A Phase 2, Real-time Assessment of Combination Therapies in Immuno-Oncology Study in Participants With Advanced Renal Cell Carcinoma (FRACTION-RCC)
Phase: PHASE2
Conditions: Advanced 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 Renal Cell Carcinoma (FRACTION-RCC) 
 
NCT Number: NCT02996110 
Document Date (Date in which document was last revised): 11-Jan-2022 

Page:
1
Protocol Number:
CA018005
IND Number:
131,073
EUDRACT Number
2016-003082-26
Date
23-Aug-2016
Revised Date:
11-Jan-2022
Clinical Protocol CA018005
A Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-ONcology Study in 
Participants with Advanced Renal Cell Carcinoma (FRACTION-RCC)
Protocol Amendment: 07
Incorporates Administrative Letter 04
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
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 
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Clinical Protocol
CA018005
BMS-986217
FRACTION-RCC
Protocol Amendment No.: 07
Date: 11-Jan-2022
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to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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Clinical Protocol
CA018005
BMS-986217
FRACTION-RCC
Protocol Amendment No.: 07
Date: 11-Jan-2022
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment
07
11-Jan-2022
Given the rapidly evolving treatment landscape in renal cell carcinoma (RCC), 
having only 1 patient left on safety follow-up, and the complexity and 
operational challenges faced, the FRACTION-RCC study is planned for 
closure once the last patient finishes the safety follow-up. The planned 
termination of the FRACTION-RCC study is not due to any safety concerns.
Due to planned early closure of the trial, 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
02-Nov-2020
Updates to study personnel
Administrative 
Letter 03
19-Jun-2019
Updates to study personnel
Revised 
Protocol 06
15-Nov-2018
•
Section 2 Schedule of Activities, Table 2-1 Screening Procedural Outline 
in FRACTION-RCC Cancer Revised Protocol was modified to include 
clarification of ECG procedure. 
•
Section 4 Objectives and Endpoints was modified to update 
Tertiary/Exploratory Objective 6 per planned analysis of patient-reported 
outcomes data.
•
Section 6.1 Inclusion Criteria were modified to clarify favorable risk 
profile and Karnofsky Performance Status requirements. 
•
Section 7.7.1 Prohibited and/or Restricted Treatments was modified to 
include language clarifying marijuana use.
•
Section 9.1 Efficacy Assessments was edited to provide language 
consistent with Table 2-1 and clarify collection of details of progressive 
disease in relation to participant’s prior therapy.
•
Paragraphs describing activities related to patient-reported outcomes 
were moved to Section 9.1.2 Patient-reported Outcomes.
•
Other key changes include updates made to safety guidance and/or 
reporting activities to align the protocol with current policies and safety 
parameters, in the following sections: Section 9.2.5 Pregnancy; Section 
9.3 Overdose; 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; and Appendix 6 Hepatic Adverse Event 
Management Algorithm.
Administrative 
Letter 02
20-Jun-2018
Updated study personnel
Revised 
Protocol 05
27-Apr-2018
•
Synopsis was revised to reflect the changes in the protocol body and is 
now included under section 1 in revised protocol 05.
•
Exclusion criteria in FRACTION-RCC Cancer Revised Protocol were 
added to exclude favorable risk patients who have not have been treated 
with sunitinib prior to randomization into Track 1 for treatment with 
nivolumab plus ipilimumab. 
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CA018005
BMS-986217
FRACTION-RCC
Protocol Amendment No.: 07
Date: 11-Jan-2022
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Document
Date of Issue
Summary of Change
•
The Schedule of Activities Table was revised to include collection of risk 
information as defined by International Metastatic RCC Database 
Consortium (IMDC) score (detailed language provided in Appendix 8), 
as well as testing for Methemoglobin level and Glucose-6-phosphate 
Dehydrogenase Deficiency. 
•
Incorporates Appendix 8 International Metastatic RCC Database 
Consortium (IMDC) Prognostic Criteria. 
•
Statistical considerations includes an updated description for enrollment 
of the participants.
•
The trial design and sample size determination were modified to allow for 
enrollment to continue until efficacy evaluation complete.
Revised 
Protocol 04
08-Feb-2018
•
Revised to allow participants to continue treatment for up to a total 
duration of 2 years.
Revised 
Protocol 03
15-Jun-2017
Incorporates Amendment 03
Amendment 
03
15-Jun-2017
•
Change of Study Director/Medical Monitor, Restoration of inadvertently 
deleted neutrophil inclusion criterion and clarification of hemoglobin
inclusion criterion
Administrative 
Letter 01
25-Apr 2017
•
Correction of wording concerning Hepatitis C antibody testing in Table 
2-1 and Table 2-2 and wording concerning Hepatitis A antibody testing 
in Table 9.4.1-1.
Revised 
Protocol 02
01-Mar-2017
Incorporates Amendment 02
Amendment 
02
01-Mar-2017
•
Removal of Legally Authorized Representitive language, Clarification of 
Inclusion Criteria, updates to the procedural outline
Revised 
Protocol 01
28-Sep-2016
Incorporates Amendment 01
Amendment 
01
28-Sep-2016
•
Clarification of the overall study design
Original 
Protocol
23-Aug-2016
Not Applicable
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Clinical Protocol
CA018005
BMS-986217
FRACTION-RCC
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07:
Given the rapidly evolving treatment landscape in renal cell carcinoma (RCC), having only 1 
patient left on safety follow-up, and the complexity and operational challenges faced, the 
FRACTION-RCC study is planned for closure once the last patient finishes the safety follow-up. 
The planned termination of the FRACTION-RCC study is not due to any safety concerns. Due to 
planned early closure of the trial,
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.
Sections in the synopsis have been updated to align with the protocol section changes listed below. 
In addition, this Protocol Amendment 07 incorporates changes from approved Administrative 
Letter 04, which do not appear in the table below.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-2, Baseline 
for Re-
randomization 
Procedural Outline
Added “Not applicable per 
Protocol Amendment 07” in the 
title. 
This change was made to clarify 
the removal of re-randomization
option.
Table 2-3, Follow-
up Procedural 
Outline
Footnote “b” marked as “Not 
applicable per Protocol 
Amendment 07.”
Added footnote “c” for 
clarification.
These changes were made to 
clarify the removal of the re-
treatment/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 coronavirus 
disease 2019 (COVID-19)
vaccination.
This change was made to address 
unknown effects of newly 
available COVID-19 vaccines.
Section 5.1.1,
FRACTION-RCC
Tracks 1 and 2 
Design; 
Section 5.1.3,
Study Phases
Updated language in these sections 
(including footnotes for Figure 
5.1.1-1) for removal of
re-treatment/ re-randomization, 
Response Follow-up, and Survival 
Follow-up related description.
These changes were made to 
clarify the removal of the re-
treatment/re-randomization option, 
Response Follow-up, and Survival 
Follow-up periods for the study.
Section 7.4.2,
Treatment Beyond
Disease 
Progression
Updated with “Not applicable per 
Protocol Amendment 07.”
This change was made to clarify 
the removal of the option for 
treatment beyond progression.
Protocol Amendment No.: 07
Date:11-Jan-2022
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CA018005
BMS-986217
FRACTION-RCC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
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
Study Follow-up;
Section 9.1.2 
Patient-reported 
Outcomes
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
•
Updated text in Section 9.1 to 
clarify discontinuation of 
efficacy assessments.
•
Added text in Section 9.5 
about discontinuing
on-treatment and post-
treatment pharmacokinetics 
sample collection.
•
Added text in Section 9.6 
about discontinuing
on-treatment and post-
treatment pharmacodynamic
assessment collection.
•
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 (non-safety) for 
the study.
Samples will not be collected 
going forward in this protocol, but 
samples collected prior to 
implementation of Protocol 
Amendment 07, may be retained 
for additional research.
Protocol Amendment No.: 07
Date:11-Jan-2022
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Clinical Protocol
CA018005
BMS-986217
FRACTION-RCC
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Appendix 2, Study
Governance
Considerations
•
Added text about remote 
monitoring.
•
Added text on the 
dissemination of clinical study
data.
•
These changes were made to 
clarify conditions where 
remote monitoring can be 
considered.
•
These changes were made to
clarify disclosure of study data 
in compliance with national 
and international standards.
All
Minor formatting and editorial 
changes.
Minor edits that do not change the 
content of the protocol were made 
to improve readability and 
consistency; therefore, they have 
not been summarized.
Protocol Amendment No.: 07
Date:11-Jan-2022
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
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 - RCC ................................................................................... 
 
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-RCC 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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Clinical Protocol
BMS-986217
CA018005
FRACTION-RCC
Protocol Amendment No.: 07
Date:11-Jan-2022
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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 ........................... 
 
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............................................................ 
 
9.1.2 Patient-reported Outcomes ...................................................................... 
 
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 Pharmacokinetics .............................................................................................. 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Peripheral Blood Markers ....................................................................... 
 
9.8.1.1 Whole Blood Single Nucleotide Polymorphism and Genotyping ... 
 
9.8.1.2 Whole Blood for Peripheral Blood Mononuclear Cell-based Assays
............................................................................................................... 
 
9.8.1.3 Serum Factors ................................................................................. 
 
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Clinical Protocol
BMS-986217
CA018005
FRACTION-RCC
Protocol Amendment No.: 07
Date:11-Jan-2022
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9.8.1.4 Circulating Tumor DNA Analysis (Plasma Biomarkers)................ 
 
9.8.2 Tissue Markers from Fresh Tumor Biopsies ............................................ 
 
9.8.2.1 Tissue Biopsies from Participants with RCC .................................. 
 
9.8.2.2 Gene Expression Analyses .............................................................. 
 
9.8.2.3 Protein Expression and Mutation ................................................... 
 
9.8.3 Tissue Markers from Archived Tumor Samples ....................................... 
 
9.8.4 Additional Research Collection ............................................................... 
 
9.8.5 Immunogenicity Assessments ................................................................... 
 
9.8.6 RNA Transcriptome Research.................................................................. 
 
9.8.7 RNA Expression Research of a Subset of RNA Species ........................... 
 
9.8.8 Proteome Research .................................................................................. 
 
9.8.9 Metabolomic Research............................................................................. 
 
9.8.10 Other Assessments ................................................................................. 
 
9.9 Medical Resource Utilization and Health Economics ...................................... 
 
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 . 
 
10.1.2 Track 2 - Anti-PD-1, Anti-PD-L1, or Anti-CTLA-4 Treatment-
experienced Participants ............................................................................ 
 
10.1.3 Tracks 1 and 2 Pharmacodynamic/Biomarker Assessment ................... 
 
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 KARNOFSKY PERFORMANCE STATUS ........................................ 
 
APPENDIX 8 INTERNATIONAL METASTATIC RCC DATABASE 
CONSORTIUM (IMDC) PROGNOSTIC CRITERIA .......................................... 
 
