A Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-ONcology Study in Participants With Advanced Gastric Cancer (FRACTION-Gastric Cancer)
Phase: PHASE2
Conditions: Advanced Gastric Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-ONcology Study in 
Participants With Advanced Gastric Cancer (FRACTION-Gastric Cancer) 
 
PROTOCOL CA018-003 
 
NCT Number: NCT02935634 
  
Document Date (Date in which document was last revised): August 13, 2021 

Page:
1
Protocol Number:
CA018003
IND Number:
131,283
EUDRACT Number:
2016-002807-24
Date:
12-Aug-2016
Revised Date:
13-Aug-2021
CLINICAL PROTOCOL CA018003
A Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-ONcology Study in 
Participants with Advanced Gastric Cancer (FRACTION-Gastric Cancer)
Protocol Amendment Number: 06
Incorporates Administrative Letters 03 and 04
Clinical Trial Physician - Medical Monitor
Bristol Myers Squibb Company
3401 Princeton Pike Lawrenceville, NJ 08648 
Phone 
email: 
  
Clinical Scientist
Bristol Myers Squibb Company
3401 Princeton Pike Lawrenceville, NJ 08648 
Phone 
email: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
Route 206 & Province Line Road
Lawrenceville, NJ 08543
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 
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).
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CA018003
BMS-986217
FRACTION-Gastric Cancer
Protocol Amendment No.: 06
Date: 13-Aug-2021
2
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 06
13-Aug-2021
Due to early closure of the trial for reasons unrelated to safety, the study 
schedule was adjusted to remove retreatment/re-randomization options, 
Response Follow-up, and Survival Follow-up periods for all parts of the 
study. No changes were made to the Treatment period or Safety Follow-
up period.
Administrative 
Letter 04
30-Sep-2020
Updates to staff/contact information for the Medical Monitor
Administrative 
Letter 03
12-Dec-2019
Updates to staff/contact information for the Medical Monitor
Revised Protocol 
05
13-Sep-2019
The nivolumab management algorithms (Appendix 6) were updated to 
include the myocarditis adverse event management algorithm. Esophagus 
Cancer Subscale (ECS) from the Functional Assessment of Cancer 
Therapy-Esophageal (FACT-E) patient-reported outcome assessment was 
added. Medical Monitor/Study Direction information was updated.
Revised Protocol 
04
03-May-2019
Collection timing and assessment of pretreatment tumor biopsy was 
clarified. Additional approval information for pembrolizumab was added. 
Option to utilize a local pathologist for tumor biopsy assessments was 
removed. Language was updated to indicate that vaccines containing 
live/attenuated viruses are prohibited. Processing of tumor biopsies was 
updated. Language describing participants who are imprisoned and 
Appendix 02 (Study Governance Considerations) were updated to align 
with the current BMS Protocol Model Document.
Administrative 
Letter 02
05-Mar-2019
Screening biopsy requirement was corrected.
Revised Protocol 
03
05-Feb-2019
The FRACTION-Gastric Master Protocol was revised to expand 
indication to esophageal cancer based on the results of CheckMate-032 
clinical study. Added clarification on timing and eligibility for efficacy 
assessment scans at FU1 and FU3. 
Administrative 
Letter 01
24-Jul-2018
Change in Medical Monitor Information
Revised Protocol 
02
14-Dec-2017
Revised to allow participants to continue on study treatment for up to 2 
years, and re-treatment is not permitted.
Stratification by PD-L1 is no longer a factor.
Typographical errors were corrected.
Revised Protocol 
01
15-Sep-2016
Incorporates Amendment 01
Amendment 01
15-Sep-2016
Typographical errors were corrected, and clarifications were made for 
consistency.
Original Protocol
12-Aug-2016
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 06:
Due to early closure of the trial for reasons unrelated to safety, the study schedule was adjusted to 
remove retreatment/re-randomization options, Response Follow-up, and Survival Follow-up 
periods for all parts of the study. No changes were made to the Treatment period or Safety Follow-
up period.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number 
& Title
Description of Change
Brief Rationale
Title page
Updated medical monitor and clinical scientist 
information.
Administrative update.
Synopsis
Removed follow-up text from study design.
These changes were made 
to clarify the removal of 
the option for treatment 
beyond progression.
Section 2, Schedule of 
Activities
1.
Removed Response/Survival Follow-up column in
Table 2-3.
2.
Footnote “b” in Table 2-3 is no longer applicable as
of Protocol Amendment 06.
3.
Added text in footnote “c” in Table 2-3 about
monitoring safety.
These changes were made 
to clarify the removal of 
the retreatment/re-
randomization option, 
Response Follow-up, and 
Survival Follow-up periods 
for the study.
Section 3.3, 
Benefit/Risk 
Assessment
Added language on the risk assessment of non-live 
COVID-19 vaccination.
This change was made to 
address unknown effects of 
newly available COVID-19 
vaccines.
Section 5.1.1, 
FRACTION-Gastric 
Cancer Tracks 1 and 2 
Design
1.
Updated FRACTION-Gastric Cancer Tracks 1 and 2
design follow-up description.
2.
Removed Response/Survival Follow-up Phase text
from footnote “c” in Figure 5.1.1-1, and marked
footnotes “d”, “e”, and “f” as not applicable as of
Protocol Amendment 06.
These changes were made 
to clarify the removal of 
the retreatment/re-
randomization option, 
Response Follow-up, and 
Survival Follow-up periods 
for the study.
Section 5.1.3, Study 
Phases
1.
Updated the number of phases of the study from 4 to
3 phases.
2.
Removed Response and Survival Follow up text.
3.
Removed reference to subject treatment beyond
progression.
4.
Added text about discontinuing the collection of
biological samples for reasons other than safety
monitoring.
5.
Added text to allow stopping Survival Follow ups as
of Protocol Amendment 06.
These changes were made 
to clarify the removal of 
Response Follow-up, 
Survival Follow-up 
periods, and collection of 
biological samples 
(nonsafety) for the study.
Section 7.4.2, 
Treatment Beyond 
Disease Progression
Removed treatment beyond disease progression text and 
replaced with “Not applicable per Protocol Amendment 
06.”
These changes were made 
to clarify the removal of 
the option for treatment 
beyond progression.
Protocol Amendment No.: 06
Date: 13-Aug-2021
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number 
& Title
Description of Change
Brief Rationale
Section 7.7.3, 
Permitted Therapy
Added text permitting non-live COVID-19 vaccination.
This change was made to 
adopt the BMS guidance 
allowing the use of 
COVID-19 vaccination and 
clarifying that the safety of 
such vaccines in study 
participants receiving 
investigational agents is 
unknown.
Section 8.1.3, Post
Study Treatment
Follow-up
Specified that participants will continue to be followed 
for safety and removed text about Survival Follow up.
These changes were made 
to clarify the removal of 
Survival Follow up for the 
study.
Section 9, Study 
Assessments and 
Procedures
1.
Updated text in Section 9.1 to clarify discontinuation 
of efficacy assessments.
2.
Added text in Section 9.5 about discontinuing
on-treatment and post-treatment PK sample
collection.
3.
Added text in Section 9.6 about discontinuing 
on-treatment and post-treatment pharmacodynamic 
assessment collection.
4.
Added text in Section 9.8 about discontinuing 
on-treatment and post-treatment biomarker 
assessment collection.
These changes were made 
to clarify the removal of 
collection of biological 
samples (nonsafety) for the 
study.
Appendix 2, Study 
Governance 
Considerations
1.
Added text about remote monitoring.
2.
Added text on the dissemination of clinical study 
data.
1. To clarify conditions 
where remote monitoring 
can be considered.
2. To clarify disclosure of 
study data in compliance 
with national and 
international standards.
Throughout Document
Updated “subject” terminology to “participant” 
throughout the document, where applicable.
This update was made to 
ensure alignment and 
consistency regarding 
terminology throughout the 
document.
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Date: 13-Aug-2021
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 06: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06 ................ 
 
TABLE OF CONTENT ................................................................................................ 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 FRACTION Program ............................................................................... 
 
3.1.1.1 Rationale for the FRACTION Program .......................................... 
 
3.1.1.2 Specific Attributes of the FRACTION Program Design ................. 
 
3.1.1.3 Rationale for Biomarker Assessments ............................................ 
 
3.2 Background ....................................................................................................... 
 
3.2.1 FRACTION-Gastric Cancer .................................................................... 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
3.3.1 Safety Monitoring on Study Treatment .................................................... 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 FRACTION-Gastric Cancer Tracks 1 and 2 Design ............................... 
 
5.1.2 Safety Monitoring Board and Other External Committees ...................... 
 
5.1.3 Study Phases ............................................................................................ 
 
5.1.3.1 Screening ......................................................................................... 
 
5.1.3.2 Treatment ........................................................................................ 
 
5.1.3.3 Follow-up ........................................................................................ 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.4.1 Rationale for Duration of Therapy .......................................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening ..................................................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Dose Reductions and Delays and Criteria to Resume Dosing ................ 
 
7.4.2 Treatment Beyond Disease Progression .................................................. 
 
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7.4.3 Management Algorithms for IO and Oncology Agents ........................... 
 
7.4.4 Treatment of Treatment-related Infusion Reactions ................................ 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability / Bioequivalence / Biocomparability
..................................................................................................................... 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
 
7.7.3 Permitted Therapy ................................................................................... 
 
7.7.4 Palliative Local Therapy .......................................................................... 
 
7.7.5 Supportive Care Management ................................................................. 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Permanent Discontinuation ..................................................................... 
 
8.1.2 Study Treatment Combination Arm Discontinuation Criteria ................. 
 
8.1.3 Post Study 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............................................................ 
 
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 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.2 Imaging Safety Assessment ...................................................................... 
 
9.5 Pharmacokinetic ................................................................................................ 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
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9.8.5 Immunogenicity Assessments ................................................................... 
 
9.8.10 Other Assessments ................................................................................. 
 
9.9 Medical Resource Utilization and Health Economics ...................................... 
 
9.9.1 Patient-reported Outcomes ...................................................................... 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.1.1 Track 1 - Anti-PD-1, Anti-PD-L1, and Anti-CTLA-4 Treatment-naïve 
Participants ................................................................................................. 
 
10.1.2 Track 2 - Anti-PD-1, Anti-PD-L1, or Anti-CTLA-4 Treatment-
experienced Participants ............................................................................ 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.3 Other Analyses ....................................................................................... 
 
10.3.3.1 Pharmacokinetic Analyses ............................................................ 
 
10.3.3.2 Immunogenicity Analyses.............................................................. 
 
10.3.3.3 Exploratory Biomarker Analyses .................................................. 
 
10.3.3.4 Outcomes Research Analyses ....................................................... 
 
10.3.4 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 RECIST V1.1 ........................................................................................ 
 
APPENDIX 6 NIVOLUMAB MANAGEMENT ALGORITHMS ............................. 
 
APPENDIX 7 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 8 COUNTRY SPECIFIC REQUIREMENTS ......................................... 
 
 
 
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APPENDIX 9 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
 
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Clinical Protocol
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CA018003
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CA018003
BMS-986217
FRACTION-Gastric Cancer
1
SYNOPSIS
Protocol Title: A Phase 2, Fast Real-time Assessment of Combination Therapies in 
Immuno-ONcology Study in Participants with Advanced Gastric Cancer (FRACTION-Gastric 
Cancer)
Study Phase: Phase 2
Rationale:
To determine which combinations show the most clinical promise and thus should be prioritized 
for registrational studies; Bristol-Myers Squibb Company (BMS) has initiated the Fast Real-time 
Assessment of Combination Therapy in Immuno-ONcology (FRACTION) Program (globally 
listed under the descriptor BMS-986217). The FRACTION Program will employ repeat core 
biopsies and serial assessments with different treatment options. Novel study treatment 
combinations and/or additional controls will be appended as FRACTION-Gastric Cancer 
Sub-Protocols. These FRACTION-Gastric Cancer Sub-Protocols will evaluate the safety profile, 
tolerability, preliminary efficacy, pharmacokinetic (PK), and pharmacodynamics of novel study 
treatment combinations in participants with advanced gastric cancer (GC).
Study Population:
Male and female participants, aged 18 years and older, with inoperable, advanced, or metastatic 
esophageal cancer (EC), gastric cancer (GC) or gastroesophageal junction (GEJ) carcinoma and 
have histologically confirmed predominant adenocarcinoma and/or squamous carcinoma, may be 
eligible for the study. The documentation of GEJ involvement can include biopsy, endoscopy, or 
imaging. 
Track-specific eligibility criteria are as follows:
•
Track 1: anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and anti-
cytotoxic T-lymphocyte antigen 4 (CTLA-4) treatment-naïve participants
−
Participants must not have received any anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment 
prior to this study. Participants previously treated with agents other than anti-PD-1, anti-
PD-L1, or anti-CTLA-4 are eligible for Track 1.
−
Participants may have been offered platinum-based chemotherapy for progressive or 
recurrent disease.
♦The platinum-based chemotherapy may have been in the adjuvant, neoadjuvant, or 
recurrent setting.
−
Participants will be required to submit a fresh tumor biopsy.
•
Track 2: anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment-experienced participants
−
Participants must have had progressive or recurrent disease during or after anti-PD-1, 
anti-PD-L1, or anti-CTLA-4 treatment. (Participants treated with any study treatment 
targeting PD-1, PD-L1, or CTLA-4 will be considered anti-PD-1, anti-PD-L1, or 
anti-CTLA-4 treatment experienced, respectively.) 
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−
Participants may have been offered platinum-based chemotherapy for progressive or 
recurrent disease.
♦The platinum-based chemotherapy may have been in the adjuvant, neoadjuvant, or 
recurrent setting.
−
Participants who have had prior treatment with any 1 of the agents (or any other agent 
targeting PD-1, PD-L1, or CTLA-4) in monotherapy or in any combination regimen in a 
FRACTION-Gastric Cancer Sub-Protocol are eligible for treatment on Track 2. 
−
Participants who have had prior combination treatment with the same immuno-oncology
(IO) combination agents (or IO agents directed against the same targets) as 1 of the 
combination regimens in a FRACTION-Gastric Cancer Sub-Protocol are eligible for study 
treatment on Track 2 but must be randomized to another combination regimen.
−
Participants will be required to submit a fresh tumor biopsy.
Objectives and Endpoints:
Objectives
Endpoints
Primary
•
To assess the efficacy (ORR, DOR, and PFSR at 24 
weeks) of each FRACTION-Gastric Cancer study 
treatment combination (relative to nivolumab in 
combination with ipilimumab, when applicable) in 
participants with advanced GC and/or EC
•
ORR defined as the proportion of all treated 
participants with a BOR of CR or PR as 
assessed per RECIST v1.1 by investigator, 
median DOR, and PFSR at 24 weeks 
Secondary
•
To investigate additional safety and tolerability of each 
FRACTION-Gastric Cancer study treatment combination 
in participants with advanced GC and/or EC
•
Incidence of AEs, SAEs, AEs leading to 
discontinuation, 
deaths, 
and 
clinical 
laboratory test abnormalities 
Tertiary/Exploratory
•
To assess the pharmacodynamic effects as a function of 
exposure, by evaluation of select biomarkers 
 
•
To explore potential associations between anti-tumor 
activity or safety and select biomarker measures
 
 
•
To evaluate the PK of each IP component
•
To evaluate the immunogenicity of each IP, when 
applicable
•
To assess the OS in treated participants 
•
To evaluate disease-related symptom improvement, as 
measured by the GaCS of the FACT-Ga and the ECS of 
the FACT-E in treated participants
•
To evaluate general health, functional status, and utility 
for health using the EQ-5D-3L in treated participants 
•
Summary measures of change (or % change) 
from baseline or baseline level biomarker 
measurements 
 
 
•
Correlation (or similar appropriate measure of 
association) 
of 
biomarker 
measure 
 
