7 
days, 8 - 14 
days, 15 - 42 
days, > 42 days
The following parameters will be summarized by treatment arm:
•
Number of dose delayed per subject, Length of Delay and Reason for Dose Delay
Reason for dose delay will be retrieved from CRF dosing pages.
7.4.2.2
Dose Interruptions
Each study therapy may be interrupted. This information will be retrieved from CRF dosing pages.
(For capecitabine and S-1, which are oral, interruption will be programmatically derived.)
The following parameters will be summarized by treatment arm:
•
Number of subject with at least one dose infusion interrupted along with reason for the 
interruptions and number of infusions interrupted per subject
7.4.2.3
IV Rate Reductions
For each study therapy dosed as IV (BMS-986213, nivolumab, oxaliplatin, leucovorin, and 
fluorouracil) IV rate may be reduced. This information will be retrieved from CRF dosing pages.
The following parameters will be summarized by treatment arm:
•
Number of subject with at least one IV rate reduction along with reason for the IV rate 
reduction and number of infusions with IV rate reduced per subject
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7.4.2.4
Dose Escalations
Dose escalations of BMS-986213 or nivolumab are not permitted.
7.4.2.5
Dose Reductions
Dose reductions of BMS-986213 or nivolumab are not permitted. 
7.4.2.6
Dose Omissions
Dose reductions of BMS-986213 or nivolumab are not permitted. 
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the UMC WHO Drug Global Dictionary.
The following summary table will be provided:
•
Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term) 
The following summary table will be provided: 
•
Prior/current medications (subjects with any prior/current medication, subjects by medication 
class and generic term) 
A by-subject listing(s) will accompany the table(s).
7.4.3.1
Immune Modulating Medication
Immune modulating concomitant medications are medications entered on an immune modulating 
medication form or available from the most current pre-defined list of immune modulating 
medications. The list of anatomic class, therapeutic class and generic name used for the selection 
at the time of the database lock will be provided.
The percentage of subjects who received immune modulating concomitant medication for
•
management of adverse event 
•
premedication 
•
other use
•
any use
•
management of drug-related select adverse event (any grade, grade 3-5) by select AE category/ 
subcategory (EU/ROW Submissions)
•
management of IMAEs (any grade, grade 3-5) by IMAE category (US Submission) will be 
reported separately for each treatment group (percentages of treated subjects by medication 
class and generic term).
For each category/subcategory of drug-related select AEs (any grade, grade 3-5) and IMAEs (any 
grade, grade 3-5), the following will be reported for each treatment group:
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•
The total immune modulating medication treatment duration (excluding overlaps), duration of 
high dose of corticosteroid, initial dose of corticosteroid, and tapering duration (summary 
statistics)
Duration represents the total duration the subject received the concomitant medication of interest. 
If the subject took the medication periodically, then DURATION in the summation of all use. 
Initial dose represents the dose of the concomitant medication of interest received at the start of 
the event. In the case multiple medications started on the same date, the highest equivalent dose is 
chosen and converted to mg/kg by dividing by the subject’s recent weight.
These analyses, except the ones related to IMAEs will be conducted using the 30-day safety 
window. The analyses related to IMAEs will be conducted using the 100-day safety window.
7.4.3.2
Subsequent Cancer Therapy
•
Number and percentage of subjects receiving subsequent therapies will be summarized. 
Categories include: 
−
Immunotherapy including commercial Nivolumab (anti-PD1 agents, anti-PD-L1 agents, 
anti-CTLA-4 agents and others) by drug name 
−
Other anti-cancer agents excluding all immunotherapy (approved and investigational) by 
drug name 
−
Surgery for treatment of tumors 
−
Radiotherapy  for treatment of tumors
−
Any combination of the above 
•
A subject listing of follow-up therapy will also be produced for subjects who had any 
subsequent therapy
7.5
Efficacy
Principal analyses of objective response rate (ORR) and progression free survival (PFS) will be 
based on the Blinded Independent Central Review (BICR) evaluation, unless noted otherwise.
Unless stated otherwise, whenever a stratified analysis is specified in the all randomized 
population, the following stratifications factors (recorded at randomization as per IRT) will be 
used, except for the analysis in LAG-3 positive or LAG-3 negative sub-groups when only PDL1 
CPS expression will be used.