APPENDIX 9 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
 
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Clinical Protocol
BMS-986217
CA018005
FRACTION-RCC
Protocol Amendment No.: 07
Date:11-Jan-2022
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Clinical Protocol
CA018005
BMS-986217
FRACTION-RCC
1
SYNOPSIS
Master Protocol
Protocol Title: A Phase 2, Fast Real-time Assessment of Combination Therapies in 
Immuno-ONcology Study in Participants with Advanced
Renal Cell Carcinoma 
(FRACTION-RCC)
Study Phase: 2
Rationale:
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 immuno-oncology (IO) agents within the Bristol-Myers 
Squibb Company (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 
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 and clinical safety data, as well as pharmacokinetic and 
pharmacodynamic information, as available. Thus, for the FRACTION Program, study treatment 
combinations that have high potential to produce transformational activity compared to the control, 
based on both preclinical and early clinical trials data, will be selected. Other studies 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),” and CA018003, “A Phase 2, Fast Real-time Assessment of Combination 
Therapies in Immuno-ONcology Study in Participants with Advanced Gastric Cancer 
(FRACTION-Gastric Cancer)” have been closed.
Study Population:
The study population consists of participants with advanced (not amenable to curative surgery or 
radiation treatment) or metastatic (American Joint Committee on Cancer Stage IV) RCC and have 
histological confirmation of RCC with a clear-cell component. In Track 1, participants must not 
have received any anti-programmed death 1 (PD-1), anti-programmed cell death ligand 1 (PD-L1), 
or anti-cytotoxic T lymphocyte antigen 4 (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). Track 1 participants with favorable risk profile by IMDC Score must have been treated 
with sunitinib prior to randomization into Track 1 nivolumab plus ipilimumab.
Protocol Amendment No.: 07
Date:11-Jan-2022
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Clinical Protocol
CA018005
BMS-986217
FRACTION-RCC
Track 2 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). All 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) end of treatment 
(EOT), defined as at the time of progression or at the time of a clinically significant event (eg, at 
EOT for participants with partial response (PR) or stable disease or at EOT for participants who 
discontinue treatment due to an AE) provided that the biopsy is an acceptable clinical risk as judged 
by the investigator for each study treatment regimen.
Participants must meet the following criteria:
•
Must be 18 years of age or older with inoperable, advanced or metastatic RCC
•
RCC must be histologically confirmed with a clear cell component.
•
Life expectancy of at least 3 months
•
Must be evaluated for risk of the disease as defined by International Metastatic RCC Database 
Consortium (IMDC) score (Appendix 8).
•
If they have received prior palliative radiotherapy to a non-CNS, treatment must be completed 
2 weeks prior to first dose.
•
Must have at least one measurable lesion (if the only measurable lesion has been irradiated, 
the lesion must have demonstrated clear progression and be measurable).
•
Must agree to 3 biopsies during the study as described in protocol.
•
Toxicities from previous anti-tumoral therapy should be resolved to Grade 1. Exceptions such 
as alopecia and fatigue, as well as long term toxicities which result in sequelae, such as 
neuropathies, are allowed.
•
Must have adequate organ function as reflected by WBC, neutrophils, creatinine, bilirubin, 
hemoglobin, ALT, and AST.
•
Must not have prior active malignancy in the last 3 years, except locally curable cancer that 
has been cured.
•
Must not have received any anti-cancer therapy during the 4 weeks prior to the first dose of 
study treatment.
•
Must not have suspected, known, progressive or untreated CNS metastasis, or CNS as only 
site of disease, unless it has been adequately treated and neurologically returned to baseline.
•
Must not have an autoimmune disease or adrenal insufficiency and must not have received 
corticosteroids or immunosuppressive therapy within 14 days of study treatment 
administration.
•
Must not have experienced prior life-threatening toxicities to IO therapy, have significant 
cardiac disease as described in the protocol, or interstitial lung disease.
•
Women of child bearing potential and males who are sexually active must adhere to the 
guidelines set forth in the protocol (Appendix 4). 
Protocol Amendment No.: 07
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Objectives and Endpoints:
Objectives
Endpoints
Primary
•
To assess the efficacy (ORR, DOR, and PFSR at 
24 weeks) of each FRACTION-RCC study 
treatment combination (relative to nivolumab in 
combination with ipilimumab, when applicable) 
in participants with advanced RCC
•
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-RCC study treatment 
combination in participants with advanced RCC
•
Incidence of AEs, SAEs, AEs leading 
to 
discontinuation, 
deaths, 
and 
clinical laboratory test abnormalities
Abbreviations: AE = adverse event; CR = complete response; BOR = best overall response; DOR = duration of 
response; ORR = objective response rate; PFSR = progression-free response rate; PR = partial response; 
RECIST v1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SAE = serious adverse event.
Overall Design:
•
This is a rolling, Phase 2, adaptive study that uses a control.
•
This is an open-label study.
•
Following screening, participants will be randomized to study treatment at Day 1, Week 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 further randomized to nivolumab in combination with 
ipilimumab or to one of the FRACTION-RCC study treatment combinations stratified by 
whether or not the participant has had prior TKI treatment.
−
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 the FRACTION-RCC study treatment combinations. In addition, participants with 
progression of disease 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. Re-randomization is not applicable per Protocol 
Amendment 07.
Number of Participants: 
In Track 1, up to 63 anti-PD-1/PD-L1 or anti-CTLA-4 treatment-naive participants will be treated 
per study treatment combination. In Track 2, up to 41 participants will be treated per study 
treatment combination.
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 care options under each Track, 
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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. 
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 does not necessarily capture the full extent of clinical benefit and since 
response can be delayed or of short duration, the BMS Medical Monitor (or designee) will also 
review other aspects of clinical benefit that may better predict overall survival benefit, such as 
duration of response and progression-free survival rate, as well as the relative performance of 
different study treatment combination arms, before making a final determination.
Enrollment may continue after reaching the indicated number of participants at Stage 1 while the 
initial efficacy evaluation is ongoing. Additional participants may be enrolled to account for 
participants who may drop out of the study without being evaluable for response or for additional 
considerations that may be needed in Stage 2 such as PK/PD analyses. In such cases, the total 
number of participants enrolled will not exceed the specified total number of participants treated 
in that arm according to Simon 2 stage.
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 adverse event (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%.
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.
Enrollment will be continued during initial efficacy evaluation (ie, with the indicated number of 
participants at Stage 1) to allow additional participants to enroll to account for unexpected trial 
impact, such as response non-evaluable participants due to early drop-out, design parameter 
change (eg, historical rate update), etc.
Treatment Arms and Duration:
Study treatment: 
A table describing the study treatments and dosage information is provided in each 
FRACTION-RCC Sub-Protocol.
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Figure 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.
Re-randomization is no longer applicable per Protocol Amendment 07. 
Abbreviations: CTLA-4 = cytotoxic T-lymphocyte antigen 4; PD-1 = programmed death-1; PD-L1 = programmed 
death ligand 1; RCC = renal cell carcinoma; TKI = tyrosine kinase inhibitor.
•
The total study duration is approximately 7 years and 18 weeks (up to 28-day Screening Phase, 
2-year Treatment Phase, 100-day Safety Follow-up Phase, up to 2-year Response Follow-up 
Phase in parallel with up to 5-year Survival Follow-up Phase), not considering 
re-randomization and retreatment. Two-year Response Follow-up to 5-year Survival Follow-
up Phase is not applicable per Protocol Amendment 07.
•
Participants can receive study treatment for a total duration of approximately 2 years 
(approximately 48 weeks of total treatment) with their Track 1 or 2 randomized study 
treatment combination.
•
Specific dosing and treatment regimens for each FRACTION-RCC study treatment 
combination and/or nivolumab in combination with ipilimumab are outlined in each 
FRACTION-RCC Sub-Protocol.
•
Guidelines for dose reductions and delays due to toxicity and for resuming study treatment for 
each FRACTION-RCC study treatment combination and/or nivolumab in combination with 
ipilimumab are provided in each FRACTION-RCC Sub-Protocol.
•
Participants will generally be allowed to continue study treatment until the first occurrence of 
one of the following: 1) completion of approximately 2 years of study treatment, 2) progressive 
disease (subject to treatment beyond progression, as detailed in Section 7.4.2 of the 
FRACTION-RCC Master Protocol), 3) clinical deterioration suggesting that no further benefit 
from study treatment is likely, 4) intolerable toxicity, 5) meeting of criteria for discontinuation 
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of study treatment, as outlined in Section 8.1 of the FRACTION-RCC Master Protocol. 
Additional study treatment-specific discontinuation criteria are provided in each 
FRACTION-RCC Sub-Protocol.
•
Two independent committees may be utilized: a Safety Monitoring Board and an Independent 
Review Committee.
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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) - Not applicable per Protocol 
Amendment 07, 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 for renal cell carcinoma 
(FRACTION-RCC) Sub-Protocol.
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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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 5 - 7 days prior to first dose. In limited circumstances, if patients cannot be treated 
within 5 - 7 days of randomization due to a study-related test, the duration can be extended 
after discussion with the BMS Medical Monitor (or designee).
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 RCC
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
Includes height and weight.
Vital Signs
X
Obtain vital signs at the screening visit and within 72 hours prior to first dose of assigned 
treatment. Includes body temperature, respiratory rate, seated blood pressure, and heart rate.
Risk information
X
Defined by International Metastatic RCC Database Consortium (IMDC) score (Appendix 8). 
This score will be retrospectively collected for participants randomized prior to protocol 
revision, if possible.
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Table 2-1:
Screening Procedural Outline
Procedure
Screening 
Visita
Notes
Karnofsky 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.
Chest x-ray
X
(see note)
Optional. Baseline chest x-ray (for future comparison) may be performed if considered to be 
clinically relevant per standard of care
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
Includes 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 free T4.
Methemoglobin
X
Methemoglobin should be tested prior to the start of study treatments
Glucose-6-phosphate Dehydrogenase 
Deficiency Testing
X
Glucose-6-phosphate dehydrogenase should be tested prior to the start of study treatment.
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.)
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 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. 
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Table 2-1:
Screening Procedural Outline
Procedure
Screening 
Visita
Notes
Mandatory Pretreatment Tumor Biopsy
X
Biopsy must be performed during the Screening Phase in all participants prior to first dose of 
assigned study treatment. Sample(s) may be retained for additional research.
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 
randomization. (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.
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, and all known 
sites of disease should be performed within 28 days prior to the 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-RCC 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; ECG = electrocardiogram; HBsAg = hepatitis B surface antigen; 
HIV = human immunodeficiency virus; IRT = Interactive Response Technology; MRI =magnetic resonance imaging; NCI = National Cancer Institute; 
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PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; QTcF = QT interval corrected with Fridericia’s formula; RCC = renal cell carcinoma; 
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 (Not applicable per Protocol Amendment 07)
Procedure
Days -1 to -28a
Notes
Eligibility Assessments
X
Participants must continue to meet eligibility criteria; otherwise, discuss with the BMS 
Medical Monitor (or designee). All inclusion/exclusion criteria should be assessed at the re-
treatment/re-randomization baseline visit and confirmed prior to first dose.
Informed Consent
X
Participants must sign informed consent for re-randomization.
Participant Registration for 
Re-randomization
X
Ensure participant continues to meet eligibility for study treatment.
Safety Assessments
Physical Examination
X
If the 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 re-randomization baseline 
and predose evaluation.
Physical Measurements
X
Includes weight.
Vital Signs
X
Includes body temperature, seated blood pressure, and heart rate. 
Karnofsky 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 the BMS Medical Monitor (or designee) 
prior to entering 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.
Risk information
X
Defined by International Metastatic RCC Database Consortium (IMDC) score (Appendix 8). 
This score will be retrospectively collected for participants randomized prior to protocol 
revision, if possible.
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Table 2-2:
Baseline for Re-randomization Procedural Outline (Not applicable per Protocol Amendment 07)
Procedure
Days -1 to -28a
Notes
Laboratory Tests
Includes 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 free T4. 
Methemoglobin
X
Methemoglobin should be tested prior to the start of study treatments
Glucose-6-phosphate Dehydrogenase 
Deficiency Testing
X
Glucose-6-phosphate dehydrogenase should be tested prior to the start of study treatment.
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 site 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 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 
re-randomization. (Note: Fine needle aspiration and bone metastases samples are not 
acceptable for submission.)
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FRACTION-RCC
Table 2-2:
Baseline for Re-randomization Procedural Outline (Not applicable per Protocol Amendment 07)
Procedure
Days -1 to -28a
Notes
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.
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 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-RCC Sub-Protocol as well.
b Within 28 days of first dose of assigned study treatment unless otherwise specified in notes section.
Abbreviations: AE = adverse event; BMS = Bristol Myers Squibb Company; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; ECG = electrocardiogram; FRACTION = Fast Real-time Assessment of Combination Therapy in Immuno-Oncology; HBsAg = hepatitis B surface antigen; 
HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; NCI = National Cancer Institute; PK = pharmacokinetic; QTcF = QT interval 
corrected with Fridericia’s formula; RCC = Renal cell carcinoma; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; 
RNA = ribonucleic acid; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of child-bearing potential.
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Note: On-treatment Procedural Outlines are in the relevant FRACTION-RCC Sub-Protocol.
Table 2-3:
Follow-up Procedural Outline
Procedure
Safety Follow-up
Response/Survival Follow-up
Notes
FU 1
30 Daysa
(± 7 Days)
FU 2
60 Days
(± 7 Days)
FU 3
100 Days
(± 7 Days)
Begins after Completion of 
Safety Follow-up Every 
12 Weeks (± 2 Weeks) until 
2 Years after Last Doseb
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. 
Karnofsky 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-RCC Sub-Protocol
Anti-drug Antibody Samplesc
X
Details are provided in each 
FRACTION-RCC 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
Procedure
Safety Follow-up
Response/Survival Follow-up
Notes
FU 1
30 Daysa
(± 7 Days)
FU 2
60 Days
(± 7 Days)
FU 3
100 Days
(± 7 Days)
Begins after Completion of 
Safety Follow-up Every 
12 Weeks (± 2 Weeks) until 
2 Years after Last Doseb
Monitor for SAEs
X
X
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.
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, 
or 30 days (+ 7 days), except for participants 
with PD who started subsequent therapy or 
have already been treated beyond progression.
Scans at FU3, or 100 days (+ 7 days), and 
every 12 weeks (+ 14 days) will only be 
collected for participants with CR, PR, or SD 
at treatment discontinuation.
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Table 2-3:
Follow-up Procedural Outline
Procedure
Safety Follow-up
Response/Survival Follow-up
Notes
FU 1
30 Daysa
(± 7 Days)
FU 2
60 Days
(± 7 Days)
FU 3
100 Days
(± 7 Days)
Begins after Completion of 
Safety Follow-up Every 
12 Weeks (± 2 Weeks) until 
2 Years after Last Doseb
Patient-reported Outcomes 
Assessmentc
X
X
X
EQ-5D-3L and FKSI-DRS
Can be collected over the phone at regularly 
scheduled time if needed.
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 Days 30, 60, and 100 (± 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 per Protocol Amendment 07:  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 Per Protocol Amendment 07: Assessments necessary for monitoring safety (eg, safety laboratory assesments, oxygen saturation, vital signs, physical 
examinations, 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 and ADA, as well as collection of data for patient-reported outcomes, should be discontinued.
Abbreviations: ADA = anti-drug antibody; AE = adverse event; BMS = Bristol Myers Squibb Company; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; EQ-5D-3L = European Quality of Life self-report questionnaire 3-level version; FKSI-DRS = Functional Assessment of 
Cancer Therapy-Kidney Symptom Index-disease-related symptoms; FRACTION = Fast Real-time Assessment of Combination Therapy in Immuno-Oncology; FU 
= follow-up; MRI = magnetic resonance imaging; NCI = National Cancer Institute; PK = pharmacokinetic; RCC = renal cell carcinoma; RECIST = Response 
Evaluation Criteria in Solid Tumors; SAE = serious adverse event.
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FRACTION-RCC
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. 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.
 