 with 
parameters of interest
•
Summary measures of PK parameters from 
serum concentration
•
Incidence of ADAs
•
OS rate at certain time points
•
Summary measures of EQ-5D-3L index and 
VAS scores, GaCS scores, and/or ECS scores,
and corresponding change form baselines for 
each score
Abbreviations: ADA = anti-dug antibody; AE = adverse event; BOR = best overall response; CR = complete 
response; DOR = duration of response; EQ 5D-3L = 3-level version of EQ-5D self-report questionnaire; EC = 
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esophageal cancer; ECS = Esophagus Cancer Subscale; FACT-E = Functional Assessment of Cancer Therapy-
Esophageal; FACT-Ga = Functional Assessment of Cancer Therapy-Gastric; GaCS = Gastric Cancer Subscale; 
GC=gastric cancer; IP = investigational product; ORR = objective response rate; OS = overall survival; 
PFSR = progression-free survival rate; PK = pharmacokinetic; PR = partial response; RECIST = Response 
Evaluation Criteria in Solid Tumors; SAE = serious adverse event; VAS = visual analog scale
Overall Design:
This is a rolling, Phase 2, adaptive study that will evaluate the preliminary efficacy, safety, 
tolerability, PK, and pharmacodynamics of novel FRACTION-Gastric Cancer study treatment 
combinations in participants with advanced GC and/or EC. The details pertaining to the specific 
study treatment regimens are provided in each FRACTION-Gastric Cancer Sub-Protocol. 
Participants will be enrolled in 1 of the 2 tracks. Participants who are anti-PD-1, anti-PD-L1, and
anti-CTLA-4 treatment naïve will be enrolled for Track 1. Participants who have had prior 
anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment will be assigned to Track 2.
Participants on Tracks 1 and 2 will begin on the Treatment Phase (with a total duration of 
approximately 2 years). Tumor assessments will be conducted according to the timing described 
in each FRACTION-Gastric Cancer Sub-Protocol. 
Participants in Tracks 1 and 2 will be treated until completion of the Treatment Phase, progression, 
toxicity, or protocol-specified discontinuation. 
Number of Participants: 
For Sub-Protocols utilizing a Simon-2 stage (optimal) design, up to 54 anti-PD-1/PD-L1 or anti-
CTLA-4 treatment-naive participants will be treated per study treatment combination in Track 1. 
In Track 2, up to 41 participants will be treated per study treatment combination.
For Sub-Protocols not utilizing a Simon-2 stage (optimal) design, a different sample size may be 
used depending on the statistical considerations for those treatment combinations. In those cases, 
sample size will be discussed within the individual Sub-Protocols.
Treatment Arms and Duration and Study Treatments:
Specific dosing and treatment regimens for each FRACTION-Gastric Cancer study treatment 
combination are outlined in each FRACTION-Gastric Cancer Sub-Protocol.
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2
SCHEDULE OF ACTIVITIES
Study assessments and procedures are presented in Table 2-1 (Screening Procedural Outline), 
Table 2-2 (Baseline for Re-randomization Procedural Outline), and Table 2-3 (Follow-up 
Procedural Outline). The On-treatment Procedural Outline(s) and exceptions for study treatment 
combination arms are included in each Fast Real-time Assessment of Combination Therapy in 
Immuno-ONcology (FRACTION)-Gastric Cancer Sub-Protocol.
Protocol Amendment No.: 06
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FRACTION-Gastric Cancer
Table 2-1:
Screening Procedural Outline
Procedure
Screening 
Visita
Notes
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol-specific informed consent is signed. 
Obtain patient identification number via IRT after signing of the written informed consent.
Utilize IRT
X
Obtain patient identification number. After completing all screening procedures, utilize IRT to 
either screen fail or obtain randomization information, as applicable. Randomization can occur 
up to 7 days prior to first dose. In limited circumstances, if patients cannot be treated within 7
days of randomization due to a study-related test, the duration can be extended after discussion 
with the medical monitor.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first 
dose.
Medical History
X
Includes prior conditions and any toxicities or allergies related to previous treatments 
Collect Data on Prior Anti-PD-1, 
Anti-PD-L1, or Anti-CTLA-4 Treatment
Exposure
X
Prior to screening for the protocol, investigative sites are required to determine the 
participant’s exposure to anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment. Those data will be 
collected as part of the Screening Phase. Toxicities from prior immunotherapies with details 
on timing, treatment, and resolution, if applicable, should be captured.
Prior Therapy
X
Radiotherapy/surgery/systemic therapy administered for the treatment of gastric cancer
Safety Assessments
Physical Examination
X
If the screening physical examination is performed within 24 hours prior to dosing on Day 1, 
then a single examination may count as both the screening and predose evaluation.
Oxygen Saturation
X
Record at rest and after mild to moderate exertion via pulse oximetry to establish baseline. 
If participant has oxygen saturation ≤90%, consult the BMS Medical Monitor (or designee) 
prior to enrollment.
Physical Measurements
X
Include height and weight
Vital Signs
X
Include body temperature, seated blood pressure, and heart rate 
ECOG Performance Status
X
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FRACTION-Gastric Cancer
Table 2-1:
Screening Procedural Outline
Procedure
Screening 
Visita
Notes
12-lead ECG
X
ECGs should be recorded after the participant has been supine for at least 5 minutes. Record 
QTcF. If ECG abnormality is noted, a repeat ECG must be performed.
Chest X-ray
X*
*Optional 
Concomitant Medication Collection
X
Includes medications taken within 14 days prior to assigned study treatment
Assessment of Baseline Signs and 
Symptoms
X
Assess within 14 days prior to first dose of study treatment.
Laboratory Tests
Include blood and urine samples
Hematology
X
Includes CBC with differential including platelets 
Serum Chemistryb
X
See Section 9.4.1.
Thyroid Function Panelb
X
If TSH is abnormal, then obtain free T3 and T4. 
Serology
X
Perform testing for Hepatitis A IgM and IgG antibodies, HBsAg, hepatitis C antibody (if 
hepatitis C antibody is positive, reflex to hepatitis C RNA), or hepatitis C RNA. 
(Note: Testing for HIV-1 and HIV-2 must be performed at sites where mandated by local 
requirements. For sites in Germany, see Appendix 8.)
Pregnancy Serum or Urine Test
X
For WOCBP only. Serum or urine, within 24 hours prior to first dose of assigned study 
treatment. An extension of up to 72 hours prior to start of study treatment is permissible in 
situations where results cannot be obtained within the standard 24-hour window.
Follicle Stimulating Hormone 
X
For women only. Refer to Appendix 4. 
Mandatory Pretreatment Tumor Biopsy
X
Biopsy must be performed during the Screening Phase in all participants prior to 
randomization. 
Tumor tissue must be 
obtained from a primary or metastatic site. Adequacy of tumor tissue must be confirmed by
central laboratory prior to randomization孱(Note: Fine needle aspiration and bone metastases 
samples are not acceptable for submission.)
Archival Tumor Tissue Block
X
An archival, formalin-fixed, paraffin-embedded tumor tissue block (preferred) or a minimum 
of 20 slides of samples from a primary or metastatic site should be provided by all 
participants, if available.
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FRACTION-Gastric Cancer
Table 2-1:
Screening Procedural Outline
Procedure
Screening 
Visita
Notes
Efficacy Assessment
Baseline Tumor Assessment
X
Assessed by RECIST v1.1 criteria (see Appendix 5)
Disease assessment with contrast-enhanced CT/MRI scans acquired on dedicated CT/MRI 
equipment is preferred for this study. CT or MRI of the chest, abdomen, pelvis孯and all known 
sites of disease should be performed within 28 days prior to first dose of study treatment. 
Assessment must include other anatomic regions, as indicated based on the participant’s tumor 
type and/or disease history.
Participants with a history of brain metastasis should have an MRI (preferred) or CT of the 
brain. 
Participants with a history of bone metastasis should have a bone scan.
AE Reporting
SAEs
X
All SAEs must be collected from the date of the participant’s written consent until 100 days 
post-discontinuation of dosing or participant’s participation in the study if the last scheduled 
visit occurs at a later time. All SAEs and AEs will be assessed using NCI CTCAE 
Version 4.03.
a Within 28 days of first dose of assigned study treatment unless specified in notes section.
b If a participant is screened and begins study treatment within 3 days, the laboratory assessments for the Screening Phase can be used for Day 1 of the On-treatment 
Procedural Outline in each FRACTION-Gastric Cancer Sub-Protocol as well.
Abbreviations: AE = adverse event; BMS = Bristol-Myers Squibb Company; CBC = complete blood count; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; CTLA-4 = cytotoxic T-lymphocyte antigen 4; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IgG = immunoglobin G; IgM = immunoglobin M; IRT = Interactive Response 
Technology; MRI = magnetic resonance imaging; NCI = National Cancer Institute; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; QTcF = 
QT interval corrected with Fridericia’s formula; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; SAE = serious adverse event; 
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of child-bearing potential.
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Table 2-2:
Baseline for Re-randomization Procedural Outline
Procedure
Days -1 
to -28a
Notes
Eligibility Assessments
X
Participants must continue to meet eligibility criteria. All inclusion/exclusion criteria 
should be assessed at the retreatment/re-randomization baseline visit and confirmed 
prior to first dose.
Informed Consent
X
Participants must sign informed consent for retreatment/re-randomization.
Participant Registration for Retreatment/Re-
randomization
X
Ensure participant continues to meet eligibility for study treatment. 
Safety Assessments
Physical Examination
X
If the retreatment/re-randomization baseline physical examination is performed 
within 24 hours prior to dosing on Day 1, then a single examination may count as 
both the retreatment/re-randomization baseline and predose evaluation.
Physical Measurements
X
Include weight
Vital Signs
X
Include body temperature, seated blood pressure, and heart rate 
ECOG Performance Status
X
12-lead ECG
X
ECGs should be recorded after the participant has been supine for at least 5 minutes. 
Record QTcF. If ECG abnormality is noted, a repeat ECG must be performed.
Concomitant Medication Collection
X
Includes medications taken within 14 days prior to study treatment
Oxygen Saturation
X
Record at rest and after mild to moderate exertion via pulse oximetry to establish 
baseline. 
If participant has oxygen saturation ≤90%, consult BMS Medical Monitor (or 
designee) prior to entering retreatment/re-randomization.
Assessment of Baseline Signs and Symptoms
X
If re-baseline or re-randomization occurs > 100 days after the last dose, signs and 
symptoms that occur up to 14 days prior to the next dose of study treatment should 
be recorded. 
Laboratory Tests
Include blood and urine samples 
Hematology
X
Includes CBC with differential including platelets
Serum Chemistryb
X
See Section 9.4.1.
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Table 2-2:
Baseline for Re-randomization Procedural Outline
Procedure
Days -1 
to -28a
Notes
Thyroid Function Panelb
X
If TSH is abnormal, then obtain free T3 and T4. 
Serology
X
Serology must be collected if > 6 months has passed since the previous assessment. 
Perform testing for Hepatitis A IgM and IgG antibodies, HBsAg, hepatitis C 
antibody (if hepatitis C antibody is positive, reflex to hepatitis C RNA), or hepatitis 
C RNA. (Note: Testing for HIV-1 and HIV-2 must be performed at sites where 
mandated by local requirements.)
Pregnancy Serum or Urine Test
X
For WOCBP only. Serum or urine, within 24 hours prior to first dose of assigned 
study treatment. An extension of up to 72 hours prior to start of study treatment is 
permissible in situations where results cannot be obtained within the standard 24-
hour window.
Follicle Stimulating Hormone
X
For women only. Refer to Appendix 4. 
Mandatory Pretreatment Tumor Biopsy
X
A mandatory pretreatment fresh tumor biopsy must be performed if a progression 
biopsy from the current study is not available. 
Sufficient tumor tissue must be obtained before start of study treatment from a 
primary or metastatic site. Tumor tissue samples must be shipped from site to central 
laboratory prior to retreatment/re-randomization. (Note: Fine needle aspiration and 
bone metastases samples are not acceptable for submission.)
Efficacy Assessments
Baseline Tumor Assessment
X
Assessed by RECIST v1.1 criteria (see Appendix 5)
Disease assessment with contrast-enhanced CT/MRI scans acquired on dedicated 
CT/MRI equipment is preferred for this study. CT or MRI of the chest, abdomen, 
pelvis, and all known sites of disease should be done within 28 days prior to first 
dose of study treatment. Assessment must include other anatomic regions, as 
indicated based on the participant’s tumor type and/or disease history.
Participants with a history of brain metastasis should have an MRI (preferred) or CT 
of the brain, or if clinically indicated. 
Participants with a history of bone metastasis should have a bone scan, or if clinically 
indicated.
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Table 2-2:
Baseline for Re-randomization Procedural Outline
Procedure
Days -1 
to -28a
Notes
AE Reporting
SAEs
X
All SAEs must be collected from the date of the participant’s written consent until 
100 days postdiscontinuation of dosing or participant’s participation in the study if 
the last scheduled visit occurs at a later time. All SAEs and AEs will be assessed 
using NCI CTCAE Version 4.03.
a Within 28 days of first dose of assigned study treatment unless otherwise specified in notes section.
b If a participant is screened and begins study treatment within 3 days, the laboratory assessments for the Screening Phase can be used for Day 1 of the On
treatment- Procedural Outline in each FRACTION-Gastric Cancer Sub-Protocol as well.
Abbreviations: AE = adverse event; BMS = Bristol-Myers Squibb Company; CBC = complete blood count; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HBsAg = hepatitis B surface antigen; 
HIV = human immunodeficiency virus; IgG = immunoglobin G; IgM = immunoglobin M; MRI = magnetic resonance imaging; NCI = National Cancer Institute;
PK = pharmacokinetic; QTcF = QT interval corrected with Fridericia’s formula; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic 
acid; SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of child-bearing potential.
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FRACTION-Gastric Cancer
Note: On-treatment Procedural Outlines are in the relevant FRACTION-Gastric Cancer Sub-Protocol
Table 2-3:
Follow-up Procedural Outline
Safety Follow-upa
Procedure
FU 1
30 Days
(± 7 Days) 
FU 2
60 Days
(± 7 Days)
FU 3
100 Days
(± 7 Days)
Notes
Safety Assessments
Physical Examination 
X
X
X
Oxygen Saturation
X
As clinically indicated
Record at rest and after mild to moderate 
exertion via pulse oximetry.
Vital Signs and Weight
X
X
X
Includes body temperature, seated blood 
pressure, and heart rate 
ECOG Performance Status
X
X
X
Review of Concomitant 
Medications
X
X
X
Laboratory Tests
Hematology and Serum 
Chemistry
X
X
PK Samplesc
X
Details are provided in each FRACTION-
Gastric Cancer Sub-Protocol.
Anti-drug Antibody Samplesc
X
Details are provided in each FRACTION-
Gastric Cancer Sub-Protocol.
AE Reporting
Monitor for Nonserious AEs
X
X
X
Nonserious AEs must be collected from 
first dose until 100 days following the last 
dose of study treatment. All SAEs and AEs 
will be assessed using NCI CTCAE 
Version 4.03.
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Table 2-3:
Follow-up Procedural Outline
Safety Follow-upa
Procedure
FU 1
30 Days
(± 7 Days) 
FU 2
60 Days
(± 7 Days)
FU 3
100 Days
(± 7 Days)
Notes
Monitor for SAEs
X
X
X
All SAEs must be collected from the date of 
the participant’s written consent until 
100 days postdiscontinuation of dosing or 
participant’s participation in the study if the 
last scheduled visit occurs at a later time. All 
SAEs and AEs will be assessed using NCI 
CTCAE Version 4.03.
Efficacy Assessments
Tumor Response 
Assessmentc
X
X
Assessed by RECIST v1.1 criteria (see 
Appendix 5).
Participants with a history of brain 
metastasis should have an MRI (preferred) 
or CT of the brain, if clinically indicated. 
Participants with a history of bone 
metastasis should have a bone scan, if 
clinically indicated.
All participants should receive scans at FU1 
except for participants who started 
subsequent therapy or participants with PD 
who have already been treated beyond 
progression.
Scans at FU3 and every 12 weeks (±14 
days) will only be collected for participants 
with CR, PR, SD, or NE at treatment 
discontinuation.
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FRACTION-Gastric Cancer
Table 2-3:
Follow-up Procedural Outline
Safety Follow-upa
Procedure
FU 1
30 Days
(± 7 Days) 
FU 2
60 Days
(± 7 Days)
FU 3
100 Days
(± 7 Days)
Notes
Patient-reported Outcomes 
Assessmentc
X
X
X
EQ-5D-3L and GaCS and/or ECS
Can be collected by telephone at regularly 
scheduled times
Collection of Survival Status 
and Subsequent Treatment
Informationc
X
X
X
Safety follow-up visits must occur in the 
office. Response (and survival) follow-up 
visits may be performed by telephone 
contact or clinic visit. 
a FU visits at 30, 60, and 100 days (± 7 days) should occur after the last dose of study treatment or coinciding with the date of discontinuation ± 7 days, if the date 
of discontinuation is greater than 30 days after the last dose, to monitor for AEs.
b Not applicable as of Protocol Amendment 06: Additional survival follow-up will be collected every 6 months for 3 additional years (2 years of response follow-
up + 3 years of survival follow-up = total of 5 years of follow-up). BMS may request that survival data be collected on all treated/randomized participants outside 
of the protocol-defined 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 or is lost to follow-up. Withdrawal of consent must be clearly documented. See Section 5.1.3.3 for details.
c As of Protocol Amendment 06: Assessments necessary for monitoring safety (eg, safety labs, oxygen saturation, vital signs, physical exams, review of 
concomitant medications, AE/ SAE reporting, etc) will continue per sub-protocol until the FU 3 visit. Tumor Scans, survival status follow-ups, and collection 
of subsequent treatment information will end once the participant has disease progression, or treatment discontinuation for any reason, whichever occurs first. 
Collection of samples for PK, ADA, biomarkers, as well as collection of data for patient-reported outcomes should be discontinued. The intent is to minimize 
the burden on study participants and site staff.
Abbreviations: AE = adverse event; BMS = Bristol-Myers Squibb Company; CR = complete response; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; ECOG = Eastern Cooperative Oncology Group; ECS = Esophagus Cancer Subscale; EQ-5D-3L = 3-level version of 
EQ-5D self-report questionnaire; FU = follow-up; GaCS = Gastric Cancer Subscale; MRI = magnetic resonance imaging; NCI = National Cancer Institute;
PD = progressive disease; PK = pharmacokinetic; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; 
SD = stable disease.
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In the event that multiple procedures are required at a single time point, the following is a list of procedures from highest priority to 
lowest:
•
Safety (clinical laboratory examinations)
•
Safety (electrocardiogram [ECG])
•
Biomarker sampling
•
Pharmacokinetic (PK) and anti-drug antibody (ADA) sampling
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FRACTION-Gastric Cancer
3
INTRODUCTION
Traditional or conventional treatment options for patients with advanced cancer include surgery, 
radiation, chemotherapy, and hormonal therapy. Despite advances in these therapies, the majority 
of patients with metastatic disease die from progressive disease (PD). Immunotherapeutic 
approaches have demonstrated clinical efficacy and have been approved in multiple countries 
worldwide and in several solid tumor malignancies, including melanoma, renal cell, lung, and 
hormone-refractory prostate cancers.1,2 Tumors may modulate and evade the host immune 
response through a number of mechanisms, including downregulation of tumor-specific antigen 
expression and presentation, secretion of anti-inflammatory cytokines, and upregulation of 
inhibitory ligands. -T-cell checkpoint regulators such as cytotoxic T-lymphocyte-antigen 4 
(CTLA-4; see Appendix 1) and programmed death-1 (PD-1, cluster of differentiation [CD] 279) 
are cell surface molecules that, when engaged by their cognate ligands, induce signaling cascades 
that downregulate T-cell activation and proliferation. One proposed model by which therapeutic 
T-cell checkpoint inhibitors derive anti-tumor activity is through breaking of immune tolerance to
tumor cell antigens by T-cell activation and proliferation.
Following on the success of anti-CTLA-4 and anti-PD-1 pathway-targeted agents in several 
cancers, the field of tumor immunotherapy is rapidly expanding. In addition to blocking these and 
other co-inhibitory pathways such as lymphocyte activation gene 3 (LAG-3), activating 
co-stimulatory pathways to potentiate anti-tumor immune responses is being evaluated as a 
promising approach.3 Members of the tumor necrosis factor receptor super family (TNFRsf) 
include several co-stimulatory proteins with key roles in B- and T-cell development, survival, 
immune activation, and anti-tumor immune responses.4 Preclinical data have provided the basis 
for clinical studies of agonist antibodies to such TNFRsf co-stimulatory receptors such as 
4-1BB,5,6 OX40,7,8 glucocorticoid-induced tumor necrosis factor receptor-related (GITR)
gene,9,10 and CD27,11,12 along with a growing list of immuno-oncology (IO) targets that modulate
other immunomodulatory mechanisms as potential therapies for patients with cancer. Overall,
enhancement of the magnitude and potency of tumor antigen-specific adaptive cellular responses
by CD8 and CD4 T cells is now considered a major goal in cancer immunotherapy.
With emerging clinical data showing significant activity of single agent immunotherapies, it is 
possible, and indeed likely, that- combination therapies could potentially lead to a greater depth of 
response and an increase in overall survival (OS), as has been noted with the combination of 
anti-PD-1 and anti-CTLA-4 in participants with
advanced melanoma
and renal cell 
carcinoma.13,14,15,16 This raises the possibility that combining agents with a broader range of 
relevant targets (eg, checkpoint blocking antibodies with agonist antibodies to T-cell 
co-stimulatory molecules and immunomodulatory agents) is likely to lead to durable, long-term 
responses and possibly even cures in this high unmet medical need population of patients with 
metastatic or refractory tumors. Preclinical data from evaluation of combinations in mouse tumor 
models indicate that treatment with the combination of IO agents may lead to enhanced anti-tumor 
activity above that from each agent alone.17 Thus, the combination of IO agents has the potential 
to provide clinical benefit to such patients with high unmet medical needs. 
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3.1
Study Rationale
3.1.1
FRACTION Program
3.1.1.1
Rationale for the FRACTION Program
Bristol-Myers Squibb Company (BMS) has an extensive portfolio of novel agents that span a 
variety of targets. Within the immune system, these include T-cell checkpoint inhibitors, 
co-stimulatory molecules acting on T cells, regulatory T cell- and natural killer (NK) cell
targeted- agents孯季treatments that alter the tumor microenvironment to favor a tumor inhibitory 
milieu, 
and 
treatments 
that 
target 
myeloid-derived 
suppressor 
cells 
or 
tumor-
associated- macrophages. In addition to agents that target the immune system, BMS has a portfolio 
of agents that directly target tumor cells. These include antibody drug conjugates and both biologic 
and small molecule inhibitors of key signaling pathways. In fact, the number of compounds to be 
evaluated has grown so large that it is no longer possible or efficient to test all possible 
combinations in a standard clinical Phase 1 or Phase 2 setting.
To determine which combinations show the most clinical promise and thus should be prioritized 
for registrational studies, BMS has initiated the FRACTION Program 孫globally listed under the 
descriptor, BMS-986217). The FRACTION Program will employ repeat core biopsies and serial 
assessments with different treatment options. These approaches are supported by the National 
Cancer Institute (NCI) Biomarker孰integrated Approaches of Targeted Therapy for Lung Cancer 
Elimination (BATTLE) program,18 the Investigation of Serial Studies to Predict Your Therapeutic 
Response with Imaging And moLecular Analysis (I-SPY 1/2 TRIAL),19 the Lung-MAP: S1400 
Biomarker-targeted Second-line Therapy in Treating Patients With Recurrent Stage IIIB-IV 
Squamous Cell Lung Cancer (NCT02154490),20 the NCI Molecular Analyses for Therapy Choice 
(NCT02465060), and the American Society of Clinical Oncology’s Targeted Agent and Profiling 
Utilization Registry.21 These studies use innovative trial designs to quickly assess new agents in 
participants with the goal of reducing the time and number of participants required to bring these 
therapies to those who will benefit from them.
The FRACTION Program will consist of several FRACTION studies, each in a specific tumor 
type and with a well-defined participant population. Each FRACTION study will have a Master 
Protocol, which will apply to all study treatment combinations selected for evaluation under that 
tumor-specific FRACTION study and any control treatments. For the FRACTION Program, it is 
intended that combination agents will be IO agents within the BMS pipeline or IO agents already 
approved; however, they may also include small molecule agents or other modalities for which 
there is scientific rationale for combining with an IO agent in a given disease. All novel 
FRACTION combinations will be selected based on sound scientific rationale, supported 
whenever possible and appropriate by in vivo model systems, to demonstrate anti-cancer activity 
and preliminary assessments of clinical tolerability.
Specific study treatment combinations and/or control treatments will be introduced in FRACTION 
Sub-Protocols for each FRACTION study; these Sub-Protocols will be appended to the Master 
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Protocol for that study and will include information appropriate to the study treatment 
combinations and/or control treatments being added to the study, including the preclinical 
rationale, preclinical toxicology孯and clinical safety data, as well as PK and pharmacodynamic 
information (PD), as available. The minimum preclinical safety information provided in each 
Sub-Protocol will include the definitive studies that were used to support the health authorities and
review for each individual agent, along with any additional preclinical safety studies that were 
conducted subsequent to the original applications. In addition, the toxicology rationale to support 
each combination will be discussed. For each agent, the established monotherapy and relevant 
combination clinical safety package from studies done outside of FRACTION will be included. 
Participants within the FRACTION Program will not be the first to be exposed to any treatment. 
Thus, for the FRACTION Program, study treatment combinations that have high potential to 
produce transformational anti-tumor activity compared to the control will be selected based on 
both preclinical and early clinical trials data. The first study in the FRACTION Program, 
Study CA018001, “Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-
ONcology Study in Subjects with Advanced Non-small Cell Lung Cancer (FRACTION-Lung),”
is ongoing. FRACTION-Renal Cell Carcinoma (RCC) is also ongoing.
3.1.1.2
Specific Attributes of the FRACTION Program Design
The specific attributes of the FRACTION Program include the following孽
•
An innovative study design providing participants with advanced cancer the possibility of 
expeditious access to innovative therapies, including combinations with approved treatments 
like nivolumab. In addition, it will provide an ongoing treatment option for participants across 
the spectrum of their disease as they progress through the FRACTION Program, as participants 
can enter into different treatment “Tracks” based upon their treatment exposure and response. 
•
A streamlined decision-making process allowing for more rapid and efficient selection of 
promising treatment options in BMS’s evolving portfolio of oncology assets. This extensive 
pipeline of novel targets and/or agents could result in an excess of 100 individual monotherapy 
and doublet combinations in need of study. The challenges to study all possible combinations 
in a traditional clinical program are daunting, especially since animal models and/or biomarker 
data still cannot effectively predict participant responses. This means that clinical exploration 
in participants is required if it is to be truly informative and would ultimately lead to 
participant’s benefit. Thus, FRACTION is designed as a way to explore and compare multiple 
IO combinations against each other and against a control treatment. 
•
A Master Protocol, in conjunction with appended FRACTION Sub-Protocols, allowing for 
operational efficiencies for the rapid and efficient opening of new study treatment combination 
arms and closing of other study treatment combination arms that have demonstrated 
unacceptable toxicity or futility 
•
A continuous throughput design allowing data to be available sooner to support either closure 
of study treatment combination arms (initial signal-seeking arms) or adaptively increasing 
sample size for further investigation with additional eligibility criteria and statistical 
considerations in a new sub-protocol if promising efficacy is seen with a treatment 
combination. This will drive and improve selection and acceleration of optimal combinations 
to help patients with cancer in dire need of new effective treatment options.
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FRACTION-Gastric Cancer
3.1.1.3
Rationale for Biomarker Assessments
There will be a core group of biomarker assessments
 
