Phase II, Randomized, Study of Multiple Administration Regimens for Nivolumab Plus Ipilimumab in Subjects With Renal Cell Carcinoma
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CA209800
IND Number:
132265
EUDRACT Number
Not Applicable
Date
25-Oct-2016
Revised Date
02-Aug-2017
Clinical Protocol CA209800
Phase II, Randomized, Study of Multiple Administration Regimens for Nivolumab plus 
Ipilimumab in Subjects with Renal Cell Carcinoma
Revised Protocol Number: 02
Medical Monitor
Anila Qureshi, MD, MPH
Bristol-Myers Squibb Research and Development
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 (e.g., 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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Revised Protocol No.: 02
Date: 02-Aug-2017
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to partners to which BMS has transferred obligations, e.g., a Contract Research 
Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Revised Protocol No.: 02
Date: 02-Aug-2017
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 02
02-Aug-2017

Adding clarifications to the protocol 

Correcting inconsistencies and text that was 
erroneously deleted in the Revised Protocol 01
Revised Protocol 01
18-Jan-2017
Incorporates Amendment 01
Amendment 01
18-Jan-2017

Incorporate additional safety parameters and 
clarifications as per the FDA guidance following the 
submission of IND 132265

Clarify inconsistencies in the original protocol as per 
the review of local Ethical Committees

Correct typo errors on the original protocol
Administrative Letter 
01
16-Nov-2016
Delete one of the eligibility criteria in the protocol synopsis 
(and align it with the text in the eligibility criteria section of 
the protocol body ) that was erroneously included in the 
original protocol 
Original Protocol
25-Oct-2016
Not Applicable
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Revised Protocol 02 will be applicable to all patients.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Synopsis

Exclusion Criteria 1 modified 
Ensure consistency with protocol body 
language
Section 2: Schedule of 
Activities

Timing for Vital Signs added; 

Timing for MDSC 
highlighted;
Duplicate Statements on Follow-
Up Assessments deleted
There was an inconsistency across the 
Schedule of Activities with regards to the 
timing of those assessments.
Section 4 Objectives and 
Endpoints, Section 10.3.2, 
Safety Analyses
Timing of Primary Endpoint 
corrected to completion of Part 1.
Primary Endpoint Analysis adjusted as
Primary Endpoint is related to safety of the 
combination dosing.
Section 7.4.3, Dose 
Discontinuation
Added Grade 3 “diarrhea, colitis, 
neurologic toxicity” as reasons for 
dose discontinuation
Text erroneously deleted from revised 
Protocol 01
Appendix 7, Performance 
Status Scales
Added comparative Table between 
ECOG and KPS
Change erroneously was not included in 
Revised Protocol 01
All
Minor clarifications, formatting 
and typographical corrections
Minor, therefore have not been summarized
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02 ......................... 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Research Hypothesis ................................................................................ 
3.2 Background ....................................................................................................... 
3.2.1 Nivolumab Mechanism of Action ............................................................. 
3.2.2 Ipilimumab Mechanism of Action ............................................................ 
3.2.3 Nivolumab Combined with Ipilimumab ................................................... 
3.2.4 Programmed Death Receptor-1 (PD-1) and Nivolumab ......................... 
3.2.5 Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Ipilimumab ............... 
3.2.6 Preclinical Summary of Nivolumab Combined with Ipilimumab ............ 
3.2.7 Renal Cell Carcinoma - Background and Standard Treatments ............. 
3.2.8 Nivolumab in Renal Cell Carcinoma ....................................................... 
3.2.9 Ipilimumab in Renal Cell Carcinoma ...................................................... 
3.2.10 Nivolumab Combined with Ipilimumab in Renal Cell Carcinoma ........ 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.5 Justification for Dose ........................................................................................ 
5.5.1 Rationale for Nivolumab combined with Ipilimumab Dosing Regimen .. 
5.5.2 Rationale for Fixed Ratio Combination Dosing ...................................... 
5.5.3 Rationale for Flat Dose 480 mg Nivolumab every 4 Weeks During 
Maintenance Phase ..................................................................................... 
5.5.4 Rationale for 2-arm Design ..................................................................... 
5.5.5 Rationale for Choice of Adverse Events by MedDRA Anaphylactic 
Reaction SMQ (Broad Scope) as a Primary Endpoint ............................... 
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 or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
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7.1 Treatments Administered .................................................................................. 
7.1.1 Part 1 Study Treatment Administration ................................................... 
7.1.2 Part 2 Study Treatment Administration ................................................... 
7.1.3 Selection and Timing of Dose .................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Dose Delay Criteria ................................................................................. 
7.4.2 Criteria to Resume Treatment .................................................................. 
7.4.3 Dose Discontinuation............................................................................... 
7.4.4 Management Algorithms for Immuno-Oncology Agents ......................... 
7.4.5 Treatment of 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 Permitted Therapy ................................................................................... 
7.7.3 Other Restrictions and Precautions ......................................................... 
7.8 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
8.1.2 Treatment Beyond Disease Progression Rationale ................................. 
8.1.3 Treatment Beyond Disease Progression .................................................. 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital signs................................................................................................. 
9.4.3 Clinical Safety Laboratory Assessments .................................................. 
9.4.4 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetic ................................................................................................ 
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9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
 