 
 
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 CD2711,12 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 
(RCC).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 a combination of IO agents may lead to enhanced anti-tumor activity 
above that from each agent alone.17 Thus, a 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 spans 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, 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 (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 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 
(NCI-MATCH, NCT02465060), and the American Society of Clinical Oncology’s Targeted Agent 
and Profiling Utilization Registry (TAPUR).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 
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 
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rationale, preclinical toxicology and clinical safety data, as well as PK and pharmacodynamic 
information, 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, 
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 activity compared to the control, based on both preclinical and early 
clinical trials data, will be selected. Other studies 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),” and CA018003, “A 
Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-ONcology Study in
Participants with Advanced Gastric Cancer (FRACTION-Gastric Cancer),” have been closed.
3.1.1.2
Specific Attributes of the FRACTION Program Design
The specific attributes of the FRACTION Program include the following:
•
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 ultimately lead to participant 
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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3.1.1.3
Rationale for Biomarker Assessments
There will be a core group of biomarker assessments (from both the peripheral blood and the 
tumor) 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. The biomarker assessments can 
be grouped as follows:
1) Blood-based biomarkers: Peripheral blood will be obtained prior to and at defined time points 
during treatment (additional details are outlined in Section 9.8) including, but not limited to, 
the following:
a) Multiparameter flow cytometry to assess the phenotype and functional/activation status of 
the immune-effector cells (including, but not limited to, discrete T-cell, myeloid, and NK 
cell populations) in the peripheral blood and how they are altered by study treatment. 
b) Proteomic assessment of various immunologically relevant cytokines, chemokines, soluble 
receptors/proteins, and potentially tumor-specific auto-antibodies, which may provide 
important pharmacodynamic parameters (eg, elicitation of interferon gamma 
(IFNγ)-dependent chemokines representing T-cell activation) as well as exploratory 
information.
c) T-cell receptor sequencing will be performed to detect expansion of antigen-directed T-
cells clones, which may provide evidence of adaptive immune responses against tumor and 
pharmacodynamics information potentially used for combination strategy. 
d) Specific biomarkers for a given asset/disease.
e) Plasma ctDNA for Tumor Mutational Burden Assessment. High tumor mutational burden 
(TMB) is an indication for increased neo-antigen presentation in tumors, which leads to 
recruitment of immune cells to the tumor site and induction of anti-tumor immunity. 
Consequently, high TMB has been correlated with increased response to nivolumab and 
other therapeutics targeting the PD (L)1 axis in NSCLC. TMB can be inferred from ctDNA 
isolated from plasma samples. TMB results from the periphery will be compared with TMB 
results from whole exome sequencing of tumor tissue biopsies if sufficient slides are 
available. Quantitative and qualitative assessment of ctDNA can also provide insight into 
dominant tumor clones and their hierarchy, clonal evolution during treatment, and 
relevance for response and nonresponse. Plasma samples for ctDNA extraction will be 
collected at the indicated time points. and kept frozen at -80°C in storage. Additional use 
of these samples may include analysis of microsatellite instability or other clinically 
relevant biomarkers.
2) Tumor tissue-based biomarkers: Three mandatory biopsies are required at the following 
timepoints: 1) baseline (prior to study treatment); 2) on-study (Day 28 On-treatment); and 
3) end of treatment (EOT), defined as at the time of progression or at the time of a clinically 
significant event (eg, at EOT for participants with partial response (PR) or stable disease (SD) 
or at EOT for participants who discontinue treatment due to an adverse event [AE]). (Details 
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regarding biopsy/processing and timing are outlined in Section 9.8.2.1). Archival tumor tissue 
blocks (preferred) or slides (a minimum of 20 slides) from a primary or metastatic site from all 
participants are to be provided, if available. The assessments to be performed on these fresh 
biopsies and archival tissue include, but are not limited to, the following:
a) Pathological assessment: to include immunohistochemical (IHC) and image analysis 
techniques and to understand the relationship between the type and geographic localization 
of immune effector cells and targets of interest in relation to the tumor and surrounding 
tissue.
b) Whole exome or whole genome sequencing: DNA may be extracted from biopsy 
specimens to monitor somatic mutations that may impact response and other efficacy 
measures. Whole exome, whole genome, or targeted sequencing methodologies may be 
employed. 
Tumor 
mutational 
load 
has 
been 
associated 
with 
response 
to 
immunomodulatory agents, including nivolumab.
c) Gene expression analysis: RNA-seq, and/or similar methodologies, will be used to assess 
gene expression patterns associated with each of the expansion tumor types and to identify 
changes in those gene expression patterns following treatments with. Ultimately, this 
approach may lead to the identification of unique baseline or on-treatment RNA expression 
signatures that could be useful for identifying patients who are likely (or unlikely) to 
respond to the combination therapy. Focus may be given to monitoring a battery of 
immunoregulatory genes associated with cancer cells or cancer-interacting lymphocytes. 
Examples within the latter group include genes associated with T-cells, NK cells, and/or 
IFN-γ signaling. Such genes have been implicated previously in tumor responses or 
rejection.
d) T-cell receptor sequencing of T-cells derived from the tumor (in conjunction with T-cell 
receptor sequencing of peripheral blood T-cells): to monitor the adaptive immune response 
against tumor and add to the pharmacodynamic information that would potentially be used 
in ranking promising combinations.
3.2
Background
3.2.1
FRACTION - RCC
Renal cell carcinoma (RCC) accounts for ∼3% of all cancers in the US.22 More than 60,000 patients 
will be diagnosed with RCC in a year, and approximately 13,000 patients will die from advanced 
disease.23 Metastatic disease is found in 30% of participants at diagnosis. Close to 90% to 95% of 
metastatic disease is of the clear-cell histology.24 With the increased use of imaging over the last 
several decades, the incidence of earlier stage and potentially more curable disease is rising.23
Multiple scoring systems are available to characterize prognosis in treatment-naïve RCC. Two of 
the most commonly used are the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic 
scoring system and the International Metastatic RCC Database Consortium (IMDC) prognostic 
scoring system.25,26 Each of these systems categorizes patients as favorable, intermediate, or poor 
risk based on how many adverse prognostic factors are present (0: favorable risk, 1 to 2: 
intermediate risk, 3 or more: poor risk). The 6 parameters of importance for IMDC prognostic 
score classification are Karnofsky Performance Status (KPS), time from diagnosis to treatment, 
hemoglobin value, corrected calcium concentration, absolute neutrophil count, and platelet count. 
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The 5 parameters included in the MSKCC prognostic score are KPS, nephrectomy status, 
hemoglobin value, lactate dehydrogenase, and corrected calcium concentration. Time from 
diagnosis to treatment is often used in place of nephrectomy status. With each system, total number 
of adverse prognostic factors present has been shown to correlate with OS. Approximately 25% of 
patients are in the favorable-risk group, 50% are in the intermediate-risk group, and 25% are in the 
poor-risk group (OS: ~9 months). In an analysis of 1,028 patients scored using the IMDC system, 
median OS for favorable-, intermediate-, and poor-risk patients is 43.2 months, 22.5 months, and 
7.8 months, respectively.27
Until recently, the cytokines interleukin 2 (IL-2) and interferon alpha (IFNα) were the only active 
treatments for advanced or metastatic RCC. However, due to each of these agent’s limited clinical 
benefit and substantial toxicity profile, newer targeted agents have largely replaced cytokines in 
the treatment of advanced or metastatic RCC.28,29,30,31 The recognition of the importance of 
hypoxia-inducible factor alpha (HIFα) signaling in the pathogenesis of clear-cell RCC has led to 
widespread study of 2 classes of targeted therapies, anti-angiogenic agents and mechanistic target 
of rapamycin (mTOR) inhibitors.32 Targeting of angiogenesis is an appropriate rationale for 
treatment because constitutive HIFα activation leads to the upregulation or activation of several 
proteins including vascular endothelial growth factor (VEGF), which can subsequently lead to 
tumor proliferation and neovasculature formation. Targeting of the mTOR pathway is important 
because activation of the upstream PI3K/Akt/mTOR signaling pathway is one method by which 
constitutive HIFα activation or upregulation occurs. There are 7 agents for the treatment of RCC 
in the US and European Union (EU): 5 that target angiogenesis (ie, the VEGF-receptor tyrosine 
kinase inhibitors (TKIs) sorafenib, sunitinib, pazopanib, and axitinib and the VEGF-binding 
monoclonal antibody bevacizumab plus interferon) and 2 that target the mTOR pathway (ie, 
everolimus and temsirolimus). Among these approved agents, none has demonstrated a statistically 
significant improvement in OS as a first-line therapy except for temsirolimus poor-risk patients. 
According to National Comprehensive Cancer Network guidelines, sunitinib, temsirolimus (poor-
risk only), bevacizumab plus interferon, and pazopanib are Category 1 recommendations for first-
line treatment of metastatic renal cell carcinoma (mRCC).33 According to European Society for 
Medical Oncology guidelines, sunitinib, bevacizumab plus interferon, and pazopanib are all 
standard treatment options for favorable- and intermediate-risk patients, but sunitinib is the only 
one also considered an alternative to temsirolimus for the treatment of poor-risk patients.34
Recently cabozantinib and levantinib have been approved in the US.
Immunotherapeutic approaches have demonstrated clinical efficacy in several advanced solid 
tumor cancers, including melanoma, non-small cell lung cancer (NSCLC), RCC, classical Hodgkin 
lymphoma, recurrent or metastatic sqamous 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.35,36,37 Nivolumab (BMS-936558), a 
programmed cell death protein-1 (PD-1) antibody, and ipilimumab (BMS-734016), a cytotoxic 
T-cell lymphocyte antigen 4 (CTLA-4) antibody, are such immunotherapies that have been 
approved in the US, Europe, Japan, and other countries.38,39,40,41
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Recently, nivolumab monotherapy was approved in the US, Canada, and Europe for the treatment 
of mRCC based on the results from Checkmate 025 (CA209025 A Randomized, Open-label, Phase 
III Study of Nivolumab versus Everolimus in Subjects with Advanced or Metastatic Clear-cell 
Renal Cell Carcinoma who have Received Prior Anti-Angiogenic Therapy, NCT01668784). In this 
study, 803 of the 821 randomized subjects were treated with either nivolumab (n = 406) or 
everolimus (n = 397). At a minimum follow-up period of 14 months, the median OS was 
25.0 months (95% confidence interval [CI], 21.8 to not estimable) in the nivolumab group and 
19.6 months (95% CI, 17.6 to 23.1) in the everolimus group.37 The OS benefit with nivolumab
was observed across prespecified subgroups, including subgroups defined according to region,
MSKCC prognostic score, and number of previous regimens of antiangiogenic therapy. The 
objective response rate (ORR) was higher with nivolumab than with everolimus (25% vs. 5%; 
odds ratio 5.98; 95% CI, 3.68 to 9.72; P < 0.001). PR were observed in 99 patients (24%) in the 
nivolumab group and in 20 patients (5%) in the everolimus group. Complete responses were 
observed in 4 patients (1%) in the nivolumab group and in 2 patients (< 1%) in the everolimus 
group. The median time to response was 3.5 months (range, 1.4 to 24.8) among the 103 patients 
with a response in the nivolumab group and 3.7 months (range, 1.5 to 11.2) among the 22 patients 
with a response in the everolimus group; the median duration of response was 12.0 months (range, 
0 to 27.6) with nivolumab and 12.0 months (range, 0 to 22.2) with everolimus. The median 
progression-free survival (PFS)was 4.6 months (95% CI, 3.7 to 5.4) in the nivolumab group and 
4.4 months (95% CI, 3.7 to 5.5) in the everolimus group (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; 
P = 0.11). The median duration of treatment was 5.5 months (range, < 0.1 to 29.6) with nivolumab 
and 3.7 months (range, 0.2 to 25.7) with everolimus.
To date, nivolumab has been generally well tolerated, with a favorable safety profile relative to 
anticipated toxicities based on an immunostimulatory mechanism of action.42
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may further 
improve anti-tumor activity.43 In vitro combinations of nivolumab plus ipilimumab increased 
IFN-γ 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.22 In addition, combining immunotherapeutic 
agents with different mechanisms of action offers the possibility of further benefit as noted with 
the combination of PD-1 and CTLA-4 inhibitors in the treatment of patients with advanced 
melanoma.13,15 In a Phase 1 study (CA209016 Phase 1 Open-Label, Parallel-group, Dose-
escalation Study of Nivolumab in Combination With VEGFR-TKIs or IPI in Subjects with 
Metastatic RCC, NCT01472081) of nivolumab in combination with ipilimumab in mRCC, the 
combination of nivolumab and ipilimumab demonstrated acceptable safety and evidence of 
antitumor activity in mRCC.44,45,46,47 Grades 3 and 4 events were manageable within established 
treatment guideline. The ORR suggests greater activity than reported previously with nivolumab 
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or ipilimumab monotherapy in RCC. Responses appear durable even after discontinuation of study 
treatment.48
Given the results of the Phase I study of nivolumab and ipilimumab, a Phase 3 study of nivolumab 
combined with ipilimumab was completed in patients with mRCC (CA209214 A Phase 3, 
Randomized, Open-label Study of Nivolumab Combined with Ipilimumab versus Sunitinib 
Monotherapy in Subjects with Previously Untreated, Advanced or Metastatic Renal Cell 
Carcinoma,” NCT02231749). The co-primary objectives of this study were to compare ORR, 
progression-free survival (PFS) (based on Independent Radiology Review Committee 
assessment), and overall survival (OS) of nivolumab combined with ipilimumab to sunitinib 
monotherapy in intermediate and poor-risk participants with previously untreated mRCC. 
Combined immunotherapy with nivolumab plus ipilimumab resulted in a greater ORR (41.6% vs 
26.5%, respectively [P < 0.0001]) and PFS (11.6 months vs 8.4 months, respectively, hazard 
ratio = 0.82 [P = 0.03]) compared to sunitinib in intermediate/poor-risk patients. Median OS was 
not reached in the nivolumab and ipilimumab arm and was 26.0 months in the sunitinib arm, a 
37% reduction in the risk of death (HR, 0.63; 99.8% CI, 0.44-0.89; P < 0.0001). In those with 
PD-L1 expression > 1%, the median PFS was significantly longer with the immunotherapy 
combination than with sunitinib (22.9 vs 5.9 months; HR, 0.48; P = 0.0003). Findings support the 
use of combined nivolumab plus ipilimumab as a potential first-line treatment for patients with 
intermediate/poor-risk metastatic RCC, particularly those patients having tumor PD-L1 expression 
≥1%.49
Taken together, these data support the use of nivolumab in combination with ipilimumab as a 
comparator and suggest that the use of nivolumab in combination with IO treatment has the 
potential to provide clinical benefit to such patients with advanced RCC (see FRACTION-RCC 
Sub-Protocols for details on further combinations).
This document will serve as the Master Protocol for the FRACTION-RCC Study 
(FRACTION-RCC; CA018005). As described above, novel study treatment combinations and/or 
additional controls will be appended as FRACTION-RCC Sub-Protocols. These FRACTION-
RCC Sub-Protocols will evaluate the safety profile, tolerability, preliminary efficacy, PK, and 
pharmacodynamics of novel study treatment combinations in participants with advanced RCC. 
The initial control treatment in the FRACTION-RCC study will be nivolumab in combination with 
ipilimumab followed by nivolumab monotherapy.
3.3
Benefit/Risk Assessment
An overall risk/benefit assessment for each novel FRACTION-RCC study treatment combination 
will be provided in each FRACTION-RCC 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.
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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 Brochures (IBs) 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-RCC study 
treatment combinations.
4
OBJECTIVES AND ENDPOINTS
The overall FRACTION-RCC study-wide objectives are presented in the following sections. Any 
changes to these objectives for specific study treatments are specified in each FRACTION-RCC 
Sub-Protocol.
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the efficacy (ORR, DOR, and PFSR at 24 
weeks) of each FRACTION-RCC study treatment 
combination (relative to nivolumab in combination with 
ipilimumab, when applicable) in participants with 
advanced RCC
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-RCC study treatment combination in 
participants with advanced RCC