 that will apply to all novel FRACTION Program study combinations so that comparisons 
of such data can be made across different study treatments. The goals of the biomarker assessments
proposed in the FRACTION Program are to 1) identify predictive biomarkers for both safety and 
efficacy of a given combination, 2) define the mechanism of action for a particular combination
(pharmacodynamic assessment), and 3) determine the mechanisms of resistance to a particular 
combination. In addition, there will be biomarker assessments that are applied specifically for a 
given combination as dictated by the biology of the combination. 
 
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3.2
Background
3.2.1
FRACTION-Gastric Cancer
Gastric and esophageal cancers are among the leading causes of mortality worldwide and are 
responsible for a combined total of 1,407,000 new cases and 1,123,000 deaths every year. These,
therefore, represent the most prevalent subtypes of GI malignancies worldwide, with an alarming 
increase in esophageal adenocarcinoma in many Western populations in recent decades.22,23
Gastric cancer (GC) is the 5th leading cancer and the 3rd leading cause of cancer-related deaths
worldwide. The incidence varies with different geographic regions, with over 70% of GCs
occurring in developing countries. While esophageal cancer (EC) has a lower incidence (8th most 
common cancer), overall mortality of EC is high. Moreover, adenocarcinoma of from gastric 
cardia, GEJ and distal esophagus is increasing in the West.24 GC and EC often present as advanced 
disease upon diagnosis.
Locally advanced unresectable and metastatic esophagagogastric carcinomas are not curable and 
highly lethal. While etiologic, epidemiologic, and biologic heterogeneity among esophagogastric 
carcinomas are well recognized, similar chemotherapy regimens are used in treatment of metastatic 
disease. Platinum compounds (oxaliplatin and cisplatin) and fluoropyrimidines (5-fluorouracil, 
capecitabine, and tegafur/gimeracil/oteracil potassium) are generally considered as standard-of-
care treatment options in metastatic EC, GC and GEJ cancer across geographic regions.25,26,27
Targeted agents that have shown benefit are trastuzumab (for HER-2 positive tumors) and 
ramucirumab for esophagogastric adenocarcinoma.28,29,30 The different biologic characteristics
and treatment approaches among regions result in different survival outcomes, with median OS
durations of 12 to 14 months in Asian countries and 8 to 11 months in the US and Europe.31,32,33
Immunotherapeutic approaches have demonstrated clinical efficacy in several advanced solid 
tumor cancers, including esophagogastric cancer, melanoma, non-small cell lung cancer (NSCLC), 
renal cell carcinoma, classical Hodgkin lymphoma, recurrent or metastatic squamous cell 
carcinoma of the head and neck, locally advanced or metastatic urothelial carcinoma, 
hepatocellular carcinoma, and microsatellite instability-high or mismatch repair deficient 
metastatic colorectal cancer.34,35,36,37,38Nivolumab (BMS-936558), a PD-1 antibody, and 
ipilimumab (BMS-734016), a CTLA-4 antibody, are such immunotherapies that have been 
approved in the US, Europe, Japan, and other countries.38,39,40,41
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may further 
improve anti-tumor activity.42 In vitro combinations of nivolumab plus ipilimumab increased IFNγ
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production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. In a murine 
melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased the 
proportion of CTLA-4- and PD-1-expressing CD4/CD8 tumor-infiltrating T-effector cells, and 
dual blockade increased tumor infiltration of T-effector cells and decreased intratumoral 
T regulatory cells, as compared to either agent alone.42
In patients with esophagogastric cancer, tumors with programmed death-ligand 1 (PD-L1)
expression have been reported to be associated with depth of muscle invasion, tumor size, and 
lymph node metastasis. The survival of patients with PD-L1- or programmed death-ligand 2 
(PD-L2)-expressing tumors is significantly worse than for those patients without 
PD-L1/PD-L2-expressing tumors. PD-L1 or PD-L2-expressing tumors have been reported in 
approximately 22% to 40% of GC, and PD-L1 has been suggested as a prognostic marker for both 
GC and EC.43,44 Thus, blockage of PD-1/PD-L1/PD-L2 might improve the survival of GC patients.
To that end, anti-PD-1 and PD-L1 inhibitors (eg, nivolumab, pembrolizumab, and avelumab) have 
been investigated in GC treatment and have demonstrated anti-tumor activity.45,46,47 Nivolumab 
showed an improvement in response rate, progression free survival, and OS compared to placebo 
in Japanese patients with GC treated with 2 or more lines of chemotherapy, irrespective of PD-L1 
status.48 Anti-PD-1 antibody pembrolizumab was approved in patients with recurrent locally 
advanced or metastatic, gastric, or GEJ adenocarcinoma whose tumors express PD-L1, as 
determined by an FDA-approved test and patients must have had disease progression on or after 2 
or more prior systemic therapies, including fluoropyrimidine-
and platinum-containing 
chemotherapy and, if appropriate, human epidermal growth factor receptor 2 (HER2)/neu-targeted 
therapy.49,50 Pembrolizumab is also approved (accelerated approval) for the treatment of patients 
with MSI-H (microsatellite instability-high)/dMMR (mismatch repair deficient) cancers with no 
satisfactory alternative treatment options.
Combining immunotherapeutic agents with different mechanisms of action offers the possibility 
of further benefit, as noted with the combination of nivolumab and ipilimumab now approved in 
the US for the treatment of patients with metastatic melanoma.38 In Study CA209032 (“A 
Phase 1/2, Open-label Study of Nivolumab Monotherapy or Nivolumab combined with 
Ipilimumab in Subjects with Advanced or Metastatic Solid Tumors,” NCT01928394), participants 
with GC or GEJ were treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg 
or nivolumab monotherapy. Participants treated with nivolumab 1 mg/kg in combination with 
ipilimumab 3 mg/kg had an objective response rate (ORR) of 24% and 12-month progression-free 
survival rate (PFSR) of 17%. This was greater than the ORR and 12-month PFSR in participants 
treated with nivolumab monotherapy, who had an ORR of 12% and a PFSR of 8%.34 This study 
treatment combination regimen has also been chosen for use in a Phase 3 registration study in first-
line GC. Hence, nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg has been chosen as 
the control treatment in FRACTION-Gastric Cancer Sub-Protocol A. (Further details are described 
in the FRACTION-Gastric Cancer Sub-Protocol A孬孱These data also suggest the potential for other 
combinations to bring additional benefit to participants with GC and GEJ.
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This document will serve as the Master Protocol for the FRACTION-Gastric Cancer study 
(FRACTION-Gastric Cancer孾季CA018003). As described above, novel study treatment 
combinations and/or additional controls will be appended as FRACTION-Gastric Cancer 
Sub-Protocols. These FRACTION-Gastric Cancer Sub Protocols- will evaluate the safety profile, 
tolerability, preliminary efficacy, PK, and pharmacodynamics of novel study treatment 
combinations in participants with advanced GC. The initial control treatment in the 
FRACTION-Gastric Cancer study will be nivolumab in combination with ipilimumab followed 
by nivolumab monotherapy孯similar to what has been administered in Study CA209032 as 
described above.
3.3
Benefit/Risk Assessment
An overall risk/benefit assessment for each novel FRACTION-Gastric Cancer study treatment 
combination will be provided in each FRACTION-Gastric Cancer Sub-Protocol.
Non-live coronavirus disease 2019 (COVID-19) vaccination is considered a simple concomitant 
medication within the study. However, the efficacy and safety of non-live vaccines (including non-
live COVID-19 vaccines) in participants receiving investigational agents is unknown.
3.3.1
Safety Monitoring on Study Treatment
Frequent safety assessments will be carried out by the Sponsor/BMS Medical Monitor (or 
designee) and investigators throughout the study to determine whether dose modification, 
additional safety measures, or termination of the study treatment combination arm is required at 
any time. In addition, AEs and serious adverse events (SAEs) will be reviewed regularly by the 
BMS Medical Monitor (or designee) and the Pharmacovigilance group to look for trends and 
potential safety signals. Treatment of AEs will follow institutional guidelines and recommended 
management algorithms, as listed in the Investigator’s Brochure (IB) and prescribing information, 
as applicable, for each combination agent and control comparator, and provided as appendices to 
this protocol. Specific algorithms for the management of immune-related AEs are provided in 
Appendix 6 and are applicable to immune-related AEs for all FRACTION-Gastric Cancer study
treatment combinations.
4
OBJECTIVES AND ENDPOINTS
The overall FRACTION-Gastric Cancer study-wide objectives are presented in the following 
sections. Any changes to these objectives for specific study treatments are specified in each 
FRACTION-Gastric Cancer Sub-Protocol.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To assess the efficacy (ORR, DOR, and PFSR at 
24 weeks) of each FRACTION-Gastric Cancer study 
treatment combination (relative to nivolumab in 
combination with ipilimumab, when applicable) in 
participants with advanced GC and/or EC
•
ORR, defined as the proportion of all treated 
participants with a BOR of CR or PR as assessed 
per RECIST v1.1 by investigator, median DOR, 
and PFSR at 24 weeks 
Secondary
•
To investigate additional safety and tolerability of 
each FRACTION-Gastric Cancer study treatment 
combination in participants with advanced GC and/or 
EC
•
Incidence of AEs, SAEs, and AEs leading to 
discontinuation, deaths, and clinical laboratory 
test abnormalities 
Tertiary/Exploratory
•
To assess the pharmacodynamic effects as a function 
of exposure, by evaluation of select biomarkers 
 
•
To explore potential associations between anti-tumor 
activity or safety and select biomarker measures
 
 
•
To evaluate the PK of each IP component
•
To evaluate the immunogenicity of each IP, when 
applicable
•
To assess the OS in treated participants
•
To evaluate disease-related symptom improvement, 
as measured by the GaCS of the FACT-Ga and the
ECS of the FACT-E in treated participants 
•
To evaluate general health, functional status, and 
utility for health using the EQ-5D-3L in treated 
participants 
•
Summary measures of change (or % change) 
from baseline or baseline level biomarker 
measurements 
 
•
Correlation (or similar appropriate measure of 
association) of biomarker measure
 