•
LAG-3 expression (≥1% or < 1%; no indeterminate allowed)
•
PD-L1 expression status (CPS ≥5, CPS ≥1 to < 5, CPS < 1 or indeterminate)
There will be no p-values presented for any of the analyses other than the primary endpoint.  All 
other analyses will be descriptive in nature.  Confidence intervals for all endpoints will be at the 
two-sided 95% level. Point estimates and confidence bounds for efficacy variables will be rounded 
to the second decimal place.
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7.5.1
Analysis of Objective Response Rate (ORR)
Primary (and secondary) objectives of the study are to compare ORR per BICR between treatment 
groups among LAG-3 positive (primary objective) and among LAG-3 negative (secondary 
objective) randomized subjects.
The number and percentage of subjects in each category of BOR per BICR (complete response
[CR], partial response [PR], stable disease [SD], progressive disease [PD], or unable to determine 
[UTD]) will be presented, by treatment group, for each LAG-3 population and overall. Estimates 
of response rate, along with its exact two-sided 95% CI by Clopper and Pearson11 will be 
presented, by treatment group for each LAG-3 population and overall. 
ORR as assessed by BICR will be compared between treatment groups using a two-sided Cochran-
Mantel-Haenszel test stratified by PD-L1 status ((CPS ≥5%, CPS ≥ 1 to <5, or CPS < 1% 
(including indeterminate)) as recorded in the IRT.   These analyses and associated 70% CIs for 
ORR difference will be performed on the All Randomized LAG-3 Positive Subjects (primary 
population), All Randomized LAG-3 Negative Subjects, and All Randomized Subjects.
The following subject-level graphics will also be provided:
•
For the responders only, time courses of the following events of interest will be graphically 
displayed: tumor response, progression, last dose received, and death
•
For response evaluable subjects (defined per RECIST 1.1 as randomized subjects with baseline 
and at least one on-study tumor assessment)
−
A bar plot showing the best % reduction from baseline in sum of diameter of target lesions 
based on BICR assessment for each subject will be produced (excluding assessments after 
PD and assessments after start of subsequent anti-cancer therapy)
−
A plot of individual time course of tumor burden change per BICR assessment will be 
produced
Similar analyses will be repeated based on the investigator’s assessment of ORR. A cross 
tabulation of BICR best response versus the investigator best response will be presented, by 
treatment group and by response categories. Concordance Rate of Responders will be computed 
as the frequency with which investigator and BICR agree on the classification of a subject as 
responder vs. non responder/UTD as a proportion of the total number of randomized subjects
(using relevant populations) assessed by both the investigator and BICR.
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7.5.3
Time to Response and Duration of Response
Duration of response (DOR) and time to response (TTR) will also be evaluated for subjects who 
achieved confirmed PR or CR. The DOR for each treatment group. The DOR will be estimated 
using the Kaplan-Meier (KM) product limit method and will be displayed graphically. A table will 
be produced presenting number of events, number of subjects involved, medians, and 95% CIs for 
the medians. Median values of DOR, along with two-sided 95% CI in each treatment group will 
be computed based on a log-log transformation method.   These analyses will be performed on the 
All Randomized LAG-3 Positive Subjects, All Randomized LAG-3 Negative Subjects, and All 
Randomized Subjects.
The status of subjects who are censored in the DOR KM analysis will be tabulated for each 
randomized treatment group including the following categories:
•
Ongoing follow-up (current [last scan within adequate window vs cutoff date], not current)
•
Off-study (lost to follow-up, withdraw consent, never treated)
•
Received subsequent anticancer therapy
TTR, which does not involve censoring, will be summarized by treatment group in all responders 
using descriptive statistics.
•
A by-subject listing will be presented including treatment group, time to response, duration of 
response, whether the subject was censored for duration of response, and, if so, the reason. 
Similar analyses will be repeated based on the investigator’s assessment of ORR.
7.5.4
Analysis of Progression-Free-Survival
One of the objectives of the study is to assess the difference in progression-free survival (as 
determined by BICR) between treatment groups in the LAG-3 positive, LAG-3 negative, and all 
randomized populations.
The analysis of PFS (as determined by BICR) will be to compare the two treatment groups via 
stratified log-rank test among all randomized subjects at a two-sided α = 0.30 level. 
The primary definition of PFS adjusting for subsequent anticancer therapy will be used in this 
analysis.
The estimate of the PFS hazard ratio between treatment groups will be calculated using a stratified 
Cox proportional hazards model, with treatment as the sole covariate. Ties will be handled using 
the exact method. A two-sided 70% CI for the hazard ratio will also be presented.