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 in the 
peripheral blood and tumor biopsy specimens
•
To explore potential associations between anti-tumor 
activity or safety and select biomarker measures in 
tumor biopsy specimens and peripheral blood prior 
to study treatment and following administration
•
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 changes in disease-related symptoms, as 
measured by the FKSI-DRS, in treated participants 
•
Summary measures of change (or % change) 
from baseline or baseline level biomarker 
measurements in peripheral blood or tumor tissue 
•
Correlation (or similar appropriate measure of 
association) of biomarker measure in peripheral 
blood or tumor tissue 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 scores, 
VAS scores, FKSI-DRS scores, and 
corresponding change from baselines for each 
score
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To evaluate general health, functional status, and 
utility for health using the EQ-5D-3L in treated 
participants 
Abbreviations: AE = adverse event; ADAs = anti-drug antibodies; CR = complete response; BOR = best overall 
response; DOR = duration of response; EQ-5D-3L = 3-level version of EQ-5D self-report questionnaire; 
FKSI-DRS = Functional Assessment of Cancer Therapy-Kidney Symptom Index-disease-related symptoms; 
FRACTION = Fast Real-time Assessment of Combination Therapy in Immuno-Oncology; IP = investigational 
product; ORR = overall response rate; OS = overall survival;; PFSR = progression-free survival rate; 
PK = pharmacokinetic; RCC = renal cell carcinoma;  SAE = serious adverse event; VAS = visual analog scale.
AEs and laboratory values will be graded according to NCI 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-RCC study treatment combinations 
in participants with advanced RCC. All novel treatment combinations will contain nivolumab. The 
details pertaining to the specific study treatment regimens are provided in each FRACTION-RCC 
Sub-Protocol.
Participants will be enrolled in 1 of 2 Tracks. Participants who are anti-PD-1, anti-PD-L1, and 
anti-CTLA-4 treatment naïve will be eligible for Track 1 and will be stratified by whether or not 
the participant has had prior TKI treatment. Participants who have had prior anti-PD-1, 
anti-PD-L1, or anti-CTLA-4 treatment will be assigned to Track 2, as outlined in Figure 5.1-1 and 
described in Section 5.1.1. 
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-RCC Sub-Protocol. 
Participants on Tracks 1 and 2 will be treated until completion of the Treatment Phase, progression, 
toxicity, or protocol-specified discontinuation (see Section 8.1).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 progressive disease (PD) will 
have the option to enter into Track 2, assuming that he or she continues to fulfill all eligibility 
criteria at each new randomization point, including a life expectancy of ≥3 months (see 
Section 5.1.1). Re-randomization is no longer applicable per Protocol Amendment 07. 
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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). Enrollment may continue after reaching the indicated 
number of participants at Stage 1 while the initial efficacy evaluation is ongoing. Additional 
participants may be enrolled to account for participants who may drop out of the study without 
being evaluable for response or for additional considerations that may be needed in Stage 2 such 
as PK/PD analyses. In such cases, the total number of participants enrolled will not exceed the 
specified total number of participants treated in that arm according to Simon 2 stage. The number 
of participants planned for enrollment may vary by Track and is described in Section 10.1. 
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.
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.
Re-randomization is no longer applicable per Protocol Amendment 07. 
Abbreviations: CTLA-4 = cytotoxic T-lymphocyte antigen 4; PD-1 = programmed death-1; PD-L1 = programmed 
death ligand 1; RCC = renal cell carcinoma; TKI = tyrosine kinase inhibitor.
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-RCC 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, 
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ADA, and pharmacodynamic analyses. Participants may withdraw or discontinue at any time 
based on criteria in Section 8.1. 
5.1.1
FRACTION-RCC 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-RCC study treatment combinations. Randomization will be stratified by 
whether or not the participant has had prior TKI treatment. 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 the 
FRACTION-RCC 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 CR, PR, or SD at the end of 2 years on Track 1 or 2 Treatment Phase will:
−
Enter study safety follow-up (FU) and complete FU1, FU2, and FU3 visits
•
Participants with PD during the Track 1 or 2 Treatment Phase will:
−
Enter study follow-up (Not applicable per Protocol Amendment 07)
−
Enter (or re-enter) Track 2, if eligible and if a new study treatment combination is available, 
and be randomized to a new combination. (Re-randomization is no longer applicable per 
Protocol Amendment 07)
−
Continue treatment beyond progression if criteria in Section 7.4.2 are met. (Not applicable 
per Protocol Amendment 07)
−
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 (or re-enter) Track 2, if eligible and if a new study treatment combination is available, 
and be randomized to a new combination. (Re-randomization is no longer applicable per 
Protocol Amendment 07)
−
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. Alternatives must be discussed with the 
BMS Medical Monitor (or designee).
a For Track 1, stratify by TKI treatment.
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 per Protocol Amendment 07: 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 per Protocol Amendment 07: 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 5.1.3.3 for details).
f Not applicable per Protocol Amendment 07: 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; FRACTION = Fast Real-time Assessment of Combination Therapy in Immuno-Oncology; PD = progressive disease; 
PR = partial response; RCC = renal cell carcinoma; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease.
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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, 
progression-free survival rate (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, anti-CTLA-4, or TKI treatment through their 
Institutional database, participant medical history, or Institutional prescreening process. Once 
determined, treatment experience is considered source data for this FRACTION-RCC study. The 
participant must be provided with the FRACTION-RCC 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 to the central laboratory. 
An adequate baseline tumor biopsy (as determined by a central laboratory pathologist or a local 
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-RCC Sub-Protocol. Study assessments are to be 
collected as outlined in the On-treatment Procedural Outline(s) in each FRACTION-RCC
Sub-Protocol.  
Assessment of response will be outlined for each combination therapy in the specific 
FRACTION-RCC 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 approximately 2 years of study treatment, 2) PD 3) clinical 
deterioration suggesting that no further benefit from study treatment is likely, 4) intolerable 
toxicity, 5) the 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 (Section 8.1 in the FRACTION-RCC Master Protocol and 
Section 8.1 in the FRACTION-RCC 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 07, 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 07, tumor scans, survival status follow-up, 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-RCC 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 are re-randomized into Track 2.
5.2
Number of Participants
In Track 1, up to 63 anti-PD-1/PD-L1 or anti-CTLA-4 treatment-naive participants will be treated 
per study treatment combination. In Track 2, up to 41 participants will be treated per study 
treatment combination. See Section 10.1 for details.
5.3
End of Study Definition
The start of the trial is defined as first visit for first participant screened. End of trial 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. To determine which 
combinations show the most clinical promise and thus 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, tumor 
biopsies, 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 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.
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 the 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
PFS compared to those who were randomized to stop treatment, with median PFS (post-
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randomization) not reached vs 10.3 months, respectively; 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.50
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 non-small cell lung cancer (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 overall survival (OS) curve begins to plateau after 2 years, with an OS rate of 25% at 2 years 
and 18% at 3 years.51 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).52
Taken together, the data suggest a shorter duration of nivolumab 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. Therefore, in 
study CA018005, treatment with BMS-986217 and nivolumab will be extended for up to 2 years 
in this study.
5.5
Justification for Dose
Please refer to individual FRACTION-RCC Sub-Protocols for their respective dose justifications.
6
STUDY POPULATION
For entry into the FRACTION-RCC study (per FRACTION-RCC Master Protocol), the following 
criteria MUST be met prior to dosing on Day 1. For entry into a study treatment per a 
FRACTION-RCC Sub-Protocol, additional treatment-specific criteria, if applicable, must also be 
met.
No exceptions will be granted.
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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 3 mandatory tumor biopsy samples (as detailed in 
“2)j)” below).
2) Type of Participant and Target Disease Characteristics
a) All participants must have advanced (not amenable to curative surgery or radiation 
treatment) or metastatic (American Joint Committee on Cancer Stage IV) RCC
b) Histological confirmation of RCC with a clear-cell component 
c) Prior adjuvant or neoadjuvant treatment with IL-2, INFα, or radiotherapy is permitted as 
long as the last administration of the last regimen (whichever was given last) occurred at 
least 4 weeks prior to randomization.
d) Prior treatment with targeted agents such as TKIs or antiangiogenic monoclonal antibodies 
are eligible.
e) Track-specific eligibility criteria
i)
Track 1: anti-PD-1, anti-PD-L1, or 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 had prior treatment for progressive or recurrent disease. 
(a) Participants who have received IL-2 or INFα are eligible.
(b) Participants may have received targeted treatment (see above)
(3) Not applicable per Amendment 02.
(4) After signing informed consent, participants will be required to submit a fresh 
tumor biopsy prior to treatment as described below [see “6.1.2)j)”]. Participants 
must have an adequate tumor biopsy (as determined by a central laboratory 
pathologist or a local pathologist) prior to randomization.
(5) Participants must be evaluated for risk of the disease as defined by International 
Metastatic RCC Database Consortium (IMDC) score. (Appendix 8).
(6) Based on the results from CheckMate-21453, participants with favorable risk profile 
by IMDC Score must have been treated with sunitinib prior to randomization into 
Track 1 nivolumab plus ipilimumab.
(7) Karnofsky Performance Status (KPS) must be ≥70% (Appendix 7).
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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 who have had prior treatment with any 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-RCC Sub-Protocol are eligible for treatment on Track 2. 
(3) Participants who have had prior combination treatment with the same combination  
agents (or IO agents directed against the same targets) as 1 of the combination 
regimens in a FRACTION-RCC 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-RCC Sub-Protocol).
(4) Participants may have received targeted treatment (see above).
(5) After signing informed consent, participants will be required to submit a fresh 
tumor biopsy prior to treatment as described below [see “6.1.2)j)”]. Eligibility will 
not be determined by this biopsy. 
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. 
i)
Participants who wish to be re-randomized to a new study treatment combination in 
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) has 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.
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j)
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 or local 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, drainage of pleural effusions with cytospins, 
or punch biopsies are not considered adequate for biomarker review and randomization. 
Biopsies of bone lesions that do not have a soft tissue component or decalcified bone 
tumor samples are also not acceptable.
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) Not applicable per Amendment 02
iv) Not applicable per Amendment 03
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)
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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
i)
Platelets ≥100×103/μL (transfusion to achieve this level is not permitted within 
4 weeks of the first study treatment administration)
ii) Hemoglobin ≥9.0 g/dL (transfusion to achieve this level is not permitted within 
4 weeks of the first study treatment administration)
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.
3) Age and Reproductive Status
4) In addition to the reproductive guidelines noted below, please refer to the individual sub-
protocol for additional requirements regarding reproductive guidelines.
a) Males and females, ages 18 years or age of majority 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-RCC Sub-Protocol is longer than approximately 5 half-lives of 
nivolumab, this will be addressed in the FRACTION-RCC Sub-Protocol.
e) WOCBP who are continuously not heterosexually active are also exempt from 
contraceptive requirements and still must undergo pregnancy testing as described in this 
section.
f)
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 posttreatment 
completion. In addition, male participants must be willing to refrain from sperm donation 
during this time. 
g) Azoospermic males are exempt from contraceptive requirements.
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Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception (Appendix 4),
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) 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.
b) 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.
c) Participants must not have other active malignancy requiring concurrent intervention.
d) Participants must not have received a prior organ allograft.
e) Participants must not have received any anti-cancer treatment (eg, chemotherapy, 
radiotherapy [except for palliative radiotherapy, which can be received up to 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 or hormonal treatment) and who 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. 
f)
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.
ii) Participants must not have uncontrolled adrenal insufficiency.
g) 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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h) 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.
i)
Participants must not have interstitial lung disease that is symptomatic or may interfere 
with the detection or management of suspected treatment-related pulmonary toxicity.
j)
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)
k) Participants who require daily supplemental oxygen treatment are excluded.
l)
Participants must not have any positive test result for hepatitis B virus or hepatitis C virus 
(HCV) indicating presence of virus, eg, 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.
m) Participants must not have evidence of active infection requiring antibacterial, antifungal, 
or antiviral treatment ≤7 days prior to initiation of study treatment.
n) 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.
o) Participants must not have known or suspected active tuberculosis.
p) Participant must not have had any major surgery (eg, nephrectomy) within 4 weeks of study 
treatment administration. Participants must have recovered from the effects of major 
surgery or significant traumatic injury at least 14 days before the first dose of study 
treatment.
q) 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.
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r)
Participants must not have received packed red blood cell or platelet transfusion within 
4 weeks prior to the first dose of study treatment.
s) 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, 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 a 
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.
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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 
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-investigational [Medicinal] Product (Non-IP/Non-IMP) and is described in each 
FRACTION-RCC 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, rescue medications) will be considered study treatment. A table 
describing the study treatments and dosage information is provided in each FRACTION-RCC
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- RCC Sub-Protocol. Study treatment will 
be dispensed at the study visits as listed in the On-treatment Procedural Outline(s) in each 
FRACTION-RCC 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 00001 (eg, 00001, 00002, 00003...00010). 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 0001-00001. The following information is required for 
enrollment:
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•
Date of obtaining informed consent 
•
Date of birth
•
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 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-RCC Sub-Protocol. If, within a given Track, study treatment arms 
from more than 1 FRACTION-RCC Sub-Protocol within the FRACTION-RCC 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, randomization of participants will be stratified by whether or not 