•
Summary measures of PK parameters from serum 
concentration
•
Incidence of ADAs
•
OS rate at certain time points
•
Summary measures of EQ-5D-3L index and VAS 
scores, GaCS scores, and/or ECS scores, and 
corresponding change form baselines for each 
score
Abbreviations: CR = complete response; BOR = best overall response; DOR = duration of response;
EQ-5D-3L = 3-level version of EQ-5D self-report questionnaire; EC = esophageal cancer; ECS = Esophagus Cancer 
Subscale; FACT-E = Functional Assessment of Cancer Therapy-Esophageal; FACT-Ga = Functional Assessment of 
Cancer Therapy-Gastric; GaCS = Gastric Cancer Subscale; GC = gastric cancer; IP = investigational product; 
RECIST = Response Evaluation Criteria in Solid Tumors; VAS = visual analog scale.
AEs and laboratory values will be graded according to NCI Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03.
5
STUDY DESIGN
5.1
Overall Design
This is a rolling, Phase 2, adaptive study that will evaluate the preliminary efficacy, safety, 
tolerability, PK, and pharmacodynamics of novel FRACTION-Gastric Cancer study treatment 
combinations in participants with advanced GC and/or EC. The details pertaining to the specific
study treatment regimens are provided in each FRACTION-Gastric Cancer Sub-Protocol孱
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Participants will be enrolled in 1 of the 2 tracks孱季Participants who are anti-PD-1, anti-PD-L1, and
anti-CTLA-4 treatment naïve will be enrolled for Track 1孱季Participants who have had prior 
anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment will be assigned to Track 2孯as outlined in Figure 
5.1-1 and described in Section 5.1.1孱
Participants on Tracks 1 and 2 will begin on the Treatment Phase (with a total duration of 
approximately 2 years). Tumor assessments will be conducted according to the timing described 
in each FRACTION-Gastric Cancer Sub-Protocol. 
Participants in Tracks 1 and 2 will be treated until completion of the Treatment Phase, progression, 
toxicity, or protocol-specified discontinuation (see Section 8.1孬孱季The decision to continue 
treatment beyond investigator-assessed progression is possible (for up to completion of that 
Treatment Phase) and should be discussed with the BMS Medical Monitor (or designee) and 
documented in the study records (see Section 7.4.2). In addition, a participant with PD has the 
option to enter into Track 2, assuming that he/she continues to fulfill all eligibility criteria at each 
new randomization point, including a life expectancy of ≥3 months (see Section 5.1.1). 
A Simon 2-stage (optimal) design will be used in both Tracks 1 and 2 to evaluate the possibility 
of terminating an arm early and/or moving promising combinations into the next phase of 
treatment development (see Section 10.1). The number of participants planned for enrollment may 
vary by track and is described in Section 10.1. Enrollment will be continued after reaching the 
indicated number of participants at Stage 1 while the initial efficacy evaluation is ongoing. This 
will allow additional participants to enroll to account for unexpected trial impact, such as response 
nonevaluable participants due to early dropout, design parameter change (eg, historical rate 
update), etc. Participants who continue to fulfill eligibility criteria may move from Track 1 into 
Track 2 or re-enter Track 2, as described in Section 5.1.1. 
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Note: Participants treated with any study treatment targeting PD-1, PD-L1, or CTLA-4 will be considered anti-PD-1, 
anti-PD-L1, or anti-CTLA-4 treatment experienced, respectively.
Physical examinations, vital sign measurements, local 12-lead ECG, and clinical laboratory 
evaluations will be performed at selected times throughout treatment on all tracks (see Section 2
and the On-treatment Procedural Outline[s] specific to each FRACTION-Gastric Cancer 
Sub-Protocol). Participants will be closely monitored for AEs and SAEs throughout the study. 
Blood and tumor tissue will be collected at specified times before and after study treatment
administration for PK, ADA, and pharmacodynamic analyses. Participants may withdraw or 
discontinue at any time based on criteria in Section 8.1. 
5.1.1
FRACTION-Gastric Cancer Tracks 1 and 2 Design
A detailed study schematic for both Tracks 1 and 2 is presented in Figure 5.1.1-1. 
Participants who are naïve to anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment will be enrolled 
in Track 1, and they will be randomized to nivolumab in combination with ipilimumab or to one
of the FRACTION-Gastric Cancer study treatment combinations. These participants will receive 
their assigned study treatment in Track 1 until completion of the Treatment Phase. 
Participants who have received prior anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment will be 
enrolled in Track 2 and randomized to nivolumab in combination with ipilimumab, or to one of 
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the FRACTION-Gastric Cancer study treatment combinations. In addition, participants with PD
who were treated in Track 1 or 2 and continue to fulfill all entry criteria may be enrolled in Track 2 
and re-randomized to a new combination other than that previously received, if applicable. These 
participants will receive their assigned study treatment in Track 2 until completion of the 
Treatment Phase. The number of participants who initially enroll in Track 2 and those who enroll 
in Track 2 after treatment on Tracks 1 or 2 is described in Section 10.1.
•
Participants with complete response (CR), PR, or SD at the end of 2 years on Track 1 or 2
Treatment Phase will:
−
Enter safety follow-up and complete FU1, FU2, and FU3 visits
•
Participants with PD during the Track 1 or 2 Treatment Phase will:
−
Enter safety follow-up and complete FU1, FU2, and FU3 visits
•
Participants with CR, PR, or SD who enter study follow-up and subsequently progress 
will:
−
Enter safety follow-up and complete FU1, FU2, and FU3 visits
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Figure 5.1.1-1:
Tracks 1 and 2 Study Design Schematic
Note: This diagram presents the protocol-mandated treatment flow for Tracks 1 and 2, including re-entry into Track 2. 
a
Participants naïve to anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment will be enrolled in Track 1; participants with prior exposure to anti-PD-1, anti-PD-L1, 
and anti-CTLA-4 treatment will be enrolled in Track 2. Following track assignment, participants will be randomized.
b CR, PR, SD, and PD, as defined by RECIST v1.1. Assessments of PR and CR must be confirmed at least 4 weeks later following initial assessment.
c Safety Follow-up Phase.
d Not applicable as of Protocol Amendment 06: If participants are eligible and if a new study treatment combination is available, they can enroll/re-randomize to 
a new combination.
e Not applicable as of Protocol Amendment 06: Each individual participant may receive multiple study treatments, including initial treatment, treatment beyond 
investigator-assessed progression, and/or entry into Track 2, assuming that the participant continues to fulfill all eligibility criteria at each new randomization 
point (see Section 5.1.3.2 for details).
f Not applicable as of Protocol Amendment 06: Participants with PD during treatment may continue treatment beyond progression up to 2 years if criteria in 
Section 7.4.2 are met.
Abbreviations: CR = complete response; RECIST = Response Evaluation Criteria in Solid Tumors.
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5.1.2
Safety Monitoring Board and Other External Committees
Two independent committees may be utilized: a Safety Monitoring Board (SMB) and an 
Independent Review Committee (IRC).
The SMB will be established to provide safety monitoring and to provide advice to the Sponsor 
regarding actions the committee deems necessary for the continuing protection of participants 
enrolled in the study. The SMB will meet at least twice per year concurrent with BMS internal 
continuous safety assessments. If needed, additional ad hoc SMB meetings may be convened. 
Safety-related data summaries and listings (by study track and study treatment arm, as appropriate) 
will be provided to SMB to facilitate safety monitoring. The SMB will act in an advisory capacity 
to BMS and will monitor participant safety throughout the study. Additional details are provided 
in the SMB Charter.
The IRC may be established at the discretion of the Sponsor. The IRC may review all available 
tumor assessment scans to determine response (Response Evaluation Criteria in Solid Tumors 
[RECIST] v1.1 criteria). IRC-determined response may be used in the analyses of ORR, PFSR, 
and duration of response (DOR).
5.1.3
Study Phases
Participants will complete up to 3 phases of the study: Screening, Treatment, and Safety 
Follow-up.
5.1.3.1
Screening
Prior to screening for the protocol, investigative sites are required to determine if a participant has 
previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment through their institutional 
database, participant medical history, or institutional prescreening process. Once determined, 
treatment experience is considered source data for this FRACTION-Gastric Cancer study. The 
participant must be provided with the FRACTION-Gastric Cancer study Institutional Review 
Board (IRB)-approved written consent. Once the consent is signed, the participant is then 
considered to have entered screening. The treatment status must be entered into the enrollment 
management system, and participants will be required to submit a fresh tumor biopsy. An adequate 
baseline tumor biopsy (as determined by a central laboratory pathologist) must be obtained prior 
to randomization.
The Screening Phase for each track will last for up to 28 days. Participants will be enrolled using 
Interactive Response Technology (IRT).
If a participant surpasses the 28-day window during the Screening Phase due to a study-related 
procedure (eg, scheduling of a tumor biopsy or waiting time for a study-related laboratory value), 
the participant must be re-consented but does not need to be assigned a new participant
identification number. To reduce any undue burden of procedure in this participant population in 
this situation, the amount of repeat procedures from the initial screening will be minimized, while 
maintaining safety and eligibility under the discretion of the BMS Medical Monitor (or designee) 
and investigator.
Enrollment in all study treatment arms in each track will be competitive. 
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5.1.3.2
Treatment
The details of the Treatment Phase duration are provided in Section 5.1. Further details of the study 
treatment administration are in each FRACTION-Gastric Cancer Sub-Protocol. Study assessments 
are to be collected as outlined in the On-treatment Procedural Outline(s) in each FRACTION-
Gastric Cancer Sub-Protocol.
Assessment of response will be outlined for each combination therapy in the specific FRACTION-
Gastric Cancer Sub-Protocol. Assessments of PR and CR must be confirmed at least 4 weeks later 
following initial assessment. Tumor progression or response endpoints will be assessed using 
RECIST v1.1 criteria for solid tumors (see Appendix 5). 
Participants will generally be allowed to continue study treatment until the first occurrence of one 
of the following: 1) completion of 2 years of study treatment, 2) PD, 3) clinical deterioration 
suggesting that no further benefit from study treatment is likely, 4) intolerable toxicity, and 
5) meeting of criteria for discontinuation of study treatment, as outlined in Section 8.1. Individual 
participants with confirmed CR will be given the option to discontinue study treatment, on a case-
by-case basis, after specific consultation and agreement between the investigator and the BMS 
Medical Monitor (or designee) in settings where the benefit/risk ratio justifies discontinuation of 
study treatment. 
All participants will be treated as per Section 5.1, unless criteria for study treatment
discontinuation are met earlier (see Section 8.1 in this FRACTION-Gastric Master Protocol and 
Section 8.1 in the FRACTION-Gastric Cancer Sub-Protocol). Upon completion of the Treatment 
Phase, all participants will enter the Safety Follow-up Phase (see Section 5.1.3.3 and Table 2-3).
As of Protocol Amendment 06, collection of blood or other biological samples for reasons other 
than safety monitoring (eg, PK, ADA, biomarkers, etc) should be discontinued. Please refer to 
Table 2-3 and Sections 9.5, 9.6, and 9.8.
5.1.3.3
Follow-up
As of Protocol Amendment 06, tumor scans, survival status follow-ups, and collection of 
subsequent treatment information will end once the participant has disease progression or 
treatment discontinuation for any reason, whichever occurs first. Any assessments for monitoring 
of safety will continue per protocol until the final follow-up visit (FU3). Please refer to Table 2-3.
Safety Follow-up
Upon completion of the Treatment Phase, all participants will enter the Safety Follow-up Phase 
once the decision is made to discontinue the participant from study treatment (eg, at EOT). 
For participants that complete all scheduled weeks of study treatment, EOT visit will be the same 
as the last scheduled and completed on-treatment visit and the start of Week 1 safety follow-up 
visit. For participants that do not complete all scheduled weeks of study treatment, EOT visit will 
be the most recent on-treatment visit (with all available safety and response data; does not need to 
be repeated) and will be considered the start of Week 1 safety follow-up visit.
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After the EOT visit, all participants will be evaluated for any new AEs until 100 days following
the last dose of study treatment, as specified in each FRACTION-Gastric Cancer Sub-Protocol. 
All SAEs must be collected from the date of the participant’s written consent until 100 days post
discontinuation of dosing or participant’s participation in the study if the last scheduled visit occurs 
at a later time. Follow-up visits should occur at Days 30, 60, and 100 (± 7 days) after the last dose 
of study treatment or coinciding with the date of discontinuation (± 7 days), if the date of 
discontinuation is greater than 30 days after the last dose, to monitor for AEs. All participants will 
be required to complete the 3 clinical safety follow-up visits, regardless of whether they start a 
new anti-cancer treatment, except for those participants who withdraw consent for study 
participation or those participants who start retreatment or are re-randomized into Track 2.
5.2
Number of Participants
For Sub-Protocols utilizing a Simon-2 stage (optimal) design, up to 54 anti-PD1/PD-L1 or CTLA-
4 treatment-naïve participants will be treated per study treatment combination, in Track 1. In 
Track 2, up to 41 participants will be treated per study treatment combination (see Section 10.1 for 
details).
For Sub-Protocols not utilizing a Simon-2 stage (optimal) design, a different sample size may be 
used depending on the statistical considerations for those treatment combinations. In those cases, 
sample size will be discussed within the individual Sub-Protocols.
5.3
End of Study Definition
The start of the study is defined as first visit for first participant screened. End of study is defined 
as the last visit or scheduled procedure shown in the Schedule of Activities for the last participant. 
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.
5.4
Scientific Rationale for Study Design
BMS has an extensive portfolio of novel agents that span a variety of targets孱季To determine which 
combinations show the most clinical promise and孯thus孯should be prioritized for future
registrational studies, BMS has initiated the FRACTION Program. The FRACTION Program will 
treat participants with different study treatment options and employ repeat blood sampling孯季tumor 
biopsies孯and serial assessments to understand markers of response to treatment. These approaches 
are supported by various precedent studies that use innovative trial designs to quickly assess new 
agents in participants孯with the goal of reducing the time and number of participants required to 
bring these treatments to those who will benefit from them. For the FRACTION Program, specific 
study treatment combinations and/or control treatments will be introduced in FRACTION Sub-
Protocols for each FRACTION study. Study treatment combinations that have high potential to 
produce transformational activity in the cancer compared to the control, based on both preclinical 
and early clinical trials data, will be selected. See Section 3.1 for details. 
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5.4.1
Rationale for Duration of Therapy
The optimal duration of immunotherapy is an important question and continues to be investigated. 
In Study CA209153, patients with previously treated advanced NSCLC who completed 1 year of 
nivolumab therapy were randomized to either continue or stop treatment, with the option of 
retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; hazard ratio (HR) =
0.42 (95% CI, 0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there 
also was a trend for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 
1.20]). Of note, the PFS curves in both groups plateau approximately 1 year after randomization 
(ie, 2 years after treatment initiation), suggesting that there may be minimal benefit in extending 
treatment beyond a total of 2 years.51
Moreover, accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be 
sufficient for long-term benefit. In Study CA209003, a dose-escalation cohort expansion trial 
evaluating the safety and clinical activity of nivolumab in patients with previously treated 
advanced solid tumors (including 129 participants with NSCLC) specified a maximum treatment 
duration of 2 years. Among 16 participants with NSCLC who discontinued nivolumab after 
completing 2 years of treatment, 12 participants were alive > 5 years and remained progression-
free without any subsequent therapy. In the CA209003 NSCLC cohort, the OS curve begins to 
plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.52 These survival 
outcomes are similar to Phase 3 studies in previously treated NSCLC, in which nivolumab 
treatment was continued until progression or unacceptable toxicity (2-year OS rates of 23% and 
29%, and 3-year OS rates of 16% to 18% for squamous and non-squamous NSCLC,
respectively).53
Taken together, the data suggest that a shorter duration of nivolumab treatment of only 1 year was 
associated with increased risk of progression in previously treated patients with NSCLC, 
suggesting that treatment beyond 1 year is likely needed. Also, treatment beyond 2 years is unlikely 
to confer additional clinically meaningful benefit, and that the risk of progression after 
discontinuing treatment at 2 years is low.
Collectively, these data suggest that there is minimal, if any, benefit derived from continuing IO 
treatment beyond 2 years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer-term treatment.
5.5
Justification for Dose
Please refer to individual FRACTION-Gastric Cancer Sub-Protocols for their respective dose 
justifications. 
6
STUDY POPULATION
For entry into the FRACTION-Gastric Cancer study (per FRACTION-Gastric Cancer Master 
Protocol), the following criteria must be met prior to dosing on Day 1. For entry into a study 
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treatment per a FRACTION-Gastric Cancer Sub-Protocol, additional treatment-specific criteria, if 
applicable, must also be met.
No exceptions will be granted.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must be able to give self-consent and then sign and date an IRB/Independent 
Ethics Committee (IEC)-approved written informed consent in accordance with regulatory 
and institutional guidelines. This must be obtained before the performance of any protocol-
related procedures that are not considered 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.
c) Participants must provide consent for mandatory tumor biopsy samples (as detailed in “2o” 
below).
2) Type of Participant and Target Disease Characteristics
a) All participants must have inoperable, advanced, or metastatic EC, GC or GEJ carcinoma 
and have histologically confirmed predominant adenocarcinoma and/or squamous 
carcinoma. The documentation of GEJ involvement can include biopsy, endoscopy, or 
imaging.
b) Participants with human epidermal growth factor receptor 2 (HER2) overexpressing tumor 
who progress after trastuzumab (or are ineligible for or unwilling to be treated with 
trastuzumab) are eligible to be enrolled.
c) Prior adjuvant or neoadjuvant chemotherapy, radiotherapy, and/or chemoradiotherapy are 
permitted, as long as the last administration of the last regimen (whichever was given last) 
occurred at least 4 weeks prior to randomization.
d) Participants must have an Eastern Cooperative Oncology Group performance status ≤1 
(see Appendix 7).
e) Track-specific eligibility criteria
i)
Track 1: anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment-naïve participants
(1).Participants must not have received any anti-PD-1, anti-PD-L1, or anti-CTLA-4 
treatment prior to this study. Participants previously treated with agents other than 
anti-PD-1, anti-PD-L1, or anti-CTLA-4 are eligible for Track 1.
(2).Participants may have been offered platinum-based chemotherapy for progressive 
or recurrent disease.
a.
The platinum-based chemotherapy may have been in the adjuvant, 
neoadjuvant, or recurrent setting.
(3).Not Applicable per Amendment 02.
(4).Not Applicable per Amendment 03.
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(5).All participants must consent to the acquisition of fresh pre- and on-treatment tumor 
biopsies for performance of correlative biomarker studies. Archival specimens may 
not be substituted for fresh baseline specimens but can be submitted to help 
understand the evolution of the tumor (ie, PD-L1 expression changes over time) for 
performance of correlative studies. Participants who either do not consent to a 
pre-treatment tumor biopsy or do not have accessible lesions are not eligible. An 
adequate baseline tumor biopsy as determined by a central laboratory pathologist 
must be obtained prior to randomization. If fresh biopsy is not clinically feasible or 
safe, the option of archival tissue can be discussed with BMS if the biopsy was 
obtained within 90 days of study enrollment and there was no intervening systemic 
anticancer or IO therapy.
ii) Track 2: anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment-experienced participants
(1).Participants must have had progressive or recurrent disease during or after 
anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment. (Participants treated with any 
study treatment targeting PD-1, PD-L1, or CTLA-4 will be considered anti-PD-1, 
anti-PD-L1, or anti-CTLA-4 treatment experienced, respectively). 
(2).Participants may have been offered platinum-based chemotherapy for GC or GEJ.
a.
The platinum-based chemotherapy may have been in the adjuvant, 
neoadjuvant, or recurrent setting.
(3).Participants who have had prior treatment with any 1 of the agents (or any other 
agent targeting PD-1, PD-L1, or CTLA-4) in monotherapy or in any combination 
regimen in a FRACTION-Gastric Cancer Sub-Protocol are eligible for treatment 
on Track 2. 
(4).Participants who have had prior combination treatment with the same IO 
combination agents (or IO agents directed against the same targets) as 1 of the 
combination regimens in a FRACTION-Gastric Cancer Sub-Protocol are eligible 
for study treatment on Track 2 but must be randomized to another combination 
regimen 
(as 
outlined 
in 
Section 5.1.1
Inclusion 
Criteria 
of 
each 
FRACTION-Gastric Cancer Sub-Protocol).
(5).All participants must consent to the acquisition of fresh pre- and on-treatment tumor 
biopsies for performance of correlative biomarker studies. Archival specimens may 
not be substituted for fresh baseline specimens but can be submitted to help 
understand the evolution of the tumor (ie, PD-L1 expression changes over time) for 
performance of correlative studies. Participants who either do not consent to a pre-
treatment tumor biopsy or do not have accessible lesions are not eligible. An 
adequate baseline tumor biopsy as determined by a central laboratory pathologist 
must be obtained prior to randomization. If fresh biopsy is not clinically feasible or 
safe, the option of archival tissue can be discussed with BMS if the biopsy was 
obtained within 90 days of study enrollment and there was no intervening systemic 
anticancer or IO therapy.
f)
At the time of screening, participants must have a life expectancy of at least 3 months 
following their most recent chemotherapy or immunotherapy for entry into all tracks. 
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i)