The PFS function for each treatment group will be estimated using the KM product limit method 
and will be displayed graphically. A two-sided 95% CI for median PFS in each treatment group 
will be computed via the log-log transformation method. 
 
 These estimates will be derived from the Kaplan Meier estimate and corresponding CIs will 
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be derived based on Greenwood14 formula for variance derivation and on log-log transformation 
applied on the survivor function15.
The source of PFS event (progression or death) will be summarized by treatment group.
Analyses of PFS may also be conducted based on the secondary definition of PFS. These analyses 
will be the same as those specified above.
The status of subjects who are censored (as per primary definition of PFS) in the PFS KM analysis 
will be tabulated for each randomized treatment group including the following categories:
•
On-study (on-treatment, in follow-up)
•
Off-study (lost to follow-up, withdraw consent, never treated)
•
No baseline tumor assessment
•
No on-study tumor assessment and no death
•
Received subsequent anticancer therapy
Similar analyses will be repeated based on the investigator’s assessment of progression.
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7.5.7
Analysis of Overall Survival
One of the objectives of the study is to assess the difference in overall survival between treatment 
groups in each of the randomized populations.
Overall survival will be compared between the treatment groups, using stratified log-rank test. The 
stratification factors will be those used in the analysis of PFS. The stratified hazard ratio between 
the treatment groups will be presented along with 70% CI. 
OS will be estimated using the KM techniques. A two-sided 95% CI for median OS in each 
treatment group will be computed via the log-log transformation method. OS rates at fixed time 
points (e.g. 6 months, depending on the minimum follow-up) will be presented along with their 
associated 95% CIs. These estimates will be derived from the Kaplan Meier estimate and 
corresponding CIs will be derived based on Greenwood formula for variance derivation and on 
log-log transformation applied on the survivor function.
The status of subjects who are censored in the OS KM analysis will be tabulated for each treatment 
group using the following categories:
•
On-study (on-treatment, in follow-up)
•
Off-study (lost to follow-up, withdraw consent, never treated)
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7.5.8
Current Status of PFS and OS Follow-up
The extent of follow-up for survival, defined as the time between randomization date and last 
known alive date (for subjects who are alive) or death date (for subjects who died), will be 
summarized descriptively (median, min, max) in months for all randomized populations.
The currentness of follow-up for survival, defined as the time between last OS contact (i.e., last 
known alive date or death date) and cutoff date (defined by last patient last visit date), will be 
summarized in months for all randomized subjects. Subjects who died and subjects with last known 
alive date on or after data cut-off date will have zero value for currentness of follow-up.
Minimum follow-up for OS, defined as the time from cutoff date to last subject’s randomization 
date, will be summarized in months for all randomized subjects.
Time from last evaluable tumor assessment to cutoff date in months will be summarized by 
treatment group and overall for all randomized subjects. Subjects who have a PFS event will be 
considered as current for this analysis. The secondary definition of PFS will be used for this 
summary. 
By-subject listing will also be produced to accompany the subject time from last evaluable tumor 
assessment.
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7.5.9
Interim analysis of Overall Survival
Interim analysis for OS will be performed at the time of the primary database lock.
7.6
Safety
Analyses in this section will be tabulated for all treated subjects by treatment group as treated, 
unless otherwise specified.
7.6.1
Deaths
Deaths will be summarized by treatment group.  These analyses will be performed on the All 
Treated LAG-3 Positive Subjects, All Treated LAG-3 Negative Subjects, and All Treated Subjects.
•
All deaths, reasons for death
•
Deaths within 30 days of last dose received, reasons for death
•
Deaths within 100 days of last dose received, reasons for death
A by-subject listing of deaths will be provided for the all enrolled subjects population.
7.6.2
Serious Adverse Events
Serious adverse events will be summarized by treatment group.  These analyses will be performed 
on the All Treated LAG-3 Positive Subjects, All Treated LAG-3 Negative Subjects, and All 
Treated Subjects.
•
Overall summary of SAEs by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
SOC/PT
•
Overall summary of drug-related SAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT
All analyses will be conducted using the 30-day safety window. 
A by-subject SAE listing will be provided for the “enrolled subjects” population.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
AEs leading to discontinuation will be summarized by treatment group.  These analyses will be 
performed on the All Treated LAG-3 Positive Subjects, All Treated LAG-3 Negative Subjects, 
and All Treated Subjects.