the participant has had prior TKI treatment. In Track 1, participants will be randomized to newly 
added study treatment arms/study treatments (through FRACTION-RCC Sub-Protocols) in a ratio 
as specified in each new FRACTION-RCC Sub-Protocol. New randomization schedules for new 
FRACTION-RCC Sub-Protocols will be generated. If accrual for current FRACTION-RCC
Sub-Protocols is still ongoing, participants will be allocated to the existing randomization schedule 
or new randomization schedule based on a prespecified allocation ratio. Details of allocation ratio 
will be specified in the new FRACTION-RCC Sub-Protocol. In Track 2, participants will be 
randomized to existing study treatment arm/study treatments and newly added study arm/study 
treatments with equal probability. 
Prespecified study treatment arm caps (according to Simon 2-stage [optimal] design) will be 
utilized to control the accrual for each combination study treatment 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 
postbaseline tumor measurements and no evidence of clinical progression or death due to disease 
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progression), the enrollment cap for that study treatment arm may be correspondingly raised if 
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-RCC study treatment combination 
and/or nivolumab in combination with ipilimumab are outlined in each FRACTION-RCC 
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-RCC study treatment combination and/or nivolumab in combination with 
ipilimumab are provided in each FRACTION-RCC Sub-Protocol.
7.4.2
Treatment Beyond Disease Progression
Accumulating evidence indicates that a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.54
Participants will be permitted to continue on study treatment beyond initial RECIST v1.1-defined 
PD as long as they meet the following criteria:
•
Participant had investigator-assessed clinical benefit.
•
Participant continues to meet relevant eligibility criteria, as determined by the BMS Medical 
Monitor (or designee) in discussion with the investigator.
•
Participant has stable performance status.
•
Participant is tolerating study treatment.
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases).
•
Participant provides written informed consent prior to receiving additional study treatment. All 
other elements of the main consent including description of reasonably foreseeable risks or 
discomforts, or other alternative treatment options will still apply.
The decision to continue study treatment beyond initial investigator-assessed progression should 
be discussed with the BMS Medical Monitor (or designee) and documented in the study records. 
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A follow-up scan should be performed at the next scheduled imaging evaluation (per the 
FRACTION-RCC Sub-Protocol) (but no sooner than 6 weeks) to determine whether there has been 
a decrease in the tumor size or continued PD. The assessment of clinical benefit should be balanced 
by clinical judgment as to whether the participant is clinically deteriorating and unlikely to receive 
any benefit from continued study treatment. If the investigator feels that the participant continues 
to achieve clinical benefit by continuing study treatment, the participant should remain on the 
study and continue to receive monitoring according to the On-treatment Procedural Outline 
specific to each FRACTION-RCC Sub-Protocol.
For participants who continue study treatment beyond initial RECIST v1.1-defined PD, further 
progression is defined as an additional 10% increase in tumor burden volume with a minimum 
5 mm absolute increase from time of initial PD assessment. This includes an increase in the sum 
of diameters of all target lesions and/or the diameters of new measurable lesions compared to the 
time of initial PD. New lesions are considered measurable at the time of initial progression if the 
longest diameter is at least 10 mm (except for pathological lymph nodes which must have a short 
axis of at least 15 mm). Any new lesion considered nonmeasurable at the time of initial progression 
may become measurable and therefore included in the tumor burden if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes which must have a short axis of 
at least 15 mm). In situations where the relative increase in total tumor burden by 10% is solely 
due to inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm. Study treatment should be discontinued in any participant for 
whom these criteria are met and should be documented. 
Not applicable per Protocol Amendment 07.
7.4.3
Management Algorithms for IO and Oncology Agents
IO agents are associated with adverse events (AE)s 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
The clinical nature of AEs noted with each FRACTION-RCC 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. 
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The management algorithms recommended for utilization for IO and non-IO agents are included 
in Appendix 6 and in each FRACTION-RCC Sub-Protocol, if not currently in the master protocol.
7.4.4
Treatment of Treatment-related Infusion Reactions
Treatment of study treatment-related infusion reactions for each FRACTION-RCC study treatment 
combination and/or nivolumab in combination with ipilimumab is provided in each 
FRACTION-RCC Sub-Protocol.
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 contact BMS 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, 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, 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
Not applicable.
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.
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7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following prohibitions and restrictions apply to all FRACTION-RCC Sub-Protocols for the 
FRACTION-RCC study. Additional FRACTION-RCC Sub-Protocol-specific prohibitions and/or 
restrictions are outlined in each FRACTION-RCC Sub-Protocol.
The following medications are prohibited during the Treatment Phase of the study:
•
Immunosuppressive agents (except for those stated in Section 7.7.3) are prohibited, unless they 
are utilized to treat an AE.
•
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.
•
Vaccines (except for those stated in Section 7.7.3) are prohibited.
•
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.
•
Any concurrent anti-neoplastic treatment (ie, chemotherapy; immunotherapy; extensive, 
nonpalliative radiation treatment; or standard or investigational agents for treatment of RCC) 
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, or 
pacemakers, 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). Adrenal replacement steroid doses of 
prednisone > 10 mg daily are permitted. A brief course (less than 3 weeks) of corticosteroids 
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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. 
Nonabsorbed 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/day 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. Influenza vaccines containing live virus or other clinically indicated 
vaccinations for infectious diseases (ie, Pneumovax®, varicella vaccine, etc) may be permitted 
but must be discussed with the BMS Medical Monitor (or designee) and may require a study 
treatment washout period prior to and after administration of the vaccine.
•
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-RCC 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, radiotherapy-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. 
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 
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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-RCC study treatment combination and/or 
nivolumab in combination with ipilimumab, as necessary, is outlined in each FRACTION-RCC 
Sub-Protocol.
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 or her or persons previously 
authorized by participant to provide this information
•
Any clinical AE, laboratory abnormality, or intercurrent illness, which, 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
•
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 (Section 5.1.3.3)
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•
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-RCC study treatment combination and/or nivolumab in combination with 
ipilimumab are provided in each FRACTION-RCC Sub-Protocol.)
•
End of study
Refer to Section 2 and the On-treatment Procedural Outline(s) specific to each FRACTION-RCC 
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 onto the 
appropriate CRF page.
Additional 
study 
treatment-specific 
discontinuation 
criteria 
are 
provided 
in 
each 
FRACTION-RCC Sub-Protocol.
8.1.1
Permanent Discontinuation
Criteria for permanent discontinuation for each FRACTION-RCC study treatment combination 
and/or nivolumab in combination with ipilimumab are provided in each FRACTION-RCC 
Sub-Protocol.
8.1.2
Study Treatment Combination Arm Discontinuation Criteria
In the event that 20% or more of study participants in a novel FRACTION-RCC 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), then consideration will be given to discontinue that 
FRACTION-RCC 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 
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decision, including the toxicity profile of that combination seen outside FRACTION-RCC, 
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 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 for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him or 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.
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.
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•
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-RCC 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-RCC 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-RCC Sub-Protocol.
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.
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MRI or CT brain scans during on-study treatment and follow-up periods are required only if 
clinically indicated for new signs and symptoms that suggest CNS involvement. 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 with PD who started subsequent therapy or have 
already been treated beyond progression. Scans at FU3 will only be collected for patients with CR, 
PR, or SD at treatment discontinuation.
Assessments will be performed at baseline and at the time points described in each 
FRACTION-RCC 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 the 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. Assessments will also be performed 30, 60, and 100 days after discontinuation of 
study treatment (ie, safety follow-up Visits 1; 2, and 3 for all participants). 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-RCC 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.55 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 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 (e.g., 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.
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9.1.2
Patient-reported Outcomes
The effects of RCC and its treatment on health status and quality of life will be assessed using the 
3-level version of the EQ-5D self-report questionnaire (EQ-5D-3L) and the Functional Assessment 
of Cancer Therapy-Kidney Symptom Index-disease related symptoms (FKSI-DRS).56,57
Participants will be asked to complete the EQ-5D-3L and FKSI-DRS during on-study clinic visits 
and during safety follow-up. The questionnaires will be provided in the participant’s preferred 
language if available and may be administered by telephone. A standardized script will be used to 
facilitate telephone administration of the EQ-5D. A similar script does not exist for the FSKI-DRS, 
though participants will be provided with a hard copy of the questionnaire to take home and use 
as a visual aid during telephone interviews. For those patients not able to vocalize the questionnaire 
response over the phone, they can complete it via pen and paper (initial and date each page) and 
mail or email to the site. Section 2 and the On-treatment Procedural Outline(s) in each 
FRACTION-RCC 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: 
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, the 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. 
The FKSI-DRS is a 9-item index of the most important symptoms associated with kidney cancer. 
The questionnaire was developed to accommodate the needs of clinical investigators interested in 
evaluating the efficacy and safety of new treatments or treatment combinations for advanced 
kidney cancer. The FKSI-DRS includes items measuring general symptoms (eg, pain, lack of 
energy, weight loss, bone pain, fatigue) as well as disease-related symptoms (eg, shortness of 
breath, coughing, fevers, blood in urine). Each 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 9 items with 
higher scores indicating less symptom burden.
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
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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, at the time points specified in 
the Schedule of Activities (see Section 2 and the On-treatment Procedural Outline(s) specific to 
each FRACTION-RCC 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 the 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. 
•
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 or 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.
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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-RCC 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.
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, Food and Drug 
Administration, and Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR 
(Suspected, Unexpected Serious Adverse Reaction) is a subset of SAEs and will be reported to the 
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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 Medical Monitor (or designee). In order for the BMS Medical Monitor (or designee) to 
collect any pregnancy surveillance information from the female partner, the female partner must 
sign an informed consent form for disclosure of this information. Information on this pregnancy 
will be collected on the Pregnancy Surveillance Form.
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and if any sexual activity (e.g. vaginal, anal, oral) has occurred between a male 
participant and a pregnant WOCBP partner(s), the information should be reported to the Sponsor 
or  designee,  even  if  the  male  participant  has  undergone  a  successful  vasectomy.  In  order  
for Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the  female  partner(s)  must  sign  an  informed  consent  form  for  disclosure of  this  information.  
Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
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9.2.7
Potential Drug-induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (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: 
1) Aminotransferase (AT) (ALT or AST) elevation > 3× ULN
AND
2) Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, preexisting chronic or acute liver disease, or the 
administration of other 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 
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, the oral contraceptive pill, and herbal medicines). All 
investigations to exclude potential causes of liver function abnormalities or hepatic signs and/or 
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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, 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. All events meeting the definition of 
overdose must be reported as an AE/SAE (see Section Appendix 3).
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-RCC 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). 
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
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Table 9.4.1-1:
Clinical Laboratory Assessments
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), hepatitis A, 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: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CBC = complete blood count; CrCl = creatinine clearance; FSH = follicle stimulating hormone; HBsAg = hepatitis B 
surface antigen; HIV = human immunodeficiency virus; LDH = lactate dehydrogenase; RNA = ribonucleic acid; 
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of child-bearing 
potential.
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
Pharmacokinetics
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-RCC Sub-Protocol.
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.
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Upon implementation of Protocol Amendment 07, PK sample collection is no longer necessary for 
any participant who is on study treatment. 
9.6
Pharmacodynamics
Pharmacodynamic measures (in the form of biomarker assessments) may be assessed for 
associations with clinical outcomes. There will be 3 types of specimens obtained for biomarker 
testing: whole blood, serum, and tumor tissue. 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 07, samples for pharmacodynamic assessments are 
no longer necessary for any participant who is on study treatment.
9.7
Pharmacogenomics
Not applicable.
9.8
Biomarkers
Planned time points for all biomarker assessments are listed in the Schedule of Activities and the 
On-treatment Procedural Outline(s) specific to each FRACTION-RCC Sub-Protocol.
Upon implementation of Protocol Amendment 07, samples for biomarker assessments (peripheral 
blood markers and tissue markers) are no longer necessary for any participant who is on study 
treatment.
9.8.1
Peripheral Blood Markers
9.8.1.1
Whole Blood Single Nucleotide Polymorphism and Genotyping
Whole blood will be collected from participants prior to study treatment initiation to generate 
genomic deoxyribonucleic acid (DNA) for candidate-based single nucleotide polymorphism 
genotyping analyses. These analyses will focus on single nucleotide polymorphisms within genes 
associated with or affecting immunoregulatory signaling to determine if natural variation within 
those genes is associated with a response to each component of each FRACTION-RCC study 