Participants who wish to be re-randomized to a new study treatment combination on 
Track 2 following progression on a prior study treatment in Tracks 1 or 2 must have a 
life expectancy of at least 3 months following the last study treatment.
g) Participants receiving prior palliative radiotherapy to a non-central nervous system (CNS) 
lesion must have completed that treatment at least 2 weeks prior to the first dose of study 
treatment. 
i)
Participants with symptomatic tumor lesions at baseline who may require palliative 
radiotherapy within 4 weeks of the first dose of study treatment are strongly encouraged 
to receive palliative radiotherapy prior to enrollment, and they must complete that 
treatment at least 2 weeks prior to the first dose of study treatment.
h) Participants must have at least 1 lesion with measurable disease, as defined by 
RECIST v1.1 criteria for solid tumors response assessment (see Appendix 5). 
i)
Participants with lesions in a previously irradiated field as the sole site of measurable 
disease will be permitted to enroll, provided that the lesion(s) have demonstrated clear 
progression and can be measured accurately.
i)
Participants with toxicity from any prior anti-cancer treatment must have their toxicity 
returned to Grade ≤1 (NCI CTCAE Version 4.03) or baseline before administration of 
study treatment.
i)
Participants with Grade ≥2 toxicities attributed to prior anti-cancer treatment that are 
not expected to resolve and result in long-lasting sequelae, such as neuropathy after a 
platinum based- treatment, are eligible.
ii) Grade >1 alopecia or fatigue is permitted.
j)
Not applicable as per revised protocol 03 Participants must allow a tumor biopsy at the 
following time points: 1) baseline (prior to study treatment); 2) on-study (Day 28 on-
treatment); and 3) EOT, defined as at the time of progression or at the time of a clinically 
significant event (eg, at EOT for participants with PR or SD or at EOT for participants who 
discontinue treatment due to an AE), provided that the biopsy is at acceptable clinical risk 
as judged by the investigator for each study treatment regimen to 1) identify predictive 
biomarkers for both safety and efficacy of a given combination, 2) define the mechanism 
of action for a particular combination (pharmacodynamic assessment), and 3) determine 
the mechanisms of resistance to a particular combination.
i)
Participants who do not have accessible or suitable lesions are not eligible. 
(1).Baseline biopsies may be collected from participants with a single measurable
lesion (primary or metastatic), as long as it is not an excisional biopsy. 
ii) For participants whose pretreatment biopsy yields inadequate tissue quantity or quality
(as determined by a pathologist in the central laboratory), re-biopsy is permitted. 
iii) The solid tumor tissue specimen must be a core-needle, biopsy or an excisional or 
incisional biopsy. Fine-needle biopsies and drainage of pleural effusions with cytospins 
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.
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(1).Punch biopsies are acceptable as long as adequate tumor material is provided. 
iv) The biopsy at progression of disease after treatment on any track may function as the 
pretreatment biopsy for subsequent treatment on Track 2.
k) Study personnel must ensure that the archival tissue block (preferred) or slides samples, if 
available, are located and shipped to the central laboratory prior to randomization within 
6 weeks of signing the written informed consent, as long as this tissue will not be used for 
the screening biopsy sample.
l)
Participants must have adequate organ function, as defined by the following:
i)
White blood cells ≥2,000/μL (stable off any growth factor after discontinuation within 
2 weeks of the first study treatment administration)
ii) Neutrophils ≥1,500/μL (stable off any growth factor after discontinuation within
2 weeks of the first study treatment administration)
iii) Platelets ≥100 × 103/μL (transfusion to achieve this level is not permitted within 
2 weeks of the first study treatment administration)
iv) Hemoglobin ≥9.0 g/dL (transfusion to achieve this level is not permitted within 
2 weeks of the first study treatment administration)
v) Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase 
(AST) 
≤3× institutional upper limit of normal (ULN)
vi) Total bilirubin ≤1.5× institutional ULN (except for participants with Gilbert’s 
syndrome who must have normal direct bilirubin)
vii)Serum creatinine ≤1.5× institutional ULN or creatinine clearance (CrCl) ≥40 mL/min 
(measured using the Cockcroft-Gault formula below):
Female 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
m) Participants must be able to comply with restrictions and prohibited activities/treatments 
listed in Section 7.7.1. 
n) Participant re-enrollment: This study permits the re-enrollment of a participant who has 
discontinued the study as a pretreatment failure (eg, participant has not been treated). If 
re-enrolled, the participant must be re-consented.
o) Participants must allow a tumor biopsy at baseline and on study. 
i)
Participants who do not have accessible or suitable lesions are not eligible. 
ii) For participants whose pretreatment biopsy yields inadequate tissue quantity or quality 
(as determined by a pathologist in the central laboratory), re-biopsy is permitted. 
iii) The solid tumor tissue specimen must be a core-needle, biopsy or an excisional or 
incisional biopsy. Fine-needle biopsies and drainage of pleural effusions with cytospins 
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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.
(1).Punch biopsies are acceptable as long as adequate tumor material is provided. 
iv) The biopsy at progression of disease after treatment on any track may function as the 
pretreatment biopsy for subsequent treatment on Track 2.
3) Age and Reproductive Status 
a) Males and females, ages 18 years or older at the time of consent
b) Women of child-bearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin) within 24 hours prior to the start of study treatment. An extension up to 
72 hours prior to the start of study treatment is permissible in situations where results 
cannot be obtained within the standard 24-hour window.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study treatment(s) plus the time required for the study treatment to 
undergo approximately 5 half-lives, plus the duration of 1 ovulatory cycle (30 days), for a 
total of 5 months posttreatment completion (see Appendix 4). If the half-life of a study 
treatment in a FRACTION-Gastric Cancer Sub-Protocol is longer than approximately 
5 half-lives of nivolumab, this will be addressed in the FRACTION-Gastric Cancer 
Sub-Protocol.
i)
WOCBP who are continuously not heterosexually active are also exempt from 
contraceptive requirements and still must undergo pregnancy testing, as described in 
this section.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception and fetal protection (see Appendix 4) for the duration of 
treatment with study treatment(s) plus approximately 5 half-lives of the study treatment,
plus the duration of sperm turnover (90 days), for a total of 7 months post-treatment 
completion. In addition, male participants must be willing to refrain from sperm donation 
during this time. 
i)
Not applicable as per revised protocol 03 Azoospermic males are exempt from 
contraceptive requirements.
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 and 
when applicable, the potential of fetal toxicity occurring due to transmission of study drug, present 
in seminal fluid, to a developing fetus, even if the participant has undergone a successful 
vasectomy or if the partner is pregnant. Investigators shall advise on the use of highly effective 
methods of contraception (Appendix 4), which have a failure rate of < 1% when used consistently 
and correctly.
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6.2
Exclusion Criteria
1) Medical Conditions 
a) Participants with HER2-positive tumor and previously untreated with trastuzumab are 
excluded; participants who are ineligible for or unwilling to be treated with trastuzumab 
are still eligible.
b) Participants with ascites that cannot be controlled with appropriate interventions.
c) Participants must not have suspected, known, or progressive CNS metastases; have 
untreated CNS metastases; or have the CNS as the only site of disease.
i)
Participants are eligible if CNS metastases are adequately treated and participants 
neurologically return to baseline (except for residual signs or symptoms related to the 
CNS treatment) for at least 2 weeks prior to study entry. In addition, participants must 
be either off corticosteroids or on a stable or decreasing dose of prednisone ≤10 mg 
daily (or equivalent) for at least 2 weeks prior to study entry.
ii) Participants must not have leptomeningeal disease or carcinomatous meningitis.
d) Participants must not have 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.
e) Participants must not have other active malignancy requiring concurrent intervention.
f)
Participants must not have received a prior organ allograft.
g) Participants must not have received any anti-cancer treatment (eg, chemotherapy or
radiotherapy [except for palliative radiotherapy, which can be received at least 2 weeks 
prior to study treatment]; biologics; or immunotherapies, including investigational 
treatments) within 4 weeks prior to the first dose of study treatment administration.
i)
Participants who have received noncytotoxic anti-cancer therapies (eg, prior use of 
targeted treatment) and who have completed treatment at least 4 weeks or 5 half-lives 
(whichever is shorter) prior to the first dose of study treatment are eligible to enroll. 
However, if 5 half-lives is shorter than 4 weeks, agreement with the BMS Medical 
Monitor (or designee) is mandatory. 
h) Participants must not have active, known, or suspected autoimmune disease. 
i)
Participants with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement treatment, 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.
i)
Participants must not have a condition requiring systemic treatment with either 
corticosteroids (prednisone > 10 mg daily or equivalent) or other immunosuppressive 
medications within 14 days of study treatment administration. 
i)
Inhaled or topical steroids and adrenal replacement steroid (prednisone > 10 mg daily 
or equivalent) are permitted in the absence of active autoimmune disease.
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j)
Participants must not have a history of life-threatening toxicity related to prior IO treatment 
(eg, anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or treatment
specifically targeting T-cell co-stimulation or immune checkpoint pathways).
i)
Participants with toxicities that are unlikely to recur with standard countermeasures 
(eg, hormone replacement treatment after adrenal crisis) are eligible.
k) Participants must not have interstitial lung disease that is symptomatic or may interfere 
with the detection or management of suspected treatment-related pulmonary toxicity.
l)
Participants must not have uncontrolled or significant cardiovascular disease including, but 
not limited to, any of the following:
i)
Myocardial infarction or stroke/transient ischemic attack within the past 6 months
ii) Uncontrolled angina within the past 3 months
iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes)
iv) QT interval corrected with Fridericia’s formula ≥480 ms
v) History of other clinically significant heart disease (eg, cardiomyopathy, congestive 
heart failure with New York Heart Association functional classification III to IV, 
myocarditis, pericarditis, or significant pericardial effusion)
m) Participants who require daily supplemental oxygen treatment are excluded.
n) Participants must not have any positive test result for hepatitis B virus or hepatitis C virus 
(HCV) indicating presence of virus, for example, hepatitis B surface antigen (Australia 
antigen) positive or hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleic 
acid [RNA] negative).
i)
Participants with a history of resolved hepatitis A virus infection are eligible.
o) Participants must not have evidence of active infection requiring antibacterial, antifungal, 
or antiviral treatment ≤7 days prior to initiation of study treatment.
p) Participants must not have a known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. 
i)
Testing for HIV must be performed at sites mandated by local requirements. (For sites 
in Germany, see Appendix 8.)
q) Participants must not have known or suspected active tuberculosis.
r)
Participants must not have had any major surgery within 4 weeks of study treatment
administration. Participants must have recovered from the effects of a major surgery or 
significant traumatic injury at least 14 days before the first dose of study treatment.
s) Participants must not have received nononcology vaccines containing live virus for 
prevention of infectious diseases within 12 weeks prior to the first dose of study treatment. 
i)
The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on 
study without restriction.
t)
Participants must not have received packed red blood cell or platelet transfusion within 
2 weeks prior to the first dose of study treatment.
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u) Participants must not have a known or underlying serious or uncontrolled medical 
condition that, in the opinion of the investigator or Sponsor, could make the administration 
of study treatment hazardous to the participants or could adversely affect the ability of the 
participant to comply with or tolerate the study.
2) Allergies and Adverse Drug Reaction
a) History of any significant treatment allergy (such as anaphylaxis or hepatotoxicity) to prior 
anti-cancer immune-modulating therapies (eg, checkpoint inhibitors and T-cell
co-stimulatory antibodies).
b) History of allergy or hypersensitivity to study treatment components.
3) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. Note: Under certain specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply, and BMS 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
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements 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
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 or has not 
been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening Phase
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 Table 2-1, Screening Procedural 
Outline, may be repeated in an effort to find all possible well-qualified participants. Consultation 
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with the BMS Medical Monitor (or designee) may be needed to identify whether repeat testing of 
any particular parameter is clinically relevant.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, 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-IP/Non-IMP 
and is described in each FRACTION-Gastric Cancer Sub-Protocol.
An IP, also known as IMP 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 
from the authorized form, used for an unauthorized indication, or 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-IPs.
7.1
Treatments Administered
Other treatments administered as part of the study that are critical to claims of efficacy 
(eg, background treatment and rescue medications) will be considered study treatment. A table 
describing the study treatments and dosage information is provided in each FRACTION-Gastric 
Cancer Sub-Protocol.
7.2
Method of Treatment Assignment
This is an open-label study. All participants will be centrally randomized using an IRT. Before the 
study is initiated, each user will receive log-in information and directions on how to access the 
IRT.
Specific study treatments are listed in each FRACTION-Gastric Cancer Sub-Protocol. Study 
treatment will be dispensed at the study visits, as listed in the On-treatment Procedural Outline(s) 
in each FRACTION-Gastric Cancer Sub-Protocol. 
All participants must be assigned a patient identification number (PID) upon providing a signed 
IRB/IEC-approved written informed consent. During the screening visit, the investigative site will 
utilize the IRT for enrollment and receive a 5-digit PID designated by BMS that will be unique 
across all sites. Enrolled participants, including those not dosed, will be assigned sequential PIDs
starting with 
. The PID will ultimately be composed of 
the site number and participant number. For example, the first participant screened (eg, enrolled) 
at Site Number 1 will have a PID of 
. The following information is required for 
enrollment:
•
Date of obtaining informed consent
•
Date of birth
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•
Gender at birth
•
Anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment experience (see Section 5.1.3.1)
Once enrolled in the IRT, participants who meet all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for randomization:
•
Participant number
•
Date of birth
Randomization participant schedules will be generated and maintained by the IRT vendor. At the 
conclusion of the trials, BMS will receive copies of all generated participant schedules from the 
vendor. Because of the nature of the study design, limited early access to the randomization 
information will be granted to the study team to facilitate early analyses for internal decision 
making (early termination of study treatment arm, etc).
Each participant who is randomized will be assigned a unique randomization number. This is not 
the primary identifier for the participant, but is used for the randomization schedule. The primary 
identifier will be the PID described above, for use on the case report form (CRF) and source 
documents. A participant being re-randomized in Track 2 will be assigned a different 
randomization number but will retain the same PID. Randomization numbers will be assigned 
using a Central Randomization System in the order in which participants qualify for study 
treatment, not in the order of study enrollment. Randomization ratios within each track will be 
specified in each FRACTION-Gastric Cancer Sub-Protocol. If, within a given track, study
treatment arms from more than 1 FRACTION-Gastric Cancer Sub-Protocol within the 
FRACTION-Gastric Cancer Master Protocol are simultaneously open to enrollment, then a new 
participant could be assigned to any of the open study treatment arms. In Track 1, participants will 
be randomized to newly added study treatment arms/study treatments (through FRACTION-
Gastric Cancer Sub-Protocols) in a ratio specified in each new FRACTION-Gastric Cancer Sub-
Protocol. New randomization schedules for new FRACTION-Gastric Cancer Sub-Protocols will 
be generated. If accrual for current FRACTION-Gastric Cancer Sub-Protocols is still ongoing, 
participants will be allocated to the existing randomization schedule or new randomization 
schedule based on a pre-specified allocation ratio. Details of allocation ratio will be specified in 
the new FRACTION-Gastric Cancer Sub-Protocol. In Track 2, participants will be randomized to 
existing study treatment arm/study treatments and newly added study treatment arm/study 
treatments with equal probability. 
Pre-specified study treatment arm caps (according to Simon 2-stage [optimal] design) will be 
utilized to control the accrual for each study treatment combination arm under different tracks 
(Tracks 1 and 2). The cap for the nivolumab in combination with ipilimumab control arm under 
Track 1 will be set equal to the largest cap among its corresponding experimental arms. In the 
event that 1 or more participants go off study without being evaluable for response (ie, with no 
post-baseline tumor measurements and no evidence of clinical progression or death due to disease 
progression), the enrollment cap for that study treatment arm may be correspondingly raised if 
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needed to ensure that a sufficient number of evaluable participants are available for 
decision making according to the Simon 2-stage (optimal) design. If the decision is made to close 
any study treatment arm for safety concerns, the cap for that study treatment arm will be reduced 
to the current number of participants already randomized. Accrual will be stopped immediately. 
Enrollment caps to Track 2 based on new participants or re-randomized participants are described 
in Section 10.1.2.
Specific instructions for randomization into the Central Randomization System will be provided 
in a separate manual.
7.3
Blinding
This is an open-label study; blinding procedures are not applicable.
7.4
Dosage Modification
Specific dosing and treatment regimens for each FRACTION-Gastric Cancer study treatment 
combination and/or nivolumab in combination with ipilimumab are outlined in each 
FRACTION-Gastric Cancer Sub-Protocol.
7.4.1
Dose Reductions and Delays and Criteria to Resume Dosing
Tumor assessments for all participants should continue as per protocol even if dosing is delayed.
Guidelines for dose reductions and delays due to toxicity and for resuming study treatment for 
each FRACTION-Gastric Cancer study treatment combination are provided in the FRACTION-
Gastric Cancer Sub-Protocols.
7.4.2
Treatment Beyond Disease Progression
Not applicable per Protocol Amendment 06. 
7.4.3
Management Algorithms for IO and Oncology Agents
IO agents are associated with AEs that can differ in severity and duration from AEs caused by 
other therapeutic classes. Early recognition and management of AEs associated with IO agents 
may mitigate severe toxicity. Management algorithms have been developed from extensive 
experience with nivolumab, ipilimumab, and their combination to assist investigators in assessing 
and managing the following groups of AEs:
•
Pulmonary
•
Gastrointestinal
•
Hepatic
•
Endocrinopathies
•
Renal
•
Skin
•
Neurological
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The clinical nature of AEs noted with each FRACTION-Gastric Cancer study treatment 
combination and/or nivolumab in combination with ipilimumab will determine the role of the 
algorithms above for use in toxicities related to its use in this study. 
The management algorithms recommended for utilization for IO and non-IO agents are included 
in Appendix 6 and in each FRACTION-Gastric Cancer Sub-Protocol.
7.4.4
Treatment of Treatment-related Infusion Reactions
Guidelines for the treatment of study treatment-related infusion reactions for each 
FRACTION-Gastric 
Cancer
study 
treatment 
combination 
are
provided 
in 
each 
FRACTION-Gastric Cancer Sub-Protocol describing that treatment combination.
7.5
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study participants. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is 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 treatment arise, the study treatment
should not be dispensed and BMS should be contacted immediately.
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 study treatment is accurately administered. This includes documentation of 
study treatment storage, administration and, as applicable, storage temperatures, reconstitution, 
and use of required processes (eg, required diluents and administration sets).
For study treatments not provided by BMS and obtained commercially by the site, storage should 
be in accordance with the product label. Infusion-related supplies (eg, intravenous bags, in-line 
filters, and 0.9% NaCl solution) will not be supplied by the Sponsor and should be purchased 
locally if permitted by local regulations.
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
•
Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2 and the Pharmacy Manual.
7.5.1
Retained Samples for Bioavailability / Bioequivalence / 
Biocomparability
Not applicable.
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7.6
Treatment Compliance
Study treatment will be administered in the clinical facility by trained medical personnel. 
Treatment compliance will be monitored by treatment accountability, as well as by recording 
administration of each study treatment in the participants’ medical records and CRF.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following prohibitions and restrictions apply to all FRACTION-Gastric Cancer Sub-Protocols 
for the FRACTION-Gastric Cancer study. Additional FRACTION-Gastric Cancer Sub-Protocol-
specific prohibitions and/or restrictions are outlined in each FRACTION-Gastric Cancer 
Sub-Protocol.
The following medications are prohibited during the Treatment Phase of the study:
1) Immunosuppressive agents (except for those stated in Section 7.7.3) are prohibited unless they 
are utilized to treat an AE.
2) Chronic systemic corticosteroids (prednisone > 10 mg daily or equivalent; except for those 
stated in Section 7.7.3) are prohibited unless they are utilized to treat an AE.
3) Vaccines (except for those stated in Section 7.7.3) are prohibited.