•
Overall summary of AEs leading to discontinuation by worst CTC grade (any grade, grade 
3-4, grade 5) presented by SOC/PT
•
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT
The analyses will be conducted using the 30-day safety window.
A by-subject AEs leading to discontinuation listing will be provided.
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7.6.4
Adverse Events Leading to Dose Modification
AEs leading to dose delay/reduction will be summarized by treatment group:
•
Overall summary of AEs leading to dose delay/reduction by worst CTC grade (any grade, 
grade 3-4, grade 5) presented by SOC/PT
•
Overall summary of related AEs leading to dose delay/reduction by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT
The analysis will be conducted using the 30-day safety window.
A by-subject AEs leading to dose delay/reduction listing will be provided.
7.6.5
Adverse Events
Adverse events will be summarized by treatment group.
The following analyses will be conducted using the 30 days safety window only:
•
Overall summary of any AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) presented 
by SOC/PT.  This analysis will be performed on the All Treated LAG-3 Positive Subjects, All 
Treated LAG-3 Negative Subjects, and All Treated Subjects, and All Treated Subjects by 
Chemotherapy
•
Overall summary of any AEs presented by worst CTC grade (any grade, grade 3-4, grade 5) 
by SOC/PT. This table will be restricted to events with an incidence greater or equal to 5% in 
any treatment group.  
•
Overall summary of any non-serious AEs presented by SOC/PT. This table will be restricted 
to events with an incidence greater or equal to 5% in any treatment group
•
Overall summary of any AEs that required immune modulating medication by worst CTC 
grade (any grade, grade 3-4, grade 5) presented by SOC/PT
•
Overall summary of drug-related AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) 
presented by SOC/PT.  This analysis will be performed on the All Treated LAG-3 Positive 
Subjects, All Treated LAG-3 Negative Subjects, and All Treated Subjects.
The following analyses will be conducted using the 30 days safety window and repeated using the 
100 days safety window:
•
Overall summary of drug-related AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT
A by-subject AE listing will be provided. A by-subject listing of any AE requiring immune 
modulating medications will also be provided.
7.6.6
Select Adverse Events (EU/ROW Submissions)
Unless otherwise specified, analyses will be performed by select AE category. Analyses will also 
be repeated by subcategory of endocrine events.
7.6.6.1
Incidence of Select AE
Select AEs will be summarized by treatment group for each category/subcategory. 
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The following analyses will be conducted using the 30-day safety window only:
•
Overall summaries of any select AEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category or Subcategory/PT
•
Overall summaries of any drug-related select AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by Category or Subcategory/PT
•
Overall summaries of any serious select AEs by worst CTC grade (any grade, grade 3-4, grade 
5) presented by Category or Subcategory /PT
•
Overall summaries of drug-related serious select AEs by worst CTC grade (any grade, grade 
3-4, grade 5) presented by Category or Subcategory /PT
•
Overall summaries of any select AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category or Subcategory /PT
•
Overall summaries of drug-related select AEs leading to discontinuation by worst CTC grade
(any grade, grade 3-4, grade 5) presented by Category or Subcategory /PT
•
Summary of frequency of unique select AEs by Category
A by-subject select AE listing will be provided.
7.6.6.2
Time-to Onset of Select AE
Time-to onset of drug-related select AEs (any grade, grade 3-5) will be summarized for each 
category/subcategory by treatment group.
Time-to onset analyses are restricted to treated subjects who experienced at least one drug-related 
select AE in the category/subcategory. The analyses will be conducted using the 30-day safety 
window.
Additional details regarding the time-to onset definition are described in time-to onset definition 
subsection of APPENDIX 1.
7.6.6.3
Time-to Resolution of Select AE
Time-to resolution of the following specific events will be summarized separately for each 
category/subcategory.
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) by treatment group
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) where immune modulating 
medication was initiated, by treatment group
Time-to resolution analyses are restricted to treated subjects who experienced the specific events. 
Time-to resolution where immune modulating medication was initiated analyses are restricted to 
treated subjects who experienced the specific events and who received immune modulating 
medication during the longest select AE.
The analyses will be conducted using the 30-day safety window.
The following summary statistics will be reported: percentage of subjects with resolution of the 
longest select AE, median time-to resolution along with 95% CI (derived from Kaplan-Meier 
estimation) and ranges.
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See time-to resolution definition subsection of APPENDIX 1 for additional details.