treatment combination and/or nivolumab in combination with ipilimumab (and/or with AEs 
observed during treatment). 
Additionally, genomic DNA from whole blood will be collected and may be used as a comparator 
for participants with tumors examined by whole exome or genome mutation analysis. Whole 
exome or whole genome sequencing methods may be used for this analysis.
Lastly, genomic DNA from whole blood will be collected and may be used for T-cell receptor 
sequencing.
9.8.1.2
Whole Blood for Peripheral Blood Mononuclear Cell-based Assays
Cytometry will be used to assess baseline and serial On-treatment alterations in 
composition/activation status of lymphocyte subsets present in peripheral blood mononuclear cell 
preparations obtained from all participants, as indicated in the On-treatment Procedural Outline(s) 
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in each FRACTION-RCC Sub-Protocol. Lymphocyte subsets to be assayed may include, but are 
not limited to, CD8+ and CD4+ T-cell subsets (activated, effector/memory; regulatory) and 
populations of those cells as defined by the expression of activation, exhaustion, or signaling 
markers such as GITR, human-leukocyte antigen-antigen D-related, PD-1, and/or intracellular 
IFNγ. NK cell populations will be monitored in a similar fashion, with a focus on characterizing 
subsets defined by the expression of activation markers (eg, NKG2D and IL-21R) and/or by 
markers that are associated with the potential of NK cells to lyse target cells (eg, CD107a, 
granzyme, and perforin).
Additional cytometry-based assays may focus on defining and monitoring the abundance of 
myeloid-derived suppressor cells, a cell type that appears to negatively impact immunologically-
driven anti-tumor activity, which has been shown to be associated with poor prognosis in 
ipilimumab-treated participants.58
Lastly, assays may be completed to characterize the presence of T-cells directed against antigens 
present on tumors, including, but not limited to, over-expressed or virally associated factors such 
as EGFR, human papillomavirus, and cancer-testis antigen (NY-ESO1); T-cell receptor 
sequencing may also be performed using peripheral blood mononuclear cell samples. Detecting 
On-treatment increases in antigen-directed T-cells will provide evidence of adaptive immune 
responses against tumors and may be correlated with clinical outcomes. 
9.8.1.3
Serum Factors
To understand the prevalence of circulating proteins and the impact they may have on the clinical 
activity and safety profile of each FRACTION-RCC study treatment combination and/or 
nivolumab in combination with ipilimumab, the protein concentrations of a panel of cytokines, 
chemokines, and other relevant immunomodulatory, serum-soluble factors will be investigated by 
enzyme-linked immunosorbent assay (ELISA) and/or other relevant multiplex-based protein assay 
methods. Examples of specific analytes to be assessed may include, but are not limited to, factors 
induced by IFNγ signaling (eg, T-cell chemoattractants CXCL9 and CXCL10). Analyses may also 
focus on factors associated with prognosis and/or responses to standard therapeutic agents. In 
addition, soluble forms of receptors (eg, sPD-1 and s-GITR) and/or ligands (eg, sPD-L1 and 
s-GITRL) may be assessed. 
Recent findings suggest that the presence of serum antibodies against melanoma-associated 
antigens may be predictive of response to immunotherapeutic agents such as ipilimumab.59 To 
explore the possibility that the presence of autoantibodies is prognostic in other indications (and 
in response to each FRACTION-RCC study treatment combination and/or nivolumab in 
combination with ipilimumab), baseline and On-treatment serum may be assessed for the presence 
and/or concentration of antibodies against specific antigens using ELISA and/or multiplex 
platform such as Invitrogen’s ProtoArray®. Focus may be given on the detection of antibodies 
against proteins previously defined as tumor antigens, which are over-expressed in RCC. The 
presence of antibodies against viral antigens may also be monitored. Blood serum samples will be 
obtained, as indicated in Section 2 and the On-treatment Procedural Outline(s) specific to each 
FRACTION-RCC Sub-Protocol.
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MicroRNAs (miRNAs) may be evaluated from serum samples for association with response as 
potential prognostic markers.
9.8.1.4
Circulating Tumor DNA Analysis (Plasma Biomarkers)
The presence of cell-free DNA in circulating blood is a well-documented phenomenon. Fragments 
of DNA are shed into the blood stream from dividing cells during cell proliferation or cell death. 
In patients with cancer, a fraction of this DNA is tumor-derived and is termed circulating tumor 
DNA (ctDNA). Albeit small, fragments of DNA average between 180 to 200 bp and specific 
genomic regions can be amplified with PCR. Moreover, several studies have detected mutations 
in ctDNA that exactly correspond to mutations from the parent tumor. Using tissue and plasma 
from patients with known driver mutations, BEAMing technology will be utilized to count the 
frequency of mutations in circulation.
9.8.2
Tissue Markers from Fresh Tumor Biopsies
9.8.2.1
Tissue Biopsies from Participants with RCC 
Tracking changes in biomarkers measured in tumor tissue during treatment is instrumental in 
determining the mechanisms of action of cancer therapeutics. To monitor the presence (or absence) 
of infiltrating lymphocytes and to track other molecular changes within tumors in response to each 
FRACTION-RCC study treatment combination and/or nivolumab in combination with 
ipilimumab, tumor biopsies will be collected, as outlined in Section 2 and the On-treatment 
Procedural Outline(s) specific to each FRACTION-RCC Sub-Protocol. All participants must have 
tumor lesions that can be biopsied or collected via core needle, excisional, or incisional biopsy at 
acceptable clinical risk (as judged by the investigator) at baseline (pretreatment).
Sufficient tumor tissue must be obtained before initiation of study treatment from a primary or 
metastatic site. Tumor tissue samples must be shipped from site to central laboratory prior to 
randomization. Mandatory biopsies are required at the following time points: 1) baseline (prior to 
study treatment); 2) on-study (Day 28 within a collection window of Days 22 to 28); 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 the EOT for participants who discontinue treatment due to an 
AE). Notify the BMS Medical Monitor (or designee) if the On-treatment or EOT biopsy may pose 
an unacceptable clinical risk.
Biopsied lesions should be distinct from index lesions being evaluated for radiological response 
(ie, participants must have at least 1 measurable tumor site by RECIST v1.1 criteria) marked for 
pretreatment and posttreatment radiological tumor assessments. Tumor sites marked for 
pretreatment and posttreatment radiological tumor assessment should be distinct from tumor sites 
being used for pretreatment and posttreatment biopsies, if at all possible. Biopsies must be 
excisional, incisional, or core-needle. Excisional biopsies are strongly encouraged where feasible. 
In circumstances when the participant has only 1 marker lesion (primary or metastatic), the 
baseline (pretreatment) biopsies from that lesion are acceptable but should not be excisional. 
Biopsies from previously irradiated lesions are only suitable if they subsequently progressed. 
Baseline samples may be obtained at any time following other screening procedures and prior to 
the first dose of study treatment. Archival specimens may not be substituted for fresh baseline 
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specimens but can be submitted to help understand the evolution of the tumor (ie, PD-L1 
expression changes over time). The On-treatment biopsy may be obtained 28 days after the first 
dose of study treatment within a collection window of 7 days before that time point. The EOT 
biopsy may be done 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 the EOT for participants who discontinue treatment 
due to an AE). Participants must consent to biopsy procedures at baseline.
As described previously, complete instructions on the collection, processing, handling, and 
shipment of all biomarker specimens will be provided in a separate procedure manual. Refer to 
this manual for information pertaining to the collection and processing of tissue via biopsy or core 
needle. Collection procedures at baseline and on study treatment (and at progression) should be 
completed on a single, appropriately assessable lesion, when applicable. In case the lesion sampled 
at baseline is no longer accessible or within acceptable clinical risk to re-biopsy during the study 
(28 days after the first dose of study treatment on the Treatment Phase or at the end of the 
Treatment Phase), tissue from alternative lesion(s) may be obtained; this should be documented. 
Immediate confirmation for presence of viable tumor cells from collected tissue samples is 
strongly recommended. If adequate tissue is not obtained following initial passages of the needle, 
repeat passages may be completed.
Participants whose On-treatment biopsy yields inadequate tissue quantity or quality (lack of tumor) 
will be allowed to continue in the study and participate in the other biomarker assay collections 
(eg, blood collections) described in Section 2 and the On-treatment Procedural Outline(s) specific 
to each FRACTION-RCC Sub-Protocol. These participants are not exempt from future biopsy 
requirements at the time of PD or prior to randomization to a new study treatment combination 
arm and should be evaluated to assess if collection is feasible. Tumor tissue will be analyzed as 
described below. If tissue obtained from a large proportion of participants is deemed inadequate 
for testing (eg, possesses low tumor cell content), additional participants may be enrolled in an 
attempt to obtain tissue specimens that are better suited for testing.
9.8.2.2
Gene Expression Analyses
Exploratory analyses of messenger RNA (and/or miRNA) will be completed using total RNA 
isolated from fresh tumor tissue (processed in RNA later). RNA-sequencing, microarrays, and/or 
similar methodologies, including but not limited to quantitative real time polymerase chain 
reaction (PCR), will be used to assess gene expression patterns associated with RCC and to identify 
changes in those gene expression patterns following treatment with each FRACTION-RCC study 
treatment combination and/or nivolumab in combination with ipilimumab, where applicable. 
Ultimately, this approach may lead to the identification of unique baseline or On-treatment RNA 
expression signatures that can be useful for identifying participants who are likely (or unlikely) to 
respond to treatment with a given FRACTION-RCC study treatment combination. Focus may be 
given to monitoring a battery of immunoregulatory genes associated with cancer cells or cancer-
interacting lymphocytes. Examples within the latter group include genes associated with T-cells, 
NK cells, and/or IFNγ signaling. Such genes have been implicated previously in tumor responses.
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9.8.2.3
Protein Expression and Mutation
A portion of the fresh biopsy specimen will be formalin fixed, paraffin embedded (FFPE), and 
analyzed by IHC to determine the abundance of immunoregulatory proteins present at the tumor 
site. Such analyses may reflect the presence of tumor-infiltrating immune cells or the expression 
of immunoregulatory proteins by the tumor and/or surrounding stroma. Analytes may include, but 
are not limited to, CD3, CD4, CD8, FoxP3, GITR, GITR ligand, PD-L1, and components of 
antigen presentation machinery (beta-2 microglobulin, major histocompatibility complex [MHC] 
Class I, and MHC Class II).
Pharmacodynamic changes in the presence or abundance of immunoregulatory proteins and other 
proteins will be sought. Baseline and pharmacodynamic measures may also be correlated with 
clinical outcomes.
Laser capture microdissection may be utilized to enrich specific regions of tumor material for use 
in similar or additional downstream applications. This enrichment may provide robust signals of 
immunomodulation that are not otherwise detectable when tumor material is prepared using 
conventional methods. Downstream applications may include, but are not limited to, cytometry, 
ELISA, and/or assessment of miRNA, and gene expression. This process may be used to 
corroborate potentially weak signals observed by standard IHC, RNA, and/or miRNA expression 
experiments described above.
Tumor tissue may also be used to investigate receptor occupancy and for proteomic analysis or 
other exploratory analysis of protein expression and characterization.
T-cell receptor sequencing of T-cells derived from the tumor may be evaluated for association with 
clinical response and to understand pharmacodynamic changes.
Lastly, DNA may be extracted from a portion of tumor material to monitor somatic mutations that 
may impact response and other efficacy measures. Tumor mutational load has been associated with 
response to immunomodulatory agents, including nivolumab.60
9.8.3
Tissue Markers from Archived Tumor Samples
In addition to fresh tumor biopsy (see Section 9.8.2), an archival FFPE tumor tissue block 
(preferred) or slide (minimum of 20 slides) samples from a primary or metastatic site are to be 
provided by all participants, if available. Molecular characterization of archival specimens will be 
similar to the characterizations described above but is likely to focus on the expression of candidate 
markers associated with response to FRACTION-RCC study treatment combination. As described 
above, DNA may be extracted from a portion of the tumor material for mutational analysis. Lastly, 
RNA may be quantified from archival specimens using in situ hybridization, real-time PCR, or 
similar methodologies. Comparing protein expression, RNA expression, and mutation profiles in 
archival versus fresh specimens may provide insights into the molecular basis for disease 
progression.
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9.8.4
Additional Research Collection
Additional research collections are mandatory for all participants, except where prohibited by local 
laws and regulations or where specific waiver is provided by the BMS Medical Monitor (or 
designee); if one of these exceptions occur, participation in additional research collection should 
be encouraged but will not be a condition of overall study participation.
This protocol will include residual sample storage for additional research. Samples to be included 
are peripheral blood samples for PK, immunogenicity, and biomarker analysis (including derived 
material), and tumor tissue. 
This collection for additional research is intended to expand the translational research and 
development capability at BMS and will support as yet undefined research aims that will advance 
our understanding of disease and options for treatment. It may also be used to support health 
authority requests for analysis and advancement of pharmacodiagnostic development to better 
target drugs to the right patients. This may also include genetic/genomic exploration aimed at 
exploring disease pathways, progression, response to treatment, etc. 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the Sponsor’s senior leaders in Research and Development to ensure the research 
supports appropriate and well-defined scientific research activities.
All residual blood and tissue samples will be retained by the BMS Biorepository for additional 
research purposes.
Samples will be securely stored by the BMS Biorepository in Hopewell, NJ or at a BMS-approved 
third-party storage management facility.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Additional research samples will be retained for 15 years or the maximum allowed by applicable 
law. No additional sampling is required for residual collections.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
9.8.5
Immunogenicity Assessments
Separate detailed instructions for the collection, processing, handling, labeling, storage, and 
shipment of PK and 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-RCC Sub-Protocol.
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 
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designated for PK or biomarker assessments 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).
9.8.6
RNA Transcriptome Research
See Section 9.8.2.2.
9.8.7
RNA Expression Research of a Subset of RNA Species
Not applicable.
9.8.8
Proteome Research
See Sections 9.8.1.3 and 9.8.2.1.
9.8.9
Metabolomic Research
Not applicable.
9.8.10
Other Assessments
Not applicable.
9.9
Medical Resource Utilization and Health Economics
Not applicable.
10
STATISTICAL CONSIDERATIONS
Additional statistical considerations may be provided in each subprotocol. Please refer to the 
specific sub-protocol for guidance.
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 care 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.
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, the BMS Medical Monitor (or designee) 
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 may continue after reaching the indicated number of participants at Stage 1 while the 
initial efficacy evaluation is ongoing. Additional participants may be enrolled to account for 
participants who may drop out of the study without being evaluable for response or for additional 
considerations that may be needed in Stage 2 such as PK/PD analyses. In such cases, the total 
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number of participants enrolled will not exceed the specified total number of participants treated 
in that arm according to Simon 2 stage. 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 Consideration
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
30% / 50%
≤8/24
≥9/24
≤24/63
≥25/63
34.5
60.0
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.
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The Track 1 Simon 2-stage (optimal) design assumes a historical response rate of 30% and a target 
response rate of 50%, based on the observed response rate of approximately 40% for the nivolumab 
and ipilimumab combination in Study CA209016 and approximately 25% for nivolumab 
monotherapy in Study CA209025. 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. 
10.1.1
Track 1 - Anti-PD-1, Anti-PD-L1, and Anti-CTLA-4 Treatment-naïve