4) Any medicinal herbal preparations within 2 weeks prior to the first dose of study treatment are 
prohibited unless prescribed by a treating physician. Use of marijuana and its derivatives for 
treatment of symptoms related to cancer treatment are permitted if obtained by medical 
prescription or if its use (even without a medical prescription) has been legalized locally, as 
long as no drug-drug interactions are outlined in the specific Sub-Protocol.
5) Any concurrent anti-neoplastic treatment (ie, chemotherapy; immunotherapy; extensive, 
nonpalliative radiation treatment; or standard or investigational agents for treatment of 
GC/GEJ) is prohibited other than those included in the study treatment combinations.
Any concomitant therapies must be recorded on the CRF from screening to follow-up.
7.7.2
Other Restrictions and Precautions
7.7.2.1
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 are 
appropriate. Magnetic resonance imaging (MRI) contrast should not be given to participants with 
severe renal insufficiency (eg, estimated glomerular filtration rate < 30 mL/min/1.73 m2) because 
of increased risk of nephrogenic systemic fibrosis in this participant population. In these 
participants, alternative imaging tests or MRI without gadolinium should be considered. In 
addition, participants are excluded from MRI if they have tattoos, metallic implants, pacemakers, 
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etc. 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 IRB/IEC.
7.7.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). A brief course (less than 3 weeks) of 
corticosteroids prophylaxis (eg, contrast dye allergy) or for treatment of nonautoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
•
Inhaled or intranasal corticosteroids (with minimal systemic absorption may be continued if 
the participant is on a stable dose) and adrenal replacement steroid doses of prednisone
> 10 mg daily or equivalent are permitted in the absence of active autoimmune disease. Non孰
absorbed intra-articular steroid injections will be permitted.
•
Immunosuppressive agents and the use of systemic corticosteroids are permitted in the context 
of treating AEs. Participants receiving corticosteroids must be at prednisone < 10 mg daily or 
equivalent prior to re-initiation of study treatment. Participants may continue to receive 
hormone replacement treatment.
•
The inactivated seasonal influenza vaccine can be given to participants while on treatment
without restriction. Vaccines containing live/attenuated virus (e.g., varicella, zoster, yellow 
fever, rotavirus, oral polio and measles, mumps, rubella [MMR]) are not permitted while on 
study treatment and until 100 days post the last dose.
•
Non-live COVID-19 vaccination is considered a simple concomitant medication within the 
study. However, the efficacy and safety of non-live vaccines (including non-live COVID-19 
vaccines) in participants receiving investigational agents is unknown.
7.7.4
Palliative Local Therapy
Palliative and supportive care for disease-related symptoms may be offered to all participants on 
the study. Limited radiation treatment or surgery to control isolated lesions is permitted for 
participants who have investigator-assessed clinical benefit following consultation with the BMS 
Medical Monitor (or designee). 
Participants should not receive study treatment during radiation because the potential for 
overlapping toxicities with radiotherapy and FRACTION-Gastric Cancer study treatment 
combinations or nivolumab in combination with ipilimumab is not known. If palliative 
radiotherapy in short courses and for isolated fields is required to control symptoms not clearly 
related to disease progression, then study treatment administration should be withheld, if possible, 
for at least 1 week before radiation and for at least 1 week after its completion. Participants should 
be closely monitored for any potential toxicity during and after receiving radiotherapy. Prior to 
resuming study treatment, radio-therapy related- AEs should resolve to Grade ≤1 or baseline, and 
participants must meet relevant eligibility criteria as determined by the BMS Medical Monitor (or 
designee) in discussion with the investigator. The BMS Medical Monitor (or designee) must be 
consulted prior to re-initiating study treatment in a participant with a dosing delay lasting 
> 8 weeks from the previous dose. 
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Details of palliative radiotherapy should be documented in the source records and electronic case 
report form (eCRF). Details in the source records should include dates of treatment, anatomic site, 
dose administered and fractionation schedule, and AEs. Symptoms requiring palliative 
radiotherapy should be evaluated for objective evidence of disease progression. Participants 
receiving palliative radiation of target lesions will have the evaluation of ORR just prior to 
radiotherapy, but these participants will no longer be evaluable for the determination of response 
subsequent to the date palliative radiation occurs.
For participants who need to undergo elective surgery (not tumor related) during the study, it is 
recommended to hold study treatment(s) for at least 2 weeks before and 2 weeks after surgery, or 
until the participant recovers from the procedure, whichever is longer. Prior to resuming study 
treatment, surgically related AEs should resolve to ≤Grade 1 or baseline, and participants must 
meet relevant eligibility criteria as determined by the BMS Medical Monitor (or designee) in 
discussion with the investigator. The BMS Medical Monitor (or designee) must be consulted prior 
to re-initiating study treatment in a participant with a dosing delay lasting > 8 weeks from the 
previous dose.
7.7.5
Supportive Care Management
Supportive care management for each FRACTION-Gastric Cancer study treatment combination 
and, as necessary, is outlined in the FRACTION-Gastric Cancer Sub-Protocol describing that 
treatment combination.
7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS-supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
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 as outlined in Section 2. 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 the treatment of either a psychiatric or a physical (eg, infectious disease) illness. (Note: 
Under specific circumstances and only in countries where local regulations permit, a 
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participant who has been imprisoned may be permitted to continue as a participant. Strict 
conditions apply and BMS approval is required.)
•
Inability to comply with the protocol
•
Pregnancy
•
Documented disease progression as defined by RECIST v1.1 (see Appendix 5), unless the 
participant meets criteria for treatment beyond progression (see Section 7.4.2) or the 
participant continues study treatment by entering another track or receiving retreatment 
(see Section 5.1.3.3)
•
Clinical deterioration while receiving active study treatment that, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the
participant
•
Discretion of the investigator
•
Protocol-defined reasons for discontinuation (Criteria for permanent discontinuation for each 
FRACTION-Gastric Cancer study treatment combination and/or nivolumab in combination 
with ipilimumab are provided in each FRACTION-Gastric Cancer Sub-Protocol.)
•
End of study
Refer to Section 2
and the On-treatment Procedural Outline(s) specific to each 
FRACTION-Gastric Cancer Sub-Protocol for data to be collected at the time of study treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately notify the BMS Medical Monitor (or 
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). Please notify the BMS 
Medical Monitor (or designee) within 24 hours of awareness of the pregnancy. If the investigator 
determines a possible favorable benefit/risk ratio that warrants continuation of study treatment, a 
discussion between the investigator and the BMS Medical Monitor (or designee) must occur.
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 posttreatment study follow-up, or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or a 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 CRF page.
Additional 
study 
treatment-specific 
discontinuation 
criteria 
are 
provided 
in 
each 
FRACTION-Gastric Cancer Sub-Protocol.
8.1.1
Permanent Discontinuation
Criteria for permanent discontinuation for each FRACTION-Gastric Cancer study treatment 
combination are provided in the FRACTION-Gastric Cancer Sub-Protocol describing that 
treatment combination.
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8.1.2
Study Treatment Combination Arm Discontinuation Criteria
In the event that 20% or more of study participants in a novel FRACTION-Gastric Cancer study 
treatment combination arm of a given track, at any given time, meet any of the toxicity criteria for 
permanent discontinuation (as described in Section 8.1.1), then consideration will be given to 
discontinue that FRACTION-Gastric Cancer study treatment combination arm in that track. This 
will include early side effects seen with combination agents and longer-term effects such as 
endocrinopathies. This action will be taken in consultation with the SMB and will consider other 
pertinent facts in coming to a decision, including the toxicity profile of that combination seen 
outside FRACTION-Gastric Cancer, participant benefit as measured by anti-tumor response, and 
comparison to nivolumab in combination with ipilimumab.
Discontinuation of a study treatment combination arm in a given track for any reason will not lead 
to discontinuation for that combination in all tracks. Safety of all open-label study treatment 
combination arms in other tracks that contain the same agent (or agents) will be assessed by SMB 
and the Sponsor. In the event of serious, unexpected, or life-threatening emergent toxicities, 
relevant study treatment combination arms may then be modified to maintain the safety of 
participants. Decisions on such steps and the re-initiation of any study treatment combination arms 
that had been stopped would be made by SMB in consultation with the Sponsor and relevant 
authorities (eg, IRB/IEC).
8.1.3
Post Study Treatment Study Follow-up
In this study, PFSR is a key endpoint of the study. Post-study follow-up is of critical importance 
and is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed (in this study or a rollover study) for
safety (Section 5).
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed up 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 posttreatment study follow-up, and entered onto the 
appropriate CRF page.
•
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.
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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 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 in Section 2 and the 
On-treatment Procedural Outline(s) specific to each FRACTION-Gastric Cancer 
Sub-Protocol.
•
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 study 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities in Section 2 and the On-treatment Procedural Outline(s) specific to each 
FRACTION-Gastric Cancer Sub-Protocol, 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 that the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities in Section 2 and the On-
treatment Procedural Outline(s) specific to each FRACTION-Gastric Cancer Sub-Protocol.
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9.1
Efficacy Assessments
Disease assessment with contrast-enhanced computed tomography (CT)/MRI scans acquired on 
dedicated CT/MRI equipment is preferred for this study. CT or MRI of the abdomen, chest, pelvis,
and all known sites of disease should be performed for tumor assessments.
CT scans should be acquired with 5-mm slices with no intervening gap (contiguous). Should a 
participant have a contraindication for CT intravenous contrast, a contrast-enhanced MRI of the
chest, abdomen, pelvis, and other known sites of disease may be obtained. MRIs should be 
acquired with slice thickness of 5 mm with no gap (contiguous). Every attempt should be made to 
image each participant using an identical acquisition protocol on the same scanner for all imaging 
time points.
MRI or CT brain scans during on-study treatment and follow-up periods are required only if there 
is a history of brain metastasis or clinically indicated for symptoms that suggest CNS involvement. 
Surveillance MRI should be performed per standard of care (approximately every 12 weeks or 
sooner). Participants with a history of bone metastasis should have a bone scan, if clinically 
indicated.
Assessments will be performed at baseline and at the time points described in each 
FRACTION-Gastric Cancer Sub-Protocol, up to and including Week 24 during the Treatment 
Phase or until disease progression per RECIST v1.1 criteria (see Appendix 5) or confirmed disease 
progression for participants treated beyond progression (defined as an additional 10% increase in 
tumor burden volume with a minimum 5 mm absolute increase from time of initial PD assessment 
[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]), discontinuation of study treatment, or withdrawal 
from the study. Please refer to Section 2 for timing of assessments. Tumor assessments at other 
time points may be performed if the investigator is concerned about tumor progression. 
Assessment of response will be outlined for each combination therapy in the specific FRACTION-
Gastric Cancer Sub-Protocol. Assessments of PR and CR must be confirmed at least 4 weeks after
initial response. Assessment of tumor response will be reported by the investigator for appropriate 
populations of participants, as defined by RECIST v1.1 criteria (see Appendix 5) for participants 
with solid tumors. Same modality/scanner should be used for all assessments.
Changes in tumor measurements and tumor responses will be assessed by the investigator using 
RECIST v1.1 criteria.54 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 CRF based on 
the investigator’s assessment using RECIST v1.1 criteria. (See Appendix 5 and Section 7.4.2 for 
specifics of RECIST v1.1 criteria to be utilized in this study.)
Tumor assessments will be submitted to a third party radiology vendor on an ongoing basis; 
participant management is not dependent on third-party review of tumor assessments.
As a participant’s response to prior therapy is an important part of medical history, additional 
details regarding the previous therapy, including but not limited to best response to therapy, timing 
of progression on prior therapy, method of how the progression was measured, existence of 
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confirmation scan to document progression and detailed information such as other clinical 
evidence (eg, increased pain requiring palliative radiotherapy) to support progression, 
response/progression dates, and reason for discontinuation will be collected in this trial.
9.1.1
Imaging Assessment for the Study
Central assessments are not planned for this study; however, copies of all scans will be stored for 
possible future central analysis, if determined to be necessary by BMS. At the Sponsor’s discretion, 
scans may be collected centrally to be reviewed by independent radiologists.
9.2
Adverse Events
The definitions of an AE or 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, that are considered related to the study treatment or the study, or that caused the 
participant to discontinue before completing the study. 
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 and
continue until 100 days following the last dose of study treatment and at the time points specified 
in the Schedule of Activities (see Section 2 and the On-treatment Procedural Outline(s) specific to 
each FRACTION-Gastric Cancer Sub-Protocol). 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 IBs represent the Reference Safety Information to determine 
expectedness of SAEs for expedited reporting. Following the participant’s written consent to 
participate in the study, all SAEs, whether related or not related to study treatment, must be 
collected, including those thought to be associated with protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). Participants who are randomized and 
never treated with study treatment must have SAEs 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 treatment or protocol-specified procedure.
•
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 section.
•
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
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•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of this 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.
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 CRF.
Immune-mediated AEs 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. Immune-mediated AEs can include events with an alternate 
etiology that were exacerbated by the induction of autoimmunity. Information supporting the 
assessment will be collected on the participant’s CRF.
9.2.2
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. (In order to prevent reporting bias, participants should not be 
questioned regarding the specific occurrence of one or more AEs.)
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 nonserious AEs of special interest (as defined in each 
FRACTION-Gastric Cancer Sub-Protocol) 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.
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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 toward 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 IB and will notify the IRB/IEC, if appropriate according to local requirements.
The Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and Food and Drug 
Administration Code of Federal Regulations 21 CFR Parts 312 and 320. A Suspected, Unexpected 
Serious Adverse Reaction (SUSAR) 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 
5 half-lives- after product administration, the investigator must immediately notify the BMS 
Medical Monitor (or designee) of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Medical Monitor (or designee) within 24 hours of awareness of the event and in 
accordance with SAE reporting procedures described in Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please call the BMS Medical Monitor (or 
designee) within 24 hours of awareness of the pregnancy.
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 
the BMS (or designee). In order for the BMS (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 (eg, 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.
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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).
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 (p-DILI) event. All occurrences 
of p-DILIs, meeting the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 
3 for reporting details).
p-DILI is defined as follows:
•
Aminotransferase (AT) (ALT or AST) elevation > 3 × ULN
AND
•
Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline
phosphatase)
AND
•
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 treatment(s) known to be hepatotoxic or cancer metastases.
The key responsibilities for investigators during p-DILI assessment include the following: (i) early 
detection, medical evaluation (including the exclusion of other potential causes), and rapid 
laboratory confirmation of liver-related abnormalities and (ii) BMS notification of p-DILI cases 
via SAE forms. Following the gathering and assessment of relevant clinical information, BMS is 
responsible for the following: (iii) timely evaluation and triaging of p-DILI cases, (iv) expedited 
reporting of p-DILI cases, and (v) expanded review of p-DILI cases, including a detailed 
assessment of all available clinical information, investigations, and biochemical data.
Investigators are expected to monitor ongoing routine and ad hoc hepatic laboratory test results to 
rapidly determine whether a participant meets p-DILI criteria. They are expected to promptly 
notify BMS of all p-DILI cases. p-DILI cases may be identified by abnormal liver biochemistry 
values, whether or not they are accompanied by liver-related signs and/or symptoms. In both cases, 
expedited confirmation with repeat laboratory testing should occur within 3 business days using a 
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Hepatic Laboratory Panel (ALT, AST, total bilirubin, and alkaline phosphatase). Any participant
with an abnormal Hepatic Laboratory Panel that meets p-DILI criteria is a candidate for study 
treatment discontinuation. Any confirmed p-DILI events must be reported (along with a 
description of the clinical findings) to BMS as an SAE within 24 hours of confirmation. 
An extensive clinical history, examination, and appropriate investigations should be obtained to 
exclude cholestatic and other apparent causes that may explain the observed abnormalities in liver 
function and/or hepatic signs and symptoms. Other apparent causes include, nonexhaustively and 
by way of example only, infectious diseases (such as active hepatitis A, B, and C), congenital 
diseases (such as Gilbert’s syndrome), neoplastic diseases (such as hepatocellular carcinoma), 
autoimmune diseases (such as primary biliary cirrhosis), and the use of concomitant hepatotoxic 
medications (such as antibiotics, oral contraceptive pill, and herbal medicines). All investigations 
to exclude potential causes of liver function abnormalities or hepatic signs and/or symptoms should 
be guided by relevant factors such as the participant’s age, gender, clinical history, and signs and 
symptoms.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, X-ray 
filming, and 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. See Appendix 3 for reporting overdose.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities in Section 2
and the On-treatment Procedural Outline(s) specific to each FRACTION-Gastric Cancer
Sub-Protocol.
9.4.1
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
A local laboratory will perform the analyses and will provide reference ranges for these tests. The 
clinical laboratory assessments are indicated in Table 9.4.1-1.
Results of clinical laboratory tests performed on Day -1 must be available prior to dosing.
Results of all laboratory tests required by this protocol must be provided to BMS, recorded either 
on the laboratory pages of the CRF or by another mechanism, as agreed upon between the 
investigator and BMS (eg, provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the 
appropriate AE page of the CRF (see Section 9.2.6). 
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Table 9.4.1-1:
Clinical Laboratory Assessments
Hematology
CBC with differential including platelets
Serum Chemistry
AST
Total protein
ALT
Albumin
Total bilirubin
Sodium
Direct bilirubin
Potassium
Alkaline phosphatase
Chloride
LDH
Carbon dioxide or bicarbonate
Creatinine
Calcium
BUN or urea
Phosphorus
Uric acid (screening only)
Magnesium
Glucose
Creatine kinase
Amylase
CrCl (screening only)
Lipase
C-reactive protein
Gamma-glutamyl transferase
Urinalysis
Protein
Leukocyte esterase
Glucose
Specific gravity
Blood
pH
Microscopic examination of the sediment if blood, protein, or leukocyte esterase are positive on the dipstick
Serology
Serum for hepatitis A (IgG and IgM) antibody, serum for hepatitis C antibody or hepatitis C RNA (if hepatitis C 
antibody is positive, reflex to hepatitis C RNA), HBsAg, and HIV-1 and HIV-2 antibodies (testing for HIV-1 and 
HIV-2 antibodies must be performed at the sites mandated by local requirements.)
Other Analyses
Pregnancy test (WOCBP only)
TSH with reflex to free T3 and free T4, as applicable
FSH, if needed to document postmenopausal status, as defined in Appendix 4
Abbreviations: BUN = blood urea nitrogen; CBC = complete blood count; FSH = follicle stimulating hormone; 
HBsAg = hepatitis 
B 
surface 
antigen; 
IgG = immunoglobin G; 
IgM = immunoglobin M; 
LDH = lactate 
dehydrogenase; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.
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9.4.2
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.
9.5
Pharmacokinetic
Separate detailed instructions for the collection, processing, handling, labeling, storage, and 
shipment of PK samples will be provided in the Laboratory Procedures Manual. 
The details pertaining to the timing of PK sample collection for Tracks 1 and 2, on treatment and 
follow-up, are provided in each FRACTION-Gastric Cancer Sub-Protocol孱
The serum samples will be analyzed for study treatments. In addition, selected serum samples may 
be analyzed by an exploratory method that measures study treatment for technology exploration 
purposes; exploratory results will not be reported.
Upon implementation of Protocol Amendment 06, PK sample collection is no longer necessary for
any participant who is on study treatment. 
 