7.6.7
Immune-Mediated Adverse Events (US Submission)
IMAEs will be summarized by treatment group for each immune-mediated category / PT using the 
100-day safety window:
•
Overall summary of non-endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 
5) where immune modulating medication was initiated presented by Category / PT
•
Overall summary of endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT
•
Overall summary of non-endocrine IMAEs leading to discontinuation by worst CTC grade 
(any grade, grade 3-4, grade 5) where immune modulating medication was initiated presented 
by Category / PT
•
Overall summary of endocrine IMAEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category / PT
•
Overall summary of non-endocrine IMAEs leading to dose delay or reduction by worst CTC 
grade (any grade, grade 3-4, grade 5) where immune modulating medication was initiated 
presented by Category / PT
•
Overall summary of endocrine IMAEs leading to dose delay or reduction by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by Category / PT
•
Summaries of time-to onset and time-to resolution of non-endocrine IMAEs where immune 
modulating medication was initiated presented by Category
•
Summaries of time-to onset and time-to resolution of endocrine IMAEs presented by Category
A by-subject listing of IMAEs will be provided. By-subject listings of time-to resolution for 
longest IMAEs cluster (any grade and grade 3-5 in separate summaries) will also be provided. For 
new studies which collect investigator assessment of potential IMAE data, a by-subject listing of 
AEs considered as immune-mediated events per investigator but not qualified for IMAEs 
definition will also be provided.
7.6.8
Other Events of Special Interest
OEOSI will be summarized by treatment group for each category.
The following analyses will be conducted using the 100-day safety window:
•
Overall summary of OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
Category / PT
•
Overall summary of drug-related OEOSI by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT
A by-subject listing of OEOSI will be provided.
7.6.9
Multiple Events
The following summary tables will be provided:
•
A table showing the total number and rate (exposure adjusted) of occurrences for all AEs
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•
A table showing the total number and rate (exposure adjusted) of occurrences for AEs 
occurring in at least 5% of subjects in any treatment group
A listing displaying the unique instances of all AEs, i.e., after duplicates have been eliminated and 
overlapping and contiguous occurrences of the same event (i.e. same PT) have been collapsed will 
be provided. No formal comparisons will be made between treatment groups.
7.6.10
Laboratory Parameters
The analysis population for each laboratory test is restricted to treated subjects who underwent that 
laboratory test.
7.6.10.1
Hematology
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: hemoglobin (HB), platelets, white blood counts (WBC), absolute neutrophils count (ANC) 
and lymphocyte count (LYMPH).
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.10.2
Serum Chemistry
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: ALT, AST, alkaline phosphatase (ALP), total bilirubin and creatinine. 
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.10.3
Electrolytes
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: sodium (high and low), potassium (high and low), calcium (high and low), magnesium 
(high and low), and Glucose Serum (fasting hyperglycemia and hypoglycemia regardless of fasting
status).
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.10.4
Additional Analyses
In addition, further analyses on specific laboratory parameters will be performed by treatment 
group:
Abnormal Hepatic Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
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•
ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN
•
Total bilirubin > 2 x ULN
•
ALP > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
Abnormal Thyroid Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
TSH value > ULN and
−
with baseline TSH value ≤ULN
−
with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH 
test
−
with all FT3/FT4 test values ≥ LLN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test.
•
TSH < LLN and
with baseline TSH value ≥LLN
−
with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal 
TSH test
−
with all FT3/FT4 test values ≤ ULN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
7.6.11
Vital Signs
Vital signs collected on the CRF will be provided in a listing.  CG and echocardiogram results will 
also be listed and summarized by treatment group
7.6.12
Physical Measurements
Physical measurements will be listed by subject.
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7.6.14
Pregnancy
A by-subject listing of pregnancy tests results will be provided for randomized female subjects.
7.6.15
Adverse Events By Subgroup
Overall summary of any AEs and drug-related AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by SOC/PT and for each treatment group for the following subgroups:
•
Sex (Male vs. Female)
•
Race
•
Age (< 65 vs. 65 - < 75 vs. 75 - < 85 vs. ≥85 vs. ≥75 vs. ≥65)
These analyses will be conducted using the 30-day safety window only.
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8
CONTENT OF REPORTS
All analyses describe in this SAP will be included in the Clinical Study Report except where 
otherwise noted. Refer to the Data Presentation Plan for mock-ups of all tables and listings.