As shown in Table 10.1-1, a minimum of 24 participants in each study treatment combination arm 
will be treated in Stage 1 for an initial evaluation of efficacy. If the number of responses observed 
in Stage 1 is ≤8/24, the study treatment combination arm would likely not be considered 
efficacious; otherwise, enrollment to Stage 2 will continue, and an additional 39 participants will 
be treated. If the total number of responses at the end of Stage 2 is ≤24/63, the study treatment 
arm will be terminated for futility; if there are more than 24 responses observed at the end of Stage 
2, the study treatment combination may be carried on for further treatment development. 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 10.1.1-
1. With the stopping boundaries as shown in Table 10.1-1, if the combination has an ORR no better 
than the historical control at 30%, then there is a 95% overall chance of stopping for futility, with 
a 73% chance of stopping at Stage 1; there is a 5% false positive rate. If the combination has an 
ORR equal to the target of 50%, then there is a 90% chance of stopping for efficacy after Stage 2, 
whereas if the true ORR is 35%, 40%, or 45%, the power would be 20%, 48%, or 74%, 
respectively.
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Figure 10.1.1-1:
Operating Characteristics of Track 1 Simon 2-stage (Optimal) Design 
(Power =90%, Alpha = 5%)
Abbreviation: ORR = overall response rate; prob = probability.
If 25 responses are observed at the end of Stage 2 (Efficacy Stop), then the 90% CI for ORR will 
be [29%, 51%]. 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 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 combination has an ORR no better 
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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 combination has an ORR equal to the target of 
20%, then it has a 90% chance of stopping for efficacy after Stage 2.
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 (Efficacy Stop), 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 (with 25% dropout rate 
considered). In Stage 2, recruitment of additional re-randomized participants will be limited to 
12 participants out of the 27 additional participants (with 25% dropout rate considered). The 
limited number of re-randomized participants may be re-adjusted depending on the enrollment 
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rates, the rate of progression in Tracks 1 and 2, and the number of currently open study treatment 
arms in Track 2.
10.1.3
Tracks 1 and 2 Pharmacodynamic/Biomarker Assessment
To assess the pharmacodynamic effects of FRACTION-RCC combination or nivolumab in 
combination with ipilimumab as stated in the exploratory objective, pretreatment and On-treatment 
whole blood, serum samples, and tumor biopsies will be required. It is of interest to ensure the 
precision of the estimate of the ratio of On-treatment biomarker assessments to pretreatment 
(baseline) levels. Assuming that a biomarker is measured as a continuous variable with log-normal 
distribution, a given number of participants per study treatment arm under different Track will 
provide the confidence that the estimate of the ratio of On-treatment to baseline values will be 
within 20% of the true value, as shown in Table 10.1.3-1.
Table 10.1.3-1:
Probability That Estimated Ratio of On-treatment to Pretreatment 
(Baseline) Value Is Within 20% of True Value
Intra-participant 
Standard Deviation 
(Log-scale)
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Probability
N = 21
100%
97%
89%
81%
72%
65%
59%
N = 24
100%
98%
92%
84%
75%
68%
62%
N = 41
100%
100%
97%
93%
87%
81%
75%
N = 63
100%
100%
99%
97%
94%
89%
84%
Abbreviations: N = number of participants.
For example, for a biomarker (eg, activated and memory CD4 and CD8 T-cells) with an 
intra-participant standard deviation of 0.5, if the true ratio of postbaseline to baseline geometric 
means is 1.2 (increase from baseline is 20%), there is 93% probability that the estimated ratio 
would be within 0.96 and 1.44 (or a percent change between -4% and 44%) with 41 participants 
per study treatment arm. If the true increase from baseline is 60%, for a biomarker with the same 
variability, then there is 93% probability that the estimated percent change would be between 28% 
and 92% with 41 participants per study treatment arm. 
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Table 10.2-1:
Populations for Analyses
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 
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Table 10.2-1:
Populations for Analyses
Population
Description
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
Response-evaluable
All treated participants with measurable disease and one 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 the 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, 
progression-free survival (PFS), and OS will be described in the statistical analysis plan.
Table 10.3.1-1:
Efficacy Analyses
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 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 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.
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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.
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 10.3.1-2.
Table 10.3.1-2:
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
Abbreviations: DOR = duration of response; ORR = overall response rate; OS = overall survival; PFSR = progression 
free survival rate.
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 at the 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- RCC 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.
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Table 10.3.2-1:
Safety Analyses
Endpoint
Statistical Analysis Methods
Incidence of AEs, SAEs, 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 system organ class 
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 the worst CTC grade on 
treatment per participant.
Abbreviations: AE = adverse event; CTC = common terminology criteria; PT = preferred term; SAE = serious adverse 
event; 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.
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-RCC 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
Table 10.3.3.2-1:
Immunogenicity Analyses
Endpoint
Statistical Analysis Methods
Incidence of ADA to individual component of 
study treatment combination 
Baseline ADA-positive participant is defined as a 
participant who has an ADA-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
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
Abbreviations: ADA = anti-drug antibody.
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10.3.3.3
Exploratory Biomarker Analyses
Table 10.3.3.3-1:
Exploratory Biomarker Analyses
Endpoint
Statistical Analysis Methods
Summary measures of change (or % change) 
from baseline in various biomarkers in the tumor 
and peripheral blood
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 from 
peripheral blood or tumor biopsy 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.
10.3.3.4
Outcomes Research Analyses
Table 10.3.3.4-1:
Outcomes Research Analyses
Endpoint
Statistical Analysis Methods
Summary measures of EQ-5D-3L index and VAS scores and 
FKSI-DRS score 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
Abbreviations: EQ-5D-3L = 3-level version of EQ-5D self-report questionnaire; FKSI-DRS = Functional Assessment 
of Cancer Therapy-Kidney Symptom Index-disease-related symptoms; 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-RCC 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 
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of Stage 1 (6 months after first treatment date of the last participant within that study treatment 
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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59 Yuan J, Adamow M, Ginsberg BA, et al. Integrated NY-ESO-1 antibody and CD8+ T-cell 
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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
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
CNS
central nervous system
COVID-19
coronavirus disease 2019
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
DNA
Deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
eCRF
Electronic case report form
ELISA
Enzyme-linked immunosorbent assay
EOT
end of treatment 
EQ-5D-3L
3-level version of EQ-5D self-report questionnaire
EU
European Union
FFPE
formalin fixed, paraffin embedded
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Term
Definition
FKSI-DRS
Functional Assessment of Cancer Therapy Kidney Cancer Symptom 
Index disease-related symptoms
FRACTION
Fast Real-time Assessment of Combination Therapy in Immuno-
ONcology
FSH
follicle stimulating hormone
FU
follow-up
GI
gastrointestinal
GITR
glucocorticoid-induced tumor necrosis factor receptor-related (gene)
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIFα
hypoxia-inducible factor alpha
HIV
human immunodeficiency virus
IB
Investigator’s Brochures
IEC
Independent Ethics Committee
IFN-γ
interferon gamma
IHC
immunohistochemical/immunohistochemistry
IMDC
International Metastatic RCC Database Consortium
IMP
investigational medicinal product
IO
immuno-oncology
IP
investigational product
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology
I SPY 1/2 TRIAL
Investigation of Serial Studies to Predict Your Therapeutic Response 
with Imaging And moLecular Analysis
KPS
Karnofsky Performance Status
LDH
lactate dehydrogenase
MHC
major histocompatibility complex
miRNA
micro ribonucleic acid
mRCC
metastatic renal cell carcinoma
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Term
Definition
MRI
magnetic resonance imaging
MSKCC
Memorial Sloan-Kettering Cancer Center
mTOR
mechanistic target of rapamycin
N1 + I3
nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg
N3 + I1
nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg
NCI
National Cancer Institute
NCI-MATCH
NCI Molecular Analyses for Therapy Choice
NK
natural killer
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
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
PR
partial response
prob
probability
PT
preferred term
QTcF
QT interval corrected with Fridericia’s formula
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical analysis plan
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Term
Definition
SD
stable disease
SMB
Safety Monitoring Board
SOC
system organ class
SUSAR
suspected, unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TAPUR
Targeted Agent and Profiling Utilization Registry
TKI
tyrosine kinase inhibitor
TNFRsf
tumor necrosis factor receptor super family
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
VAS
visual analog scale
VEGF
vascular endothelial growth factor
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:
•
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 the 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 
serious breach is a breach of the conditions and principles of GCP in connection with the study 
or the protocol, which is likely to affect, to a significant degree, the safety, physical, or mental 
integrity of the subjects of the study or the scientific value of the study.
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 or debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
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 and any updates. 
The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and 
other information (eg, expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or a 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 the IRB/IEC or 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(ies) 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 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 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 are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, global or local) sample
informed consent form, which will include all elements required by ICH, GCP, and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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 to inquire about the details of the study.
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•
Obtain an informed consent signed and personally dated by the participant 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 prior to the beginning of the 
study, and after any revisions are completed for new information.
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 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 must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participants' signed 
informed consent form, and, in the United States, the participants’ signed Health Insurance 
Portability and Accountability Act (HIPAA) authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects 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 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.
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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.
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 or wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, 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 
The investigator or designee accepts responsibility for documenting 
traceability and study drug integrity in accordance with requirements 
applicable 
under 
law 
and 
the
standard 
operating 
procedures
(SOPs)/standards of the sourcing pharmacy.
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If
Then
vendors 
(examples 
include IP 
sourced from 
the sites’ stock 
or commercial 
supply, or a 
specialty 
pharmacy)
These records should include:
•
label identification number or batch number 
•
amount dispensed to and returned by each participant, including unique 
participant identifiers
•
dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
Abbreviations: IP = investigational product; SOP = standard operating procedure.
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 case report form (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, eCRFs 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 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 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, including SAE/pregnancy CRFs, must be promptly reviewed, signed, and 
dated by the investigator or qualified physician, who is a subinvestigator and who was delegated 
this task on the Delegation of Authority Form. Subinvestigators in Japan may not be delegated 
the CRF approval task. For eCRFs, 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.
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Each individual electronically signing eCRFs 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 
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 or retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, or IRB). 
Notice of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS or a vendor, or sourced by the 
investigator) such as partially used study treatment containers, vials, and syringes may be 
destroyed on site. 
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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 treatment 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 standard operating procedures 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 
method of disposal (ie, 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 Study 
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 and not supplied by BMS is solely the responsibility of the 
investigator or designee.
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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 AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For 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)
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 (CTA) 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 CTA.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
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 duration of 
the washout period 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.
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 
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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. 
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. 
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•
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.
•
Male participants will be required to always use a latex or other synthetic condom during any 
sexual activity (eg, vaginal, anal, oral) with WOCBP; even if the participants have undergone 
a successful vasectomy or if their partner is already pregnant or breastfeeding. Males should 
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continue to use a condom while on study plus 5 half-lives of study treatments plus 90 days
(duration of sperm turnover). Withdrawal (coitus interruptus) and/or the use of a spermicide 
without a condom are not acceptable methods of contraception or fetal protection.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined 5 half-lives plus an 
additional 90 days after the end of treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, oral) even 
if the participants have undergone a successful vasectomy, while on study plus 5 half-lives of 
study treatments plus 90 days (duration of sperm turnover). Withdrawal (coitus interruptus) 
and/or the use of a spermicide without a condom are not acceptable methods of contraception 
or fetal protection.
•
Refrain from donating sperm for the duration of the study treatment and 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 (eg, ‘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 (eg, 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: ie, an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in 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: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the 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
Timepoint 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.
•
Verification of Progression: Not required.
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.
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APPENDIX 7
KARNOFSKY 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
0
Symptoms, but fully 
ambulatory
Normal activity with effort.
80
1
Cares for self.
Unable to carry on normal 
activity or to do active work.
70
1
Symptomatic, but in 
bed < 50% of the 
day.
Requires occasional assistance, 
but able to care for most of his 
needs.
60
2
Requires considerable 
assistance and frequent medical 