 
Please refer to Table 2-3.
9.6
Pharmacodynamics
Pharmacodynamic measures (in the form of biomarker assessments) may be assessed for 
associations with clinical outcomes. 
 
 The sample subtypes and testing plans 
associated with each are described in Section 9.8. Complete instructions on the collection, 
processing, handling, and shipment of all samples described herein will be provided in a separate 
Laboratory Procedures Manual.
Upon implementation of Protocol Amendment 06, samples for pharmacodynamic assessments are 
no longer necessary for any participant who is on study treatment.
 
 
Please refer to Table 2-3.
9.7
Pharmacogenomics
Not applicable.
9.8
Biomarkers
Planned time points for all biomarker assessments are listed in the Schedule of Activities in 
Section 2 and the On-treatment Procedural Outline(s) specific to each FRACTION-Gastric Cancer
Sub-Protocol.
Upon implementation of Protocol Amendment 06, samples for biomarker assessments are no 
longer necessary for any participant who is on study treatment.
 
 
 Please refer to Table 2-3.
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9.8.5
Immunogenicity Assessments
Separate detailed instructions for the collection, processing, handling, labeling, storage, and 
shipment of immunogenicity samples will be provided in the Laboratory Procedures Manual.
The details pertaining to the timing of immunogenicity sample collection for the On-treatment 
Phase and Follow-up are provided in each FRACTION-Gastric Cancer Sub-Protocol孱
The serum samples will be banked for analyses of ADAs by validated immunoassays. In addition, 
selected serum samples may be analyzed by an exploratory method that detects ADAs for 
technology exploration purposes; exploratory results will not be reported. Serum samples 
designated for PK 
 may also be used for immunogenicity analysis, if 
required (eg, insufficient volume for complete immunogenicity assessment or to follow up on 
suspected immunogenicity-related AE).
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9.8.10
Other Assessments
Not applicable.
9.9
Medical Resource Utilization and Health Economics
9.9.1
Patient-reported Outcomes
The effects of GC and its treatment on health status and quality of life will be assessed using the 
3-level version of EQ-5D self-report questionnaire (EQ-5D-3L) and Functional Assessment of 
Cancer Therapy-Gastric (FACT-Ga) Gastric Cancer Subscale (GaCS), and/or Esophagus Cancer 
Subscale (ECS) from the Functional Assessment of Cancer Therapy-Esophageal (FACT-E).58,59,60
Participants will be asked to complete the assessments during on-study clinic visits and/or at 
designated visits during the Safety and Survival Follow-up Phases. The questionnaires will be 
provided in the participant’s preferred language (if available) or in English and may be 
administered by telephone during the Survival Follow-up Phase. A standardized script in the 
participant’s preferred language (if available) will be used to facilitate telephone administration of 
the EQ-5D-3L. Section 2 and the On-treatment Procedural Outline(s) in each FRACTION-Gastric
Cancer Sub-Protocol provide information regarding the timing of patient-reported outcomes 
assessments.
Participants’ reports of general health, functional status, and utility for health will be measured 
using the EQ-5D-3L. The EQ-5D-3L is a standardized instrument used to measure self-reports of 
health status and functioning. The instrument’s descriptive system consists of 5 dimensions, which 
are mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
has 3 levels, reflecting “no health problems,” “moderate health problems,” and “extreme health 
problems.” A dimension for which there are no problems is said to be at Level 1, while a dimension 
for which there are extreme problems is said to be at Level 3. Thus, the vectors 11111 and 33333 
represent the best health state and the worst health state, respectively, described by the EQ-5D-3L. 
Altogether, the instrument describes 35 or 243 health states. Empirically derived weights can be 
applied to an individual’s responses to the EQ-5D-3L descriptive system to generate an index 
measuring the value to society of his or her current health. Such preference-weighting systems 
have been developed for Japan, United Kingdom, US, Spain, Germany, and numerous other 
populations. In addition, the EQ-5D-3L includes a visual analog scale that allows respondents to 
rate their own current health on a 101-point scale ranging from “best imaginable” to “worst 
imaginable” health. 
In addition to the EQ-5D (which all participants will complete), participants will also complete 
one or more disease-specific symptom subscales based on their cancer type:
•
Participants with GC cancer will complete the Functional Assessment of Cancer Therapy-
Gastric (FACT-Ga) Gastric Cancer Subscale (GaCS) 
•
Participants with EC will complete the Esophagus Cancer Subscale (ECS) from the Functional 
Assessment of Cancer Therapy-Esophageal (FACT-E).
•
Participants with GEJ will complete items from both the GaCS and ECS subscales.
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The FACT-Ga is a validated, cancer-targeted measure of disease-related symptoms, functioning, 
and well-being. Nineteen of the FACT-Ga questionnaire’s items comprise the disease-specific 
GaCS, which assesses GC symptoms and impacts relating to pain, reflux, dysphagia, eating 
difficulties, tiredness, weakness, interference, and difficulty planning. Each GaCS item is rated on 
a 5-point scale ranging from 0 (not at all) to 4 (very much). A summary score is derived by 
aggregating responses for the 19 items, with higher scores indicating less symptom burden.
The FACT-E is a validated, cancer-targeted measure of disease-related symptoms, functioning, 
and well-being. Seventeen of the FACT-E questionnaire’s items comprise the disease-specific 
ECS, which assesses esophageal cancer symptoms and impacts relating to swallowing, eating, dry 
mouth, trouble breathing, communicating with others, appetite, coughing, pain and weight loss. 
Each ECS item is rated on a 5-point scale ranging from 0 (not at all) to 4 (very much). A summary 
score is derived by aggregating responses for the 17 items, with higher scores indicating less 
symptom burden.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
Sample sizes are guided by Simon 2-stage (optimal) designs. Because of the different participant 
populations (anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment-naïve versus anti-PD-1, 
anti-PD-L1, or anti-CTLA-4 treatment experienced) and existing options under each track, 
different criteria are applied to determine the number of participants for each stage and the strength 
of the efficacy signal that would recommend proceeding to the next stage. Details are described in 
subsequent sections and in Table 10.1-1. Any additional statistical considerations unique to the 
new treatment combinations will be described in the new sub-protocols.
For sample size calculation and for simplicity of description, recommendations for stopping or 
progressing to the next stage are based on the number of objective responses observed. However, 
since best overall response (BOR) does not necessarily capture the full extent of clinical benefit 
and since response can be delayed or of short duration, BMS will also review other aspects of 
clinical benefit that may better predict OS benefit, such as DOR and PFSR, as well as the relative 
performance of different study treatment combination arms, before making a final determination.
Enrollment will be continued after reaching the indicated number of participants at Stage 1 while 
the initial efficacy evaluation is ongoing. This will allow additional participants to enroll to account 
for unexpected trial impact, such as response nonevaluable participants due to early dropout, 
design parameter change (eg., historical rate update), etc.
Although the sample size calculations are based on efficacy considerations, safety will also be 
continuously assessed and will be taken into account in the decision to continue or terminate a 
study treatment arm. In Track 2, 41 participants per study treatment arm in Stages 1 and 2 
combined will result in 88% probability of detecting an AE that has a true rate of 5%. More 
participants per study treatment arm in Stages 1 and 2 combined will result in a higher probability 
of detecting an AE that has a true rate of 5%.
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Table 10.1-1:
Simon 2-stage (Optimal) Design Considerations
Track
Historical 
ORR/
Target ORR
Stage 1 Responders/Stage 1 n
Stage 2 Responders/Total n
Expected n with 
Historical ORR
Expected n with 
Target ORR
Consider 
Futility
Go to Stage 2
Consider 
Futility
Consider 
Efficacy
1
20%/40%
≤4/19
≥5/19
≤15/54
≥16/54
30.4
51.6
2
5%/20%
≤1/21
≥2/21
≤4/41
≥5/41
26.6
39.8
Note: Numbers of responses serve as a guideline; however, the totality of efficacy data will be considered when making decisions to terminate or continue an arm.
The Track 1 Simon 2-stage (optimal) design assumes a historical response rate of 20% and a target response rate of 40%, based on the 
observed response rate of approximately 24% for the nivolumab in combination with ipilimumab and approximately 12% for nivolumab 
monotherapy participants in Study CA209032. A false positive rate of 5% and power of 90% are used.
Because there is very little data available on participants with prior anti-PD-1, anti-PD-L1, or anti CTLA-4 treatment, the Track 2 design 
is not based on an observed historical response rate. Rather, the assumption is made that a response rate below 5% would not be worth 
further study and that a target response rate of 20% would be worth pursuing in this population. A false positive rate of 5% and power 
of 90% are used.
With regard to sample size, participants who are re-randomized to a different study treatment in Track 2 will be counted once for each 
randomization; participants who are retreated within the same study treatment arm will only be counted once.
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10.1.1
Track 1 - Anti-PD-1, Anti-PD-L1, and Anti-CTLA-4 Treatment-naïve 
Participants
As shown in Table 10.1-1, a minimum of 19 participants in each study treatment combination arm 
will be treated in Stage 1 for an initial evaluation of efficacy. If the total number of responses 
observed in Stage 1 is ≤4/19, the study treatment combination arm would likely not be considered 
efficacious; otherwise, enrollment to Stage 2 will continue, and an additional 35 participants will 
be treated. If the total number of responses at the end of Stage 2 is ≤15/54, the study treatment 
combination arm will be terminated for futility; if there are more than 15 responses observed at 
the end of Stage 2, the study treatment combination arm may be carried on for further treatment 
development. The totality of efficacy data and response profile for each combination arm will be 
considered when making decisions to terminate or continue an arm.
The operating characteristics of this Simon 2-stage (optimal) design are provided in Figure 10.1.1-
1. With the stopping boundaries as shown in Table 10.1-1, if the study treatment combination arm 
has an ORR no better than the historical control at 20%, then there is a 95% overall chance of 
stopping for futility, with a 67% chance of stopping at Stage 1; there is a 5% false positive rate. If 
the study treatment combination arm has an ORR equal to the target of 40%, then there is a 90% 
chance of declaring efficacy after Stage 2, whereas if the true ORR is 25%, 30%, or 35%, the 
power would be 21%, 49%, or 75%, respectively.
Figure 10.1.1-1:
Operating Characteristics of Track 1 Simon 2-stage (Optimal) Design 
(Power = 90%, Alpha = 5%)
Abbreviation: prob = probability.
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If 16 responses are observed at the end of Stage 2 (Declare Efficacy), then the 90% confidence 
interval (CI) for ORR will be (19%, 42%). The CI is calculated using the Clopper-Pearson method.
As stated in Section 10.1, the number of responses given here is used for sample size calculation 
and for simplicity of description. Before making a decision to terminate or continue an arm, BMS 
will also review the totality of all available data, which includes other aspects of efficacy that may 
help predict OS benefit, such as DOR and PFSR; clinical safety information; and biomarker data,
as well as the relative performance of other treatment arms.
10.1.2
Track 2 - Anti-PD-1, Anti-PD-L1, or Anti-CTLA-4 Treatment-experienced 
Participants
For each study treatment combination arm under Track 2, the Simon 2-stage (optimal) design will 
be used. Initially, 21 participants per study treatment combination arm will be treated in Stage 1
and preliminary efficacy will be assessed when those participants are evaluable. If 1 or fewer 
responses are observed in Stage 1, the study treatment combination arm would likely not be 
considered efficacious; otherwise, Stage 2 will be initiated and enroll an additional 20 participants, 
for a total of 41 participants per study treatment combination arm. The totality of efficacy data and 
response profile for each combination will be considered when making decisions to terminate or 
continue an arm.
The operating characteristics of this Simon 2-stage (optimal) design are provided in Figure 10.1.2-
1. With the stopping boundaries as shown in Table 10.1-1, if the study treatment combination arm 
has an ORR no better than 5%, then there is a 95% overall chance of stopping for futility, with a 
72% chance of stopping at Stage 1; there is a 5% false positive rate. If the study treatment 
combination arm has an ORR equal to the target of 20%, then it has a 90% chance of declaring
efficacy after Stage 2.
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Figure 10.1.2-1:
Operating Characteristics of Track 2 Simon 2-stage (Optimal) Design 
(Power =90%, Alpha = 5%)
Abbreviation: prob = probability.
If 5 responses are observed at the end of Stage 2 (Declare Efficacy), then the 90% CI for ORR will 
be (5%, 24%). The CI is calculated using the Clopper-Pearson method.
As stated in Section 10.1, the number of responses given here is used for sample size calculation 
and for simplicity of description. Before making a decision to terminate or continue an arm, BMS 
will also review the totality of all available data, which includes other aspects of efficacy that may 
help predict OS benefit, such as DOR and PFSR; clinical safety information; and biomarker data,
as well as the relative performance of other treatment arms.
Both participants previously treated in any track (re-randomized participants) and new participants 
who meet eligibility criteria are permitted to enter Track 2. Some slots in Track 2 will be reserved 
for re-randomized participants to ensure that both types of participants are enrolled in Track 2. At 
the initiation of the study, recruitment of re-randomized participants will be limited to 
11 participants per Track 2 study treatment combination arm in Stage 1. In Stage 2, recruitment of 
additional re-randomized participants will be limited to 12 participants out of the 27 additional 
participants. The limited number of re-randomized participants may be re-adjusted depending on 
the enrollment rates, the rate of progression in Tracks 1 and 2, and the number of currently open 
study treatment arms in Track 2.
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10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign informed consent
Randomized
All participants who are randomized to any study treatment arm of any track 
in this study
Treated
All participants who are randomized and take at least 1 dose of study 
treatment
PK
All treated participants who have evaluable concentration time data
Immunogenicity
All treated participants who have available immunogenicity assessment data
Biomarker
All treated participants who have available biomarker data
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Population
Description
Response-evaluable
All treated participants with measurable disease and 1 of the following: 1) at 
least 1 postbaseline tumor measurement, 2) clinical progression, or 3) death
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock. Below is a 
summary of planned statistical analyses of the primary and secondary endpoints.
10.3.1
Efficacy Analyses
The primary efficacy analyses will be performed on treated population for the final analysis. 
Efficacy analyses based on the response-evaluable population may be performed for interim 
analyses, when the minimum follow-up period is less than sufficient to warrant adequate 
interpretation of the result. Details on censoring scheme on time-to-event endpoints such as DOR, 
PFS, and OS will be described in the SAP.
Endpoint
Statistical Analysis Methods
ORR
BOR for a participant will be assessed per 
RECIST v1.1 by investigator.
Estimate of ORR and corresponding 2-sided exact 95% CI 
will be derived using the Clopper-Pearson method by study 
treatment under each track.
Median DOR
DOR for a participant with a BOR of CR or PR 
is defined as the time between the date of first 
response and the date of the first objectively 
documented tumor progression per 
RECIST v1.1 or death, whichever occurs first.
Median DOR using the Kaplan-Meier method and 
corresponding 2-sided 95% CI will be derived using 
Brookmeyer and Crowley methodology (using log-log 
transformation) by study treatment under each track.
PFSR at 24 weeks
PFS for a participant is defined as the time from 
the first dosing date to the date of first 
objectively documented disease progression or 
death due to any cause, whichever occurs first.
Estimate by the Kaplan-Meier method and corresponding 
95% CI will be derived based on Greenwood formula by 
study treatment under each track.
OS rate at certain time points
OS for a participant is defined as the time from 
the first dosing date to the date of death due to 
any cause.
Estimate by the Kaplan-Meier method and corresponding 
95% CI will be derived based on Greenwood formula by 
study treatment under each track.
Treatments under each track for different populations will be analyzed independently. There is no 
intention to combine the same study treatment across tracks for efficacy analyses.
Efficacy from retreatment will be assessed and analyzed separately from the initial treatment.
Participants re-randomized into Track 2 will be combined with participants originally randomized 
into Track 2 for efficacy analysis.
Specific analyses to be performed for each track are shown in Table 10.3.1-1.
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Table 10.3.1-1:
Analyses Planned for Each Track
Track
ORR
DOR
PFSR
OS
Track 1
End of Simon Stages 1 and 2
X
X
X
X
Track 2
End of Simon Stages 1 and 2
X
X
X
X
Early Termination at Simon Stage 1
X
X
Track 1 - Anti-PD-1, Anti-PD-L1, and Anti-CTLA-4 Treatment-naïve Participants
The following additional analyses will be performed for Track 1 anti-PD-1, anti-PD-L1, and 
anti-CTLA-4 treatment-naïve participants combined at end of Stage 2. These efficacy analyses 
will be performed when the study treatment arms have been fully enrolled and followed up for at 
least 6 months. A descriptive odds ratio and estimate of the difference in ORRs, along with 
corresponding 2-sided 95% CIs, will be provided to evaluate differences between the 
2 randomized study treatment arms (FRACTION-Gastric Cancer study treatment combination arm 
and nivolumab in combination with ipilimumab control arm). Additionally, for each study
treatment arm, the ORR and corresponding 95% CIs will be calculated using Clopper-Pearson 
method. A descriptive hazard ratio and corresponding 2-sided 95% CI of PFS and OS will be 
estimated in a Cox proportional hazards model using study treatment as a single covariate to 
evaluate difference between the 2 study treatment arms (experimental and control arms). The PFS 
and OS curves for each study treatment arm will be estimated. Two-sided 95% CIs for median 
PFS and OS will be computed. PFSR at 24 weeks and survival rates at certain time points
(eg, 2 years) will be estimated. Associated 2-sided 95% CIs will be calculated.
10.3.2
Safety Analyses
All safety analyses will be performed on the treated population.
Endpoint
Statistical Analysis Methods
Incidence of AEs, SAEs, and AEs 
leading to discontinuation and deaths
AEs will be graded according to 
CTCAE Version 4.03.
Frequency distribution of treated participants with AE using the worst 
CTC grade on treatment. Participants will be counted once at the PT 
level, once at the SOC level, and once in the “Total subject” row at 
their worst CTC grade, regardless of SOC or PT.
Laboratory abnormalities
Laboratory values will be graded 
according to CTCAE Version 4.03.
Laboratory shift table using worst CTC grade on treatment per 
participant.
Abbreviations: CTC = Common Terminology Criteria; PT = preferred term; SOC = system organ class.
Same treatments under different tracks with different populations may be combined for safety 
analyses.
10.3.3
Other Analyses
Not applicable.
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10.3.3.1
Pharmacokinetic Analyses
The concentration-time data obtained in this study may be combined with data from other studies 
in the clinical development program to develop a population PK model. This model may be used 
to evaluate the effects of intrinsic and extrinsic covariates on the PK of each component of each 
FRACTION-Gastric Cancer study treatment combination and/or nivolumab in combination with 
ipilimumab and to determine measures of individual exposure (such as steady-state peak, trough, 
and time-averaged concentration). Model-determined exposures may be used for exposure-
response-analyses of selected efficacy and safety endpoints. Results of population PK and 
exposure-response analyses will be reported separately.
10.3.3.2
Immunogenicity Analyses
Endpoint
Statistical Analysis Methods
Incidence of ADA to individual component of study treatment 
combination arm
Baseline ADA-positive participant is defined as a participant
who has an ADA孰detected sample at baseline.a An 
ADA-positive participant is a participant with at least 
1 ADA-positive sample relative to baseline after initiation of 
the study treatment孱
Frequency distribution of baseline 
ADA-positive participants and ADA-positive 
participants after initiation of the study 
treatment
a Baseline sample is the last sample before initiation of the study treatment.
10.3.3.3
Exploratory Biomarker Analyses
Endpoint
Statistical Analysis Methods
Summary measures of change (or % change) from baseline in 
various biomarkers 
Summary statistics by planned study day and 
treatment under each track; plots of the time 
course of biomarkers
If there is indication of meaningful pattern over time, further analysis (eg, by linear mixed model) 
may be performed to characterize the relationship. Methods such as, but not limited to, logistic 
regression will be used to explore possible associations between biomarker measures 
 