9
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates: 
•
For missing and partial adverse event onset dates, imputation will be performed using the 
Adverse Event Domain Requirements Specification16
•
For missing and partial adverse event resolution dates, imputation will be performed as 
follows:
−
If only the day of the month is missing, the last day of the month will be used to replace 
the missing day. If the imputed date is after the death date or the last known alive date, then 
the latest known alive date or death date is considered as the resolution date. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
•
Missing and partial non-study medication domain dates will be imputed using the derivation 
algorithm described in 4.1.3 of BMS Non-Study Medication Domain Requirements 
Specification17.
•
Missing and partial radiotherapy and surgery dates will be imputed using algorithm described 
in APPENDIX 2.
•
For death dates, the following conventions will be used for imputing partial dates:
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known alive date and the 
maximum will be considered as the death date. 
−
If the month or the year is missing, the death date will be imputed as the last known alive 
date. 
−
If the date is completely missing but the reason for death is present, the death date will be 
imputed as the last known date alive. 
•
For date of progression after start of study therapy, the following conventions will be used for 
imputing partial dates: 
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. In case of the date of death is present and complete, the imputed progression 
date will be compared to the date of death. The minimum of the imputed progression date 
and date of death will be considered as the date of progression. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
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•
For date of progression to prior therapies, the following conventions will be used for imputing 
partial dates: 
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
•
For other partial/missing dates, the following conventions were used: 
−
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day. 
−
If both the day and the month are missing, “July 1” will be used to replace the missing 
information. 
−
If a date is completely missing, it will be considered as missing. 
The following conversion factors will be used to convert days to months or years: 
1 month = 30.4375 days and 1 year = 365.25 days.
Duration (e.g. time-to onset, time-to resolution) will be calculated as follows:
Duration = (Last date - first date + 1)
Last known alive date will be defined based on all appropriate dates collected on the CRF.
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
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10
DOCUMENT HISTORY
Table 10-1:
Document History
Version 
Number
Date
Author
Description
1
06APR2020
Original version
2
14JUL2020
-changed PD-L1 CPS stratification factor to 
consistently have 3 categories throughout 
document
-Sections 2.1, 
 and 6.2.1- added 
information on CPS rescore for certain subjects 
and the rescore will be the primary value used 
for those subjects.
-updated wording of PD-L1 in multiple spots to 
read PD-L1 CPS.
Section 8 was switched with section 9 so 
conventions come at the end of the SAP.
-Section 7.2.1 - added analysis for All 
Randomized LAG-3 Positive Subjects
-Section 7.3.2 - added RACE display and 
REGION display.
-Section 2.1 - changed the wording for the FU 
and survival visits to take directly from the 
protocol.
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APPENDIX 1
TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION AND 
CONVENTIONS FOR SELECT ADVERSE EVENTS, IMMUNE-
MEDIATED ADVERSE EVENTS AND EVENTS OF SPECIAL 
INTEREST
Time-to onset definition
Time-to onset of AE (any grade) for a specific category is defined as the time between the day of 
the first dose of study treatment and the onset date of the earliest AE (of any grade) in this category.
The time-to onset of AE (grade 3-5) for a specific category is defined similarly with an onset date 
corresponding to a grade 3-5 AE.
Time-to onset of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
Time-to onset for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Time-to resolution definition
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific category
or subcategory will be collapsed into what will be termed “clustered” AEs. For example, if a 
subject (without pre-treatment AE) experienced an AE from 1st to 5th January, another AE (with 
different PT but within same category) from 6th to 11th January and same AE from 10th to 
12th January, these will be collapsed into one clustered AE from 1st to 12th January.  Table 10-2 is
summarizing key derivation steps for each type of clustered AEs.
Time-to resolution of AE (any grade) for a specific category is defined as the longest time from 
onset to complete resolution or improvement to the grade at baseline among all clustered AEs
experienced by the subject in this category per adverse event criteria category. Events which 
worsened into grade 5 events (death) or have a resolution date equal to the date of death are 
considered unresolved. If a clustered AE is considered as unresolved, the resolution date will be 
censored to the last known alive date. Improvement to the grade at baseline implies that all 
different events in the clustered adverse event should at least have improved to the corresponding 
(i.e. with same preferred term) baseline grade. This measure is defined only for subjects who 
experienced at least one AE in the specific category.
The time-to resolution of AE (grade 3-5) for a specific category is defined similarly with an onset 
date corresponding to a grade 3-5 AE.