care.
50
2
Needs to be in bed 
> 50% of the day, 
but not bedridden
Disabled.
Requires special care and 
assistance.
40
3
Severely disabled.
Hospitalization indicated 
though death non imminent.
30
3
Unable to get out of 
bed
Very sick.
Hospitalization necessary.
Active supportive treatment 
necessary.
20
4
Moribund
10
4
Dead
0
5
Dead
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APPENDIX 8
INTERNATIONAL METASTATIC RCC DATABASE 
CONSORTIUM (IMDC) PROGNOSTIC CRITERIA 
Adverse Prognostic Factors
Clinical 
KPS < 80%
Time from diagnosis to treatment < 1 year
Laboratory 
Hemoglobin < LLN
Corrected calcium > ULN
Absolute neutrophil count > ULN
Platelet count > ULN
LLN = Lower limit of normal
ULN = Upper limit of normal
Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]), where 
4.0 represents the average albumin level in g/dL.
Corrected calcium (mmol/L) = measured total Ca (mmol/L) + 0.02 (40 - serum albumin [g/L]), 
where 40 represents the average albumin level in g/L
Risk Group Based on Number of Adverse Prognostic Factors
Number of Adverse Prognostic Factors Present
Risk Group
0
Favorable
1-2
Intermediate
3-6
Poor
Reference:  Heng D, Xie W, Regan M, et al. Prognostic factors for overall survival in patients with metastatic renal 
cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter 
study. J Clin Oncol 2009; 27(34):5794-5799.
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APPENDIX 9
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 06, 15-Nov-2018
Section 2 Schedule of Activities, Table 2-1 Screening Procedural Outline in FRACTION-RCC 
Cancer Revised Protocol was modified to include clarification of ECG procedure. Section 4 
Objectives and Endpoints was modified to update Tertiary/Exploratory Objective 6 per planned 
analysis of patient-reported outcomes data. Section 6.1 Inclusion Criteria were modified to clarify 
favorable risk profile and Karnofsky Performance Status requirements. Section 9.1 Efficacy 
Assessments was edited to provide language consistent with Table 2-1 and clarify collection of 
details of progressive disease in relation to participant’s prior therapy. Section 7.7.1 Prohibited 
and/or Restricted Treatments was modified to include language clarifying marijuana use. 
Paragraphs describing activities related to patient-reported outcomes were moved to Section 9.1.2 
Patient-reported Outcomes. Other key changes include updates made to safety guidance and/or 
reporting activities to align the protocol with current policies and safety parameters, in the 
following sections: Section 9.2.5 Pregnancy; Section 9.3 Overdose; 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; and Appendix 6 Hepatic Adverse Event Management Algorithm.
Summary of key changes of Revised Protocol 06
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
Table 2-3: Follow-Up 
Procedural Outline
Notes for Utilize IRT were modified and 
time to randomization is now 5 - 7 days. 
Modified to read:
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.
Clarified the collection windows for scans 
during the follow up period. Clarified that 
patient-reported outcomes can be 
collected over the phone if needed.
Compliance with current IRT 
manual.
The changes were made based on 
recent need for assessment of ECG 
in sub-protocol C.
Clarified the collection windows for 
tumor response assessment. Allows 
patient-reported outcomes 
information to be collected even if 
visit is delayed.
Section 4, Table 4-1 
Objectives and Endpoints
Modified Tertiary/Exploratory Objective 
6 to read “To evaluate changes in disease-
related symptoms, as measured by the 
FKSI-DRS, in treated participants”.
Changed since the patient-reported 
outcomes data are to be analyzed 
using descriptive statistics and 
because no directional hypothesis is 
specified for EQ-5D outcomes.
Section 6.1 Inclusion Criteria
Modified to read:
2)e)i)6) Based on the results from 
CheckMate-214 participants with 
favorable risk profile by IMDC Score 
must have been treated with sunitinib 
prior to randomization into Track 1 
nivolumab plus ipilimumab”. 
Added: 
The word, “favorable” and KPS 
was inadvertently missed during 
protocol version 05. This was a 
typographical error. 
KPS status requirements were 
specified.  
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Summary of key changes of Revised Protocol 06
Section Number & Title
Description of Change
Brief Rationale
2)e)i)7) Karnofsky Performance Status 
(KPS) must be ≥70% (Appendix 7)
3)f) Added text to address fetal protection.
Required by 
 (Women 
Of Child Bearing Potential and 
Clinical Trials Policy)
Section 7.7.1 Prohibited 
and/or Restricted Treatments
Added that use of marijuana and its 
derivatives are permitted for treatment of 
symptoms related to cancer treatment to 
4th bullet.
Marijuana has become legalized in 
many geographic regions and is 
increasingly being used for cancer 
patients. Multiple institutions have 
requested the use of marijuana 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.
9.1 Efficacy assessments 
Added: All participants should receive 
scans at FU1, except for participants with 
PD who started subsequent therapy or 
have already been treated beyond 
progression. Scans at FU3 and every 12 
weeks will only be collected for patients 
with CR, PR, or SD at treatment 
discontinuation.
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 (e.g. increased pain requiring 
palliative radiotherapy)  to support 
progression, response/progression dates, 
and reason for discontinuation will be 
collected in this trial.
Clarification language to be 
consistent with tumor assessments 
for f/u periods in Schedule of 
Assessments (SOA)
Addition of collection of details of 
progressive disease in relation to 
participant’s prior therapy.
9.1.2 Patient-reported 
Outcomes
Moved paragraphs describing activities 
related to patient reported outcomes from 
Section 9.9.1 to Section 9.1.2.
Patient-reported outcomes reflect 
efficacy, rather than medical 
resource utilization and health 
economics in this study.
9.2.5 Pregnancy
Text added to address fetal protection.
Required by 
 (Women 
Of Child Bearing Potential and 
Clinical Trials Policy)
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Summary of key changes of Revised Protocol 06
Section Number & Title
Description of Change
Brief Rationale
9.3 Overdose
Modified the section to state that “All 
events meeting the definition of overdose 
must be reported as an AE/SAE” and 
added a reference to Appendix 3.
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
Updated the safety reporting appendix to 
include current language on AEs and 
SAEs related to progressive disease and 
overdose.
Clarified the need to report 
abnormal lab tests or other safety 
assessments when the final 
diagnosis is not available. 
Included language to clarify that 
disease-related events and events 
associated with lack of efficacy will 
be reported as AEs if the event 
meets the criteria of an AE. 
Text was added to clarify the need 
for the investigator to report the 
specific term of “intentional 
overdose” as an AE term. All other 
types of overdose should NOT  be 
reported as an AE but should be 
recorded elsewhere on the CRF. 
There are no changes to the 
reporting of AEs associated with 
any type of overdose.
Appendix 4, Contraception 
Guidance for Female 
Participants of Child Bearing 
Potential
Changes to instructional text and prompt 
choice 2 (Male Partners WOCBP -
Choice: Teratogenic/Non-Genotoxic)
Required by 
 (Women 
Of Child Bearing Potential and 
Clinical Trials Policy)
Appendix 6 Hepatic Adverse 
Event Management 
Algorithm
Footnote stating I-O therapy may be 
delayed rather than discontinued if 
AST/ALT ≤8 x ULN or T. bili ≤5 x 
ULN was removed.
Language was modified to align 
protocol with current Nivolumab 
Investigator Brochure and 
nivolumab program safety 
parameters.
Overall Rationale for the Revised Protocol 05, 27-Apr-2018
Exclusion criteria in FRACTION-RCC Cancer Revised Protocol were added to exclude favorable
risk patients who have not have been treated with sunitinib prior to randomization into Track 1 for 
treatment with nivolumab plus ipilimumab. The Schedule of Activities Table was revised to 
include collection of risk information as defined by International Metastatic RCC Database 
Consortium (IMDC) score (detailed language provided in Appendix 8), as well as testing for 
Methemoglobin level and Glucose-6-phosphate Dehydrogenase Deficiency. Circulating tumor 
DNA to Biomarker Assessment. Statistical considerations includes an updated description for 
enrollment of the participants. The trial design and sample size determination were modified to 
allow for enrollment to continue until efficacy evaluation is complete.
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Summary of key changes of Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
Section 1, Synopsis
Synopsis was revised to reflect the 
changes in the protocol body and is now 
included under section 1 in revised 
protocol 05. 
Synopsis is now being added as 
section 1 in the revised protocol 
instead of stand-alone supplemental 
document. 
Section 2, Schedule of 
Activities; Table 2-1: On-
treatment Procedural Outline, 
Table 2-2, Baseline for Re-
randomization Procedural 
Outline 
Edits to tables for risk score collection, as 
well as methemoglobin level and 
Glucose-6-phosphate Dehydrogenase 
Deficiency testing.
Risk score collection was added 
based on the results of the 
CheckMate-214 clinical trial
Section 3.1.1.3 , Rationale 
for Biomarker Assessments 
1) Blood-based biomarkers
2) Tumor tissue-based 
biomarkers
1)c) modified to read:
T-cell receptor sequencing will be 
performed to detect expansion of antigen-
directed T-cells clones, which may 
provide evidence of adaptive immune 
responses against tumor and 
pharmacodynamics information 
potentially used for combination strategy.
Plasma ctDNA for Tumor 
Mutational Burden Assessment was 
added to the list of blood-based 
biomarkers.
Other changes describe details and 
rationale for the following 
biomarkers assessment: T-cell 
receptor sequencing, plasma 
ctDNA, whole exome or genome 
sequencing, gene expression 
analysis.
1)e) added: 
Plasma ctDNA for Tumor Mutational 
Burden Assessment. High tumor 
mutational burden (TMB) is an indication 
for increased neo-antigen presentation in 
tumors, which leads to recruitment of 
immune cells to the tumor site and 
induction of anti-tumor immunity. 
Consequently, high TMB has been 
correlated with increased response to 
nivolumab and other therapeutics 
targeting the PD (L)1 axis in NSCLC. 
TMB can be inferred from ctDNA 
isolated from plasma samples. TMB 
results from the periphery will be 
compared with TMB results from whole 
exome sequencing of tumor tissue 
biopsies if sufficient slides are available. 
Quantitative and qualitative assessment of 
ctDNA can also provide insight into 
dominant tumor clones and their 
hierarchy, clonal evolution during 
treatment, and relevance for response and 
nonresponse. Plasma samples for ctDNA 
extraction will be collected at the 
indicated time points and kept frozen at -
80 °C in storage. Additional use of these 
samples may include analysis of 
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Summary of key changes of Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
microsatellite instability or other clinically 
relevant biomarkers.
2)b) modified to read: 
Whole exome or whole genome 
sequencing: DNA may be extracted from 
biopsy specimens to monitor somatic 
mutations that may impact response and 
other efficacy measures. Whole exome, 
whole genome, or targeted sequencing 
methodologies may be employed. Tumor 
mutational load has been associated with 
response to immunomodulatory agents, 
including nivolumab.
2)c) modified to read:
Gene expression analysis: RNA-seq, 
and/or similar methodologies, will be used 
to assess gene expression patterns 
associated with each of the expansion 
tumor types and to identify changes in 
those gene expression patterns following 
treatments with. Ultimately, this approach 
may lead to the identification of unique 
baseline or on-treatment RNA expression 
signatures that could be useful for 
identifying patients who are likely (or 
unlikely) to respond to the combination 
therapy. Focus may be given to 
monitoring a battery of immunoregulatory 
genes associated with cancer cells or 
cancer-interacting lymphocytes. Examples 
within the latter group include genes 
associated with T-cells, NK cells, and/or 
IFN-γ signaling. Such genes have been 
implicated previously in tumor responses 
or rejection.
Section 5.1 Overall Design
Added rationale for continuous enrollment 
within section 5.1:
Enrollment may continue after reaching 
the indicated number of participants at 
Stage 1 while the initial efficacy 
evaluation is ongoing. Additional 
participants may be enrolled to account 
for participants who may drop out of the 
study without being evaluable for 
response or for additional considerations 
that may be needed in Stage 2 such as 
PK/PD analyses. In such cases, the total 
number of subjects enrolled will not 
exceed the specified total number of 
Added to allow enrollment to 
continue until efficacy evaluation 
complete.
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Summary of key changes of Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
participants treated in that arm according 
to Simon 2 stage. 
Section 6.1 Inclusion Criteria
Inclusion Criteria were updated to add 
additional criteria based on the results of 
CheckMate-214 clinical trial:
2)i)(5) Participants must be evaluated for 
risk of the disease as defined by 
International Metastatic RCC Database 
Consortium (IMDC) score (Appendix 8).
2)i)(6) Based on the results from 
CheckMate-214 , participants must have 
been treated with sunitinib prior to 
randomization into Track 1 nivolumab 
plus ipilimumab.
Added clarification to criterion 3) Age 
and Reproductive Status: 
In addition to the reproductive guidelines 
noted below, please refer to the individual 
sub-protocol for additional requirements 
regarding reproductive guidelines.
The changes were made based on 
the results of the CheckMate-214 
clinical trial.
Section 9.8.1.4 Circulating 
Tumor DNA Analysis 
(Plasma Biomarkers)
9.8.1.4 Circulating Tumor DNA Analysis 
(Plasma Biomarkers)
The presence of cell-free DNA in 
circulating blood is a well-documented 
phenomenon. Fragments of DNA are shed 
into the blood stream from dividing cells 
during cell proliferation or cell death. In 
patients with cancer, a fraction of this 
DNA is tumor-derived and is termed 
circulating tumor DNA (ctDNA). Albeit 
small, fragments of DNA average 
between 180 to 200 bp and specific 
genomic regions can be amplified with
PCR. Moreover, several studies have 
detected mutations in ctDNA that exactly 
correspond to mutations from the parent 
tumor. Using tissue and plasma from 
patients with known driver mutations, 
BEAMing technology will be utilized to 
count the frequency of mutations in 
circulation.
Added to provide rationale for 
ctDNA assessment.
Section 10, Statistical 
Considerations
Added clarification under Section 10, 
Statistical Considerations 
Additional statistical considerations may 
be provided in each subprotocol. Please 
refer to the specific sub-protocol for 
guidance.
Clarified where additional statistics 
are located
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Summary of key changes of Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
Section 10.1, Sample size 
determination
The following language 
“Additional participants may be enrolled 
to account for participants who may drop 
out of the study without being evaluable 
for response. For example, assuming a 
25% dropout rate, up to 32 additional 
participants per study treatment arm could 
be enrolled into Track 1 Stage 1 to 
achieve 24 “evaluable” participants (with 
any over-enrollment counting toward 
Stage 2), while in Stage 2, an additional 
13 participants over the planned 39 could 
be enrolled to achieve 63 total evaluable 
participants. Similarly in Track 2 Stage 1, 
up to 28 participants may initially be 
enrolled to achieve 21 evaluable
participants”,
is replaced with:
“Enrollment may continue after reaching 
the indicated number of participants at 
Stage 1 while the initial efficacy 
evaluation is ongoing. Additional 
participants may be enrolled to account 
for participants who may drop out of the 
study without being evaluable for 
response or for additional considerations 
that may be needed in Stage 2 such as 
PK/PD analyses. In such cases, the total 
number of subjects enrolled will not 
exceed the specified total number of 
participants treated in that arm according 
to Simon 2 stage.” 
Added to allow enrollment to 
continue until efficacy evaluation 
complete.
Appendix 8
Addition of. International Metastatic RCC 
Database Consortium (IMDC) score
Appendix 8 was amended to 
provide description of International 
Metastatic RCC Database 
Consortium (IMDC) score
All
Minor formatting and typographical 
corrections
Minor, therefore have not been 
summarized.
Overall Rationale for the Revised Protocol 04, 08-Feb-2018
The FRACTION-RCC Master protocol was revised to allow participants to continue treatment for 
up to a total duration of 2 years.
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Summary of key changes of Revised Protocol 04
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-RCC 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 up to 2 years 
total duration.
Emerging data suggests that 
patients may derive clinical benefit 
beyond 6 months of 
immunotherapy. Therefore, patients 
will continue on study treatment for 
up to 2 years.
Table 2-1, Screening Procedural Outline
1. Duration of 
randomization prior to 
first dose extended
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 from to allow for 
completion of study related tests.
2. Data to be collected on 
toxicities from treatment 
with prior 
immunotherapies.
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 prior toxicities.
Table 2-3, Follow-up Procedural Outline
Karnofsky Performance 
Status assessment added at 
Follow-up visits 2 and 3
Collect performance status during 
follow-up.
Section 3.1, Introduction; Section 3.2.1, 
FRACTION-RCC
Included updates from 
recent clinical studies.
Most recent results of studies 
provided.
Throughout
Minor rewording/re-
formatting for 
clarification.
Minor, therefore have not been 
summarized.
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