 and clinical outcomes. Additional details will be provided in the 
statistical analysis plan. Exploratory biomarker/pharmacodynamic analysis may be presented 
separately from the main clinical study report.
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10.3.3.4
Outcomes Research Analyses
Endpoint
Statistical Analysis Methods
Summary measures of EQ-5D-3L index and VAS scores and 
GaCS and/or ECS scores with corresponding change from 
baseline for each score
EQ-5D-3L index scores will be derived using the United 
Kingdom weighting algorithm.
Summary statistics by planned study day and 
treatment under each track
Questionnaire completion rate
Defined as the proportion of questionnaires actually received 
out of the expected number
Summary statistics by planned study day and 
treatment under each track
Proportion of participants reporting no, moderate, or severe 
problems in each of the 5 EQ-5D-3L dimensions 
Proportion will be based on the number of participants 
assessed at each assessment time point.
Summary statistics by planned study day and 
treatment under each track
VAS = visual analog scale.
10.3.4
Interim Analyses
Data from individual study treatment arms under each track of this study may emerge at different 
times; timely decisions (including early termination) for each individual study treatment under 
different tracks are needed. Database lock and analysis for certain FRACTION-Gastric Cancer
study treatment combination arms will be performed when all participants in these study treatment 
combination arms (under each track) have completed treatment and with sufficient follow-up. 
Potential interim analyses for each study treatment combination arm under each track at the end 
of Stage 1 (6 months after the first treatment date of the last participant within that arm) will be 
performed. These interim analyses will be performed independent of each other.
The SMB will have access to interim reports of safety and will provide advice to the Sponsor 
regarding study treatment arm termination due to safety concerns.
The statistical analysis plan will further describe the planned interim analyses.
Additional interim analyses may also be performed for administrative purposes or publications. 
No formal inferences requiring any adjustment to statistical significance level will be performed.
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11
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28 Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, 
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51 Spigel DR, et al. Randomized results of continuous vs 1-year fixed-duration in patients with 
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53 Felip E, et al. Three-year follow-up from Checkmate 017/057: Nivolumab versus docetaxel in 
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discussion presentation at the European Society of Medical Oncology Annual Meeting. 2017 
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tumours: revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228-47.
58 Brooks RG. EuroQol: the current state of play. Health Policy 1996;37(1):53-72.
59 Garland SN et al. Prospective Evaluation of the Reliability, Validity, and Minimally Important 
Difference of the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) Quality-of-
Life Instrument. Cancer. 2011;117:1302–12.
60 Darling G, Eton DT, Sulman J, et al. Validation of the Functional Assessment of Cancer 
Therapy Esophageal Cancer Subscale. Cancer 2006;107(4):854-63.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransferase
BATTLE
Biomarker-integrated Approaches of Targeted Therapy for Lung cancer 
Elimination
BMS
Bristol-Myers Squibb Company
BOR
best overall response
BUN
blood urea nitrogen
CD
cluster of differentiation
CI
confidence interval
COVID-19
coronavirus disease 2019
CNS
central nervous system
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CT
computed tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte antigen 4
dMMR
mismatch repair deficient
DOR
duration of response
EC
esophageal cancer
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
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Term
Definition
EOT
end of treatment 
EQ-5D-3L
3-level version of EQ-5D self-report questionnaire
FACT-Ga
Functional Assessment of Cancer Therapy-Gastric
FRACTION
Fast Real-time Assessment of Combination Therapy in 
Immuno-ONcology
FSH
follicle stimulating hormone
FU
follow-up
GaCS
Gastric Cancer Subscale
GC
gastric cancer
GEJ
gastroesophageal junction
GITR
glucocorticoid-induced tumor necrosis factor receptor-related 
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IFNγ 
interferon gamma
IHC
immunohistochemical/immunohistochemistry
IMP
investigational medicinal product
IO
immuno-oncology
IP
investigational product
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology
LAG-3
lymphocyte activation gene 3
LDH
lactate dehydrogenase
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Term
Definition
MRI
magnetic resonance imaging
MSI-H
microsatellite instability-high
NCI
National Cancer Institute
NK
natural killer
NSCLC
non-small cell lung cancer 
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed death-1
p-DILI
potential drug-induced liver injury
PD-L1
programmed death-ligand 1
PD-L2
programmed death-ligand 2
PFS
progression-free survival
PFSR
progression-free survival rate
PID
patient identification number
PK
pharmacokinetic(s)
PR
partial response
prob
probability
PT
preferred term
QTcF
QT interval corrected with Fridericia’s formula
Q2W
every 2 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SMB
Safety Monitoring Board
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Term
Definition
SOC
system organ class
SUSAR
suspected, unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TNFRsf
tumor necrosis factor receptor super family
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
VAS
visual analog scale
WOCBP
women of child-bearing potential
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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 electronic case report form (eCRF) 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 one or more subjects/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/participants. The 
investigator or Bristol-Meyers Squibb (BMS) should also provide the IRB/IEC with a copy of the 
Investigator Brochure or product labeling information to be provided to subjects/participants and 
any updates. 
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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.
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 subjects/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 
subjects/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 subjects/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 subjects/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 by subjects/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. 
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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.
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 subjects/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 subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects’/participants’ signed informed consent form and, in the United States, the 
subjects’/participants’ signed Health Insurance Portability and Accountability Act 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 subjects/participants are the most important 
considerations and should prevail over interests of science and society.
For the Fast Real-time Assessment of Combination Therapies
in Immuno-ONcology 
(FRACTION) Program, participants should receive consent forms that include relevant 
information for all treatments to which they are eligible for enrollment; participants will not 
receive consent forms that include data relevant to agents within the FRACTION Program that are 
not within the Sub-Protocol for which they are screened. Informed consents to Sub-Protocols that 
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are closed, terminated early, or in any way no longer in effect will not be provided to new 
participants as an eligible treatment consent. Participants in any follow-up phase for a 
Sub-Protocol that is closed or terminated will receive pertinent updated safety and risk information 
if it becomes known. Participants in any follow-up phase may receive revised informed consent 
via mail and follow-up phone call by the investigator site.
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).
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.
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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 (eg, 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 standard operating procedures 
(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.
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 adverse events (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 serious adverse events (SAEs) 
and pregnancy, which will be reported on the electronic SAE form and Pregnancy Surveillance 
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form, respectively. If electronic SAE form is not available, a paper SAE form can be used. Spaces 
may be left blank only in those circumstances permitted by study-specific CRF completion 
guidelines provided by Sponsor or designee. 
The confidentiality of records that could identify subjects/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. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. 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
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
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. 
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 
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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, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If
Then
Study treatments supplied by BMS (including 
its vendors)
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, 
or 
to 
meet 
local 
regulations 
(eg, cytotoxics or biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, 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 following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
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method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non-study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national, or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the Signatory Investigator will be selected as appropriate 
based on the following criteria:
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
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 REPORTINGADVERSE 
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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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 serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The durations of 
the washout periods below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels.
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
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End of Relevant Systemic Exposure
End of relevant systemic exposure is the time point where the Investigational Medicinal Product 
(IMP) or any active major metabolites has decreased to a concentration that is no longer considered 
to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in context of 
safety margins from the no-observed adverse effect level or the time required for 5 half-lives of 
the IMP to pass.
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 approximately 5 half-lives after the end 
of study treatment, plus 30 days.
Local laws and regulations may require use of alternative and/or additional contraception methods.
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 ovulation and/or implantation (These methods of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited)b 
−
oral (birth control pills)
−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)b
•
Intrauterine device (IUD)c
•
Intrauterine hormone-releasing system (IUS) (This method of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited) b,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 treatment. 
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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 treatment, 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
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.
•
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 (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal(coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
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.
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•
Male participants are required to use a condom for study duration and until the end of relevant 
systemic exposure defined as approximately 5 half-lives after the end of treatment plus an 
additional 90 days. 
•
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 approximately 
5 half-lives after the end of treatment plus an additional 90 days 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 approximately 5 half-lives plus an additional 90 days after the 
end of treatment. 
•
Refrain from donating sperm for the duration of the study treatment and for approximately 
5 half-lives plus an additional 90 days after the end of 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
RECIST v1.1
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Measurable disease 
is defined by the presence of at least one measurable tumor lesion. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable lesions
Measurable lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm)
•
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
•
20 mm by chest x-ray
•
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.2
Non-measurable lesions
•
All other lesions, including small lesions (longest diameter < 10 mm 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, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that in not 
measurable by reproducible imaging techniques.  
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan or 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.
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1.3.2
Cystic lesions
•
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
•
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same subject, these are preferred for selection as target lesions.
1.3.3
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion. 
1.4
Specifications by methods of measurements
1.4.1
Measurement of lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 28 days before the 
beginning of the treatment.
1.4.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
1.4.2.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated
lung.
1.4.2.3
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
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1.4.2.4
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response.  
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
2.1
Target lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
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 below, 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.
2.1.1
Lymph nodes
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 scan. Only the short axis of these nodes will contribute to the baseline sum. Nodes 
that have a short axis <10 mm are considered non-pathological and should not be recorded or 
followed.
2.2
Non-target lesions
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’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
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3
TUMOR RESPONSE EVALUATION 
3.1
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.
3.1.1
Special notes on the assessment of target lesions
3.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded and should be 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.
3.1.1.2
Target lesions that become ‘too small to measure’
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:
•
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 (note: in case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).   
3.1.1.3
Target 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. 
•
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 
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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’.
3.2
Evaluation 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 (<10 mm short axis).
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) above the normal limits.
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).
3.2.1
Special notes on assessment of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the subject also has measurable disease
•
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 
quality for unequivocal progression status. 
3.2.1.2
When the subject has only non-measurable disease
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that 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. 
•
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are non-measurable) a useful test that can be applied when assessing subjects for 
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: i.e. 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 a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. 
•
If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD 
at that point. 
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3.2.1.3
Tumor markers
Tumor markers alone cannot be used to assess objective tumor responses. If markers are initially 
above the upper normal limit, however, they must normalize in order for a subject to be considered 
as having attained a complete response. 
3.3
New lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new lesion 
should be unequivocal: i.e. 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 subject’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.
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 subject
who has visceral disease at baseline and while on study has a CT or MRI brain scan ordered which 
reveals metastases. The subject’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and 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.
3.3.1
FDG-PET evaluation
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of the qualitative assessment 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: 
•
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
•
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 date of PD will be the date of the initial positive 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.
4
RESPONSE CRITERIA
4.1
Time point response
A response assessment should occur at each time point specified in the protocol.
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For subjects who have measurable disease at baseline Table 1 provides a summary of the overall 
response status calculation at each time point.
Table 1.
Time point response: subjects 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, NE =not evaluable.
4.1.1
Missing assessments and not evaluable designation
When no imaging/measurement is done at all at a particular time point, the subject is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned time point 
response.
4.1.2
Confirmation scans  
•
Verification of Response: Confirmation of PR and CR is required at least 4 weeks later to 
ensure responses identified are not the result of measurement error. To be assigned a status of
CR or PR, changes in tumor measurements must be confirmed by consecutive repeat 
assessments that should be performed no less than 28 days after the criteria for response are 
first met. For this study, the next scheduled tumor assessment can meet this requirement.
•
4.2
Best overall response: All timepoints
The best overall response is determined once all the data for the subject is known. It is the best 
response recorded from the start of the study treatment until the objectively documented 
progression per RECIST v1.1 or subsequent anticancer therapy, whichever occurs first (taking into 
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account any requirement for confirmation). The subject’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. 
Best response is defined as the best response across all time points with subsequent confirmation. 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point as specified in the protocol (generally 4 weeks later). 
In this circumstance, the best overall response can be interpreted as specified in Table 2. When SD 
is believed to be best response, it must meet the protocol specified minimum time from baseline.
Measurements must have met the SD criteria at least once after study entry at a minimum interval 
(in general not less than 6 weeks).
Table 2.
Best overall response when confirmation of CR and PR IS required
Overall response
Overall response
BEST overall response
First time point
Subsequent time point
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
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, NE = not evaluable.
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 
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when subsequent scans suggest small lesions were likely still present and in fact the subject 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.
4.3
Duration of response
4.3.1
Duration of overall response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.
4.3.2
Duration of stable disease  
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
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APPENDIX 6
NIVOLUMAB 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. The frequency and severity of the related 
adverse events covered by these algorithms will depend on the immuno-oncology agent or regimen 
being used.
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APPENDIX 7
ECOG PERFORMANCE STATUS
STATUS
SCALES
STATUS
KARNOFSKY
ZUBROD-ECOG-
WHO
Normal, no complaints
100
0
Normal activity
Able to carry on normal 
activities
Minor signs or symptoms of 
disease
90
1
Symptoms, but fully 
ambulatory
Normal activity with effort
80
Cares for self. Unable to carry 
on normal activity or to do 
active work
70
2
Symptomatic, but in 
bed < 50% of the 
day.
Requires occasional assistance, 
but able to care for most of his 
needs
60
Requires considerable 
assistance and frequent medical 
care
50
3
Needs to be in bed 
> 50% of the day, 
but not bedridden
Disabled. Requires special care 
and assistance
40
Severely disabled. 
Hospitalization indicated 
though death non imminent
30
4
Unable to get out of 
bed
Very sick. Hospitalization 
necessary. Active supportive 
treatment necessary
20
Moribund
10
Dead
0
5
Dead
From:
Minna JD, Higgins GA and Glatstein EJ. Cancer of the lung. In: DeVita V, 
Hellman S, Rosenberg S (Eds.). Cancer:  Principles and Practice of Oncology, 
Lippincott, Philadelphia, 1984, p. 536.
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APPENDIX 8
COUNTRY SPECIFIC REQUIREMENTS 
Countries: Germany, et al. 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 p, i)a
“Known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiency syndrome (AIDS)”to be 
replaced with “Positive test for HIV”.
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APPENDIX 9
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 05, 13-Sep-2019
The FRACTION-Gastric Cancer Master Protocol (CA018003) was updated to include the 
myocarditis adverse event management algorithm in Appendix 6: Nivolumab Management 
Algorithms. 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number 
& Title
Description of Change
Brief Rationale
Title Page
Medical Monitor/Study Director information was updated
Administrative information 
was updated.
Synopsis
The synopsis was updated to align with the protocol 
changes.
The synopsis was updated 
to align with the protocol 
changes.
Section 2 Schedule of 
Activities Table 2-3 
Follow-up Procedural 
Outline
The Note associated with Procedure Patient-reported 
Outcomes Assessment was updated to include the use of 
the Esophagus Cancer Subscale.
With the addition of 
participants with 
esophageal cancer, the
Esophagus Cancer 
Subscale (ECS) from the 
Functional Assessment of 
Cancer Therapy-
Esophageal (FACT-E) 
patient-reported outcome 
assessment was added
Section 4 Objectives 
and Endpoints Table 
4-1 Objectives and 
Endpoints
Exploratory objective “To evaluate disease-related 
symptom improvement, as measured by the GaCS of the 
FACT-Ga in treated participants” was updated to include 
ECS of the FACT-E.
The corresponding endpoint was updated to include ECS 
scores.
Section 9.9.1 Patient-
reported Outcomes
This section was updated to include Esophagus Cancer 
Subscale (ECS) from the Functional Assessment of 
Cancer Therapy-Esophageal (FACT-E). A description of 
when each assessment is used, was added. A description 
of the FACT-E assessment was added. 
Section 10.3.3.4 
Outcomes Research 
Analyses
ECS scores were added to the endpoint “Summary 
measures of EQ-5D-3L index and VAS scores and GaCS 
with corresponding change from baseline for each score.”
Section 5.2 Number of 
Participants
A clarification was made that the number of participants 
is appropriate for Sub-Protocols using a Simon-2 stage 
(optimal) design. For Sub-Protocols not utilizing a 
Simon-2 stage design, a different sample size may be 
used depending on the statistical considerations for those 
treatment combinations. In those cases, sample size will 
be discussed within the individual Sub-Protocols.
This information was 
updated to provide 
clarification.
Section 5.4.1 
Rationale for Duration 
of Therapy
The following statement was removed: “Therefore, in 
FRACTION-Gastric Cancer Sub-Protocol A, treatment 
with BMS-986217 and nivolumab will be extended for up 
to 2 years.”
This statement was 
removed because this 
Master Protocol is not 
specific to Sub-protocol A.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number 
& Title
Description of Change
Brief Rationale
Appendix 6
Nivolumab Management Algorithms were updated to 
include the myocarditis adverse event management 
algorithm.
BMS has updated the 
management algorithms 
associated with nivolumab. 
These new algorithms 
replace the previous 
algorithms. 
All
Typographical errors corrected.
Minor, therefore have not 
been summarized.
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Overall Rationale for the Revised Protocol 04, 03-May-2019
The FRACTION-Gastric Master Protocol was revised to add information about the approval of 
pembrolizumab for the treatment of patients with MSI-H/dMMR cancers with no satisfactory 
alternative treatment options. It was also updated to clarify pretreatment tumor biopsy collection 
timing and assessment of adequacy.
Summary of Key Changes of Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 2 Schedule of 
Activities, 
Table 2-1 Screening 
Procedural Outline
In the note associated with “Mandatory 
Pretreatment Tumor Biopsy,” collection timing 
was updated from “prior to first dose of study 
treatment” to “prior to randomization.” It was 
clarified that the adequacy of the tumor tissue 
must be confirmed by the central laboratory prior 
to randomization.
Collection timing and 
assessment of pretreatment 
tumor biopsies was updated to 
clarify the information for 
study sites.
Section 3.2.1 
FRACTION-Gastric 
Cancer
An update was made to indicate that 
pembrolizumab is an Anti-PD-1 antibody. The 
following information was also added: 
“pembrolizumab is also approved (accelerated 
approval) for the treatment of patients with MSI-
H/dMMR cancers with no satisfactory alternative 
treatment options.”
This update was made to 
explicitly describe anti-PD-1 
as an SOC option for MSI-H 
cancers in lack of satisfactory 
treatment alternatives.
Section 5.1.3.1 Screening
The sentence “Fresh biopsy must be confirmed 
received by the central lab before randomization” 
(per Administrative Letter 02) was removed and 
replaced with “An adequate baseline tumor biopsy 
(as determined by a central laboratory pathologist) 
must be obtained prior to randomization.”
Tissue quality is critical for 
biomarker analysis. Local 
laboratory confirmation has led 
to inconsistent tissue quality 
and missing biomarker data.
Section 6.1 Inclusion 
Criteria
Inclusion Criteria 2) e) i) 5) and Inclusion Criteria 
2) e) ii) 5) were updated: The sentences “Fresh 
biopsy must be confirmed received by central lab 
before randomization. The biopsy sample must 
meet the minimum quality requirements and H&E 
assessment is to be performed primarily at the 
central laboratory.” were removed and replaced 
with “An adequate baseline tumor biopsy as 
determined by a central laboratory pathologist 
must be obtained prior to randomization.”
Assessment of pretreatment 
tumor biopsies was updated to 
clarify the information for 
study sites.
Section 6.1 Inclusion 
Criteria
Inclusion Criteria 2) j) ii) and Inclusion Criteria 2) 
o) ii) were updated to remove the option to have a 
local pathologist assess the adequacy of the biopsy 
tissue quantity and quality.
Tissue quality is critical for 
biomarker analysis. Local 
laboratory confirmation has led 
to inconsistent tissue quality 
and missing biomarker data.
Section 6.2 Exclusion 
Criteria
The following information in bold was added to 
exclusion criteria 3) a): “Under certain specific 
circumstances, and only in countries where local 
regulations permit, a person who has been 
imprisoned may be included or permitted to 
continue as a participant.
This update was made to align 
with the BMS protocol model 
document standards.
Section 7.7.3 Permitted 
Therapy
Language was updated to indicate that vaccines 
containing live/attenuated virus are not permitted 
while on study treatment and until 100 days after 
This update was made to align 
with the program-wide 
standard for nivolumab.
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Summary of Key Changes of Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
the last dose. The option to discuss the use of live 
vaccines with the BMS medical monitor (or 
designee) was removed.
Section 8.1 
Discontinuation from 
Study Treatment
The following note was added to the description 
of participants who are imprisoned or 
involuntarily incarcerated: “Under specific 
circumstances and only in countries where local 
regulations permit, a participant who has been 
imprisoned may be permitted to continue as a 
participant. Strict conditions apply and BMS 
approval is required.”
This update was made to align 
with the current version of the 
BMS Protocol Model 
Document.
Appendix 02: Study 
Governance 
Considerations
Language was updated to indicate that “subject” 
also refers to “participant.” The definition of 
serious breach was updated. A section describing 
“scientific publications” was added. Additional 
minor clarifications were made.
Updates were made to align 
with the current version of the 
BMS Protocol Model 
Document.
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Overall Rationale for the Revised Protocol 03, 05-Feb-2019
The FRACTION-Gastric Master Protocol was revised to expand indication to esophageal cancer 
based on the results of CheckMate-032 clinical study. Added clarification on timing and eligibility for 
efficacy assessment scans at FU1 and FU3.
Sections in synopsis have been updated to align with the protocol section changes listed below.
Summary of Key Changes of Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 2, Schedule of 
Activities; Table 2-1: 
Screening Procedural 
Outline;
Table 2-2: Baseline for 
Re-randomization 
Procedural Outline
In Table 2-1, Notes for Utilize IRT were modified 
and time to randomization is now up to 7 days.
In Table 2-1 and Table 2-2, 12-lead ECG Notes 
now reads as:
ECGs should be recorded after the participant has 
been supine for at least 5 minutes. Record QTcF. 
If ECG abnormality is noted, a repeat ECG 
must be performed.
Compliance with current IRT 
manual.
The bolded phrase was added 
at the end. The requirement to 
perform and evaluate ECG was 
further reinforced with the 
need to perform repeat ECG in 
case of abnormal findings.
Section 2, Schedule of 
Activities; Table 2-3: 
Follow-up Procedural 
Outline;
Section 9.1 Efficacy 
Assessments
In Table 2-3, Tumor Response Assessment Notes 
now reads as: 
All participants should receive scans at FU1 
except for participants who started subsequent 
therapy or participants with PD who have already 
been treated beyond progression.
Scans at FU3 and every 12 weeks (±14 days) will 
only be collected for participants with CR, PR, 
SD, or NE at treatment discontinuation.
Section 9.1 now includes same language for 
consistency with Table 2-3. 
Clarification on timing and 
eligibility for scans at FU1 and 
FU3
Section 3.2 Background;
Section 4 Objectives and 
Endpoints, Table 4-1: 
Objectives and Endpoints;
Section 11 References
Background and Table 4-1 were revised to include 
esophageal cancer (EC). New references are added 
to support EC indication. 
Revised to expand indication 
to EC based on the results of 
CheckMate-032 clinical study 
that demonstrated clinical 
efficacy of nivolumab + 
ipilimumab combination in 
esophagogastric cancers. 
Section 6.1 Inclusion 
Criteria;
2) Type of Participant and 
Target Disease 
Characteristics
Criteria 2) a) modified to be read as:
All participants must have inoperable, advanced, 
or metastatic EC, GC or GEJ carcinoma and have 
histologically confirmed predominant 
adenocarcinoma and/or squamous carcinoma.
Criteria has been modified and 
revised to expand indication to 
EC 
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Summary of Key Changes of Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
Criteria 2) e) i) (5) and Criteria 2) e) ii) (4) has 
been updated to be read as: 
All subjects must consent to the acquisition of 
fresh pre- and on-treatment tumor biopsies for 
performance of correlative biomarker studies. 
Archival specimens may not be substituted for 
fresh baseline specimens but can be submitted to 
help understand the evolution of the tumor (ie, 
PD-L1 expression changes over time) for 
performance of correlative studies. Subjects who 
either do not consent to a pre-treatment tumor 
biopsy or do not have accessible lesions are not 
eligible. Fresh biopsy must be confirmed received 
by central lab before randomization. The biopsy 
sample must meet the minimum quality 
requirements and H&E assessment is to be 
performed primarily at the central laboratory. If 
fresh biopsy is not clinically feasible or safe, the 
option of archival tissue can be discussed with 
BMS if the biopsy was obtained within 90 days of 
study enrollment and there was no intervening 
systemic anticancer or IO therapy. 
Biopsy requirements has been 
updated in order to:
1.
To reflect PD-L1 testing is 
no longer a stratification 
factor and PD-L1 results 
are therefore not relevant 
in screening phase
2.
Ensuring tissue quality 
remains crucial, and this 
was clarified
3.
Option of using archival 
tissue was introduced with 
specific requirements to 
allow optimal correlative 
analyses
Section 6.1 Inclusion 
Criteria, 3) Age and 
Reproductive Status;
Section 9.2.5 Pregnancy
Criteria 3) e) and Section 9.2.5 has been modified 
to add the text to address fetal protection.
Required by POL-009087 
(Women Of Child Bearing 
Potential and Clinical Trials 
Policy)
Section 6.1 Inclusion 
Criteria, Criteria 2) j) and 
Criteria 3) e) i)
These criteria are not applicable after the 
implementation of this revised protocol and “Not 
applicable as per revised protocol 03” has been 
added in the front of both criterias. 
Criteria 2) j) has been revised 
for tumor biopsy and is now 
added as a new criteria 2) o). 
Criteria 3) e) i) is not 
applicable since there is no 
fetal tox information available 
and it is required for 
azoospermic males to follow 
contraception guidelines.
Section 7.7.1 Prohibited 
and/or Restricted 
Treatments
Added to 4th bullet that use of marijuana and its 
derivatives are permitted for treatment of 
symptoms related to cancer treatment.
Marijuana has become 
legalized in many geographic 
regions and is increasingly 
being used for cancer patients. 
Multiple institutions have 
requested the use of marijuana 
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Summary of Key Changes of Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
in the protocol as patients are 
legally utilizing marijuana for 
multiple purposes, including 
but not limited to pain, 
poor/loss of appetite, anxiety, 
anorexia, and nausea.
Section 9.1 Efficacy 
Assessments
Added “As participant’s response to prior therapy 
is an important part of medical history, additional 
details regarding the previous therapy, including 
but not limited to best response to therapy, timing 
of progression on prior therapy, method of how 
the progression was measured, existence of 
confirmation scan to document progression and 
detailed information such as other clinical 
evidence (eg, increased pain requiring palliative 
radiotherapy) to support progression, 
response/progression dates, and reason for 
discontinuation will be collected in this trial.”
Addition of collection of 
details of progressive disease 
in relation to participant’s prior 
therapy.
Text under third paragraph was modified 
regarding brain metastasis and clarification was
added.
Text has been modified to add 
clarification that participants 
with a history of brain 
metastasis or symptoms should 
have a surveillance MRI study 
per standard care. 
Section 9.3 Overdose
Last statement was updated
Modified text to be consistent 
with revised language in 
Appendix 3.
Appendix 3 Adverse 
Events and Serious 
Adverse Events: 
Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, 
and Reporting;
Appendix 4 
Contraception Guidance 
for Female Participants of 
Child Bearing Potential;
Appendix 6 Management 
Algorithms
Mentioned appendices have been updated
Modifications have been made 
to align with the most current 
protocol appendix model 
document 
All
Minor rewording/re-formatting for clarification.
For clarity and consistency 
within the document. 
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Overall Rationale for the Revised Protocol 02, 14-Dec-2017
The FRACTION-Gastric Master Protocol was revised to allow participants with complete 
response, partial response, or stable disease to continue treatment for up to a total duration of 
2 years. Additionally, PD-L1 status was removed as a stratification factor.
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of 
Change
Brief Rationale
Section 2, Schedule of Activities; Table 2-2, 
Baseline for Re-randomization Procedural 
Outline; Section 3.1.1.2, Specific Attributes 
of the FRACTION Program Design; Section 
5.1, Overall Design; Section 5.1.1, 
FRACTION-Gastric Cancer Tracks 1 and 2 
Design; Figure 5.1.1-1, Tracks 1 and 2 Study 
Design Schematic; Section 5.1.3.2, 
Treatment; Section 5.1.3.3, Follow-up; 
Section 5.4.1, Rationale for Duration of 
Therapy
Participants will receive 
treatment of up to 2 years 
total duration.
Emerging data suggest that patients 
may derive clinical benefit beyond 
6 months of immunotherapy. 
Therefore, patients will continue on 
study treatment for up to 2 years and 
re-treatment is not permitted.
Table 2-1, Screening Procedural Outline; 
Section 5.1.3.1, Screening; Section 6.1, 
Inclusion Criteria “2.e.i.5” and “2.e.ii.1”; 
 
Changes made to reflect 
that PD-L1 status will no 
longer be a stratification 
factor, and therefore, 
results will no longer be 
needed before 
randomization
Expression of PD-L1 on tumor is 
not required for clinical benefit 
based on a randomized clinical trial 
in gastric cancer (ATTRACTION 
2). Therefore, PD-L1 will not be 
used as a stratification factor.
Table 2-1, Screening Procedural Outline
1. Duration of 
randomization prior to 
first dose extended
2. Data to be collected on 
toxicities from treatment 
with prior 
immunotherapies
1. To allow patients to complete all 
the post-randomization procedures 
required for a sub-protocol, duration 
between randomization and start of 
treatment can be extended to allow 
for completion of study-related 
tests.
2. For patients previously treated 
with PD-1/PD-L1/CTLA-4, 
enrolling directly into Track 2, we 
will collect additional data on 
details of adverse events with prior 
immunotherapies.
Section 10.1.1, Track 1 - Anti-PD-1, Anti-
PD-L1, and Anti-CTLA-4 Treatment-naïve 
Participants; Section 10.1.2, Track 2 - Anti-
PD-1, Anti-PD-L1, and Anti-CTLA-4 
Treatment-experienced Participants; 
Number of participants 
updated
Updated based on removal of 
prospective stratification of PD-L1
Table 2-3, Follow-up Procedural Outline
ECOG Performance 
Status assessment added 
at Follow-up visits 2 and 
3
Collect performance status during 
follow-up.
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Summary of key changes of Revised Protocol 02
Section Number & Title
Description of 
Change
Brief Rationale
Section 3.1, Study Rationale; Section 3.1.1.1, 
Rationale for the FRACTION Program; 
Section 3.2.1, FRACTION-Gastric Cancer
Included updates from 
recent clinical studies
Throughout
1. Minor rewording/re-
formatting for 
clarification
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