Time-to resolution of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
The time-to resolution of AE (any grade or grade 3-5, drug-related or all) where immune 
modulating medication was initiated is defined similarly. For data presentation not restricted to 
IMAE, the additional condition that the subject started an immune modulating medication during 
the longest AE resolution period will be applied.
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Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Table 10-2:
Derivation of Clustered AE
Type of clustered AE
Derivation
Any grade
Collapse any on-treatment AE from the same category
Drug-related of any grade
Collapse any on-treatment drug-related
AE from the same category
Grade 3-5
Collapse any on-treatment AE from the same category.
Resolution will be based on the onset date of the earliest grade 3-
5 records (if no grade 3-5 record, clustered AE is excluded)
Drug-related of Grade 3-5
Collapse any on-treatment drug-related AE from the same 
category
Resolution will be based on the onset date of  the earliest grade 3-
5 record (if no Grade 3-5 record, clustered AE is excluded)
The algorithm for collapsing adverse event records is using the following conventions:
For each subject and specified category, the corresponding adverse event records will be collapsed 
when:
1) Multiple adverse event records have the same onset date.
2) The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).
3) The onset date of an event record is after the onset date and prior to or on the resolution date 
of a preceding event record (overlapping events).
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APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS
Procedures – Imputation Rules. 
If reported procedure start date is a full valid date then set start date equal to the date part of 
procedure start date. 
In case of partial date use imputation rules described below: 
•
If only day is missing then 
−
If month and year of procedure match month and year of first dose date then impute as date 
of first dose; 
−
If month and year of procedure don't match month and year of first dose date then impute 
as first day of that month and year. 
•
If both day and month are missing, then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
Note: Imputation is not applicable to data where start date is not collected (for example "PRIOR 
RADIOTHERAPY" CRF). Set start date to missing in this case. 
If reported end date is a full valid date then set end date equal to the date part of the reported end 
date. 
In case of partial date use imputation rules described below: 
•
If reported end date is partial then set end date equal to the last possible reported end date based 
on the partial entered reported end date. 
•
If reported end date is missing, continuing, unknown or invalid then set end date equal to the 
most recent database extraction date. 
If end date was imputed then compare end date to the death date or last known alive date if subject 
is not dead. If posterior then end date should be imputed to death date (or last known alive date if 
subject not dead). 
Note: Imputation of partial dates only applies to data entered on "RADIOTHERAPY” CRF page. 
For other CRF pages in case of partial dates set end date to missing.  
Surgeries – Imputation Rules. 
If reported surgery date is a full valid date then set start date equal to the date part of surgery date. 
In case of partial date, use one of the two imputation rules described below: 
A. For data collected on "PRIOR SURGERY RELATED TO CANCER" CRF page: 
•
If only day is missing then impute as the first day of the month; 
•
If both day and month are missing then then impute as 01JAN of the year; 
•
If date is completely missing or invalid then leave missing. 
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B. For data collected on other CRF pages (deemed to be on-treatment/subsequent surgeries): 
•
If only day is missing then 
−
If month and year of surgery match month and year of first dose date then impute the 
missing date as the date of first dose; 
−
If month and year of surgery don't match month and year of first dose date then impute as 
first day of that month and year; 
•
If both day and month are missing then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
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11
REFERENCES
8
Brookmeyer R. and Crowley J. A confidence interval for the median survival time. Biometrics 
38:29-41, 1982
9
Klein, J. P. and Moeschberger, M. L. (1997), Survival Analysis: Techniques for Censored and 
Truncated Data, New York: Springer-Verlag
10 Global Biometric Sciences, SAS Analysis Dataset Specification, Unique Adverse Events. 
Version 2.0, April 22, 2015
11
Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in the 
case of the binomial". Biometrika 26: 404–413.
14 Greenwood, M. The errors of sampling of the survivorship tables, Reports on Public Health 
and Statistical Subjects, 33, Appendix 1, HMSO, London, 1926
15 Kalbfleisch, J. D. and Prentice, R. L. (1980), The Statistical Analysis of Failure Time Data, 
New York: John Wiley & Sons.
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16 Adverse Event Domain Requirements Specification Bristol Myers Squibb Co. PRI. Version 
2.3.0 April 23, 2018
17 Non-Study Medication Domain Requirements Specification Bristol Myers Squibb Co. PRI. 
Version 2.10.0 April 23, 2018
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