 
 
 
 
 
 
9.9 Medical Resource Utilization and Health Economics ...................................... 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.2.1 Pharmacokinetic Analyses as a Secondary Endpoint ................... 
10.3.2.2 Other Pharmacokinetic Analyses .................................................. 
 
10.3.2.4 Outcomes Research Analyses ....................................................... 
10.3.2.5 Other Analyses .............................................................................. 
10.3.2.6 Interim Analyses............................................................................ 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERANCE 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 1.1 GUIDELINES .................................................................. 
APPENDIX 6 INTERNATIONAL METASTATIC RCC DATABASE 
CONSORTIUM (IMDC) PROGNOSTIC CRITERIA .......................................... 
APPENDIX 7 PERFORMANCE STATUS SCALES ................................................. 
APPENDIX 8 MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS ................................................................................................................. 
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1
SYNOPSIS
Protocol Title: Phase II, Randomized, Study of Multiple Administration Regimens for 
Nivolumab plus Ipilimumab in Participants with Renal Cell Carcinoma
Study Phase: Phase II
 
 
 
 
 
Study Population:
The study population for this trial will include adult participants (≥18 years) with histological 
confirmation of RCC with a clear-cell component.
Key Inclusion Criteria: 

Histological confirmation of RCC with a clear-cell component

Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage 
IV) RCC

No prior systemic therapy for RCC with the following exception:
o
One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such 
therapy did not include a checkpoint inhibitor and if recurrence occurred at least 
6 months after the last dose of adjuvant or neoadjuvant therapy.

Karnofsky Performance Status (KPS) of at least 70%

Measurable disease as per RECIST 1.1 (investigator assessed)

Tumor tissue (formalin-fixed paraffin-embedded (FFPE) archival or recent acquisition) must 
be received by the central vendor (block or unstained slides) in order to randomize a participant
to study treatment. (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not 
acceptable for submission).

Participants with favorable, intermediate and poor risk categories will be eligible for the study.
o
To be eligible for the Intermediate-Risk cohort one or two of the following prognostic 
factors as per International Metastatic RCC Database Consortium (IMDC) risk factors 
include:
a) KPS equal to 70%
b) Less than 1 year from diagnosis to randomization
c) Hemoglobin less than the LLN
d) Corrected calcium concentration greater than 10 mg/dL
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e) Absolute neutrophil count greater than the ULN
f) Platelet count greater than the ULN
o
If more than two factors are present they will be eligible for Poor-Risk cohort. If none 
of the above factors are present, participants are only eligible for the Favorable-Risk 
cohort. 
Key Exclusion:

Active brain metastases or leptomeningeal metastases. Baseline imaging of the brain is 
required within 28 days prior to randomization.

Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways.

Any active or recent history of a known or suspected autoimmune disease or recent history of 
a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or 
immunosuppressive medications except for syndromes which would not be expected to recur 
in the absence of an external trigger. Participants with vitiligo or type I diabetes mellitus or 
residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement 
are permitted to enroll.

Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 14 days prior to first dose of 
study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone 
equivalents are permitted in the absence of active autoimmune disease.

Uncontrolled adrenal insufficiency.

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.

Known history of testing positive for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS).

Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.

Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, 
in the investigator’s opinion, would increase the risk associated with study participation or 
study drug administration or interfere with the interpretation of safety results.

Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.

Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal 
radiation therapy less than 14 days prior to the first dose of study drug.

Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have 
not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug.
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
Any of the following laboratory test findings:
a) WBC < 2,000/μL
b) Neutrophils < 1,500/μL
c) Platelets < 100,000/μL
d) AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
e) Total Bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dL)
f) Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance 
< 40 mL/min (measured or calculated by Cockroft-Gault formula).
Objectives and Endpoints:
Objective
Endpoint
Primary
The primary objective is to evaluate the 
difference in safety between 
co-administered FRC nivolumab 3 mg/kg 
and ipilimumab 1 mg/kg relative to 
sequentially administered nivolumab 
3 mg/kg and ipilimumab 1 mg/kg as 
measured by the incidence of AEs in the 
Broad Scope MedDRA Anaphylactic 
Reaction SMQ occurring within 2 days 
after dosing during the combination, Part 1 
period.
The primary endpoint of the study is the incidence of AEs 
in the Broad Scope MedDRA Anaphylactic Reaction 
SMQ occurring within 2 days after dosing during the 
combination, Part 1 period. This incidence rate is defined 
as the number of participants who experienced at least 
1 AE in the MedDRA Anaphylactic Reaction broad scope 
SMQ with onset on the day of or within 2 days after any 
study therapy infusion during the combination period 
(Part 1) divided by number of treated participants. The 
analysis of the primary endpoint will occur at the time of 
first (primary) analysis when all participants who are still 
on-treatment have had at least Part 1 period completed.
Secondary
To evaluate incidence of AEs in the Narrow 
Scope MedDRA Anaphylactic Reaction 
SMQ
The first secondary endpoint is the incidence of 
AEs in the MedDRA Anaphylactic Reaction 
narrow scope SMQ occurring within 2 days 
after any study therapy infusion during the 
combination period (Part 1). This incidence rate 
will be defined similarly to the primary endpoint 
except that the event rate will be based on terms
within the narrow scope SMQ rather than the 
broad scope.
To evaluate drug-related Grade 3 - 5 AE 
incidence rate  defined using National 
Cancer Institute Common Terminology 
The second secondary endpoint is the 
drug-related Grade 3 - 5 AE incidence rate 
defined using NCI CTCAE version 4.0 criteria. 
The drug-related Grade 3 - 5 AE rate is defined 
as number of participants who experienced at 
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Objective
Endpoint
Criteria for Adverse Events (NCI CTCAE) 
version 4.0 criteria
least 1 AE of Grade 3 or higher, judged to be 
related to study drug by the investigator, with 
onset on or after the first dose of study treatment 
and within 30 days of the last dose of study 
treatment, divided by number of treated 
participants.
To evaluate all causality Grade 3 - 5 AE 
incidence rate defined using NCI CTCAE 
version 4.0 criteria
The third secondary endpoint is the all causality 
Grade 3 - 5 AE incidence rate defined using 
NCI CTCAE version 4.0 criteria. The all 
causality Grade 3 - 5 AE rate is defined as 
number of participants who experienced at least 
1 AE of Grade 3 or higher with onset on or after 
the first dose of study treatment and within 
30 days of the last dose of study treatment, 
divided by number of treated participants.
To determine PK comparisons of 
nivolumab and ipilimumab administered as 
FRC to that of sequentially administered 
nivolumab and ipilimumab
The fourth secondary endpoint is PK 
comparisons of nivolumab and ipilimumab 
administered as FRC to that of sequentially 
administered nivolumab and ipilimumab. PK 
will be measured using serum 
concentration-time data.
To evaluate the objective response rate 
(ORR), as determined by investigators
The fifth secondary endpoint is ORR as 
determined by investigators. The ORR is 
defined as the number of participants with a 
BOR of CR or PR divided by the number of 
treated participants. The BOR is defined as the 
best response designation, as determined by the 
investigator, recorded between the date of 
randomization and the date of objectively 
documented progression per RECIST 1.1 or the 
date of first subsequent anti-cancer therapy, 
whichever occurs first. For participants without 
documented progression or subsequent therapy, 
all available response designations will 
contribute to the BOR assessment.
To evaluate progression free survival (PFS)
The sixth secondary endpoint is PFS. PFS is 
defined as the time between the date of 
randomization and the first date of documented 
progression, as determined by the investigator, 
or death due to any cause, whichever occurs 
first. Participants who die without a reported 
progression will be considered to have 
progressed on the date of their death. 
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Objective
Endpoint
Participants who did not progress or die will be 
censored on the date of their last evaluable 
tumor assessment. Participants who did not have 
any on study tumor assessments and did not die 
will be censored on their date of randomization. 
Participants who started anti-cancer therapy 
without a prior reported progression will be 
censored on the date of their last evaluable 
tumor assessment prior to the initiation of first 
subsequent anti-cancer therapy.
Overall Design:
Study Design and Duration: 
This is a Phase 2, open-label, randomized 2-arm study of the fixed ratio combination 
(BMS-986237) of nivolumab and ipilimumab in a 3:1 ratio (nivolumab 3 mg/kg and ipilimumab 
1 mg/kg). The study is divided into two parts.
In Part 1, Arm A, BMS-986237 will be administered as one 60-minute infusion, every 3 weeks for 
up to 4 doses.
In Part 1, Arm B, nivolumab and ipilimumab will be administered sequentially within the same 
day, as two separate infusions, one 60-minute nivolumab infusion and one 30-minute ipilimumab 
infusion with a 30-minute break between each infusion, every 3 weeks for up to 4 doses.
Six weeks after the last dose in Part 1, participants will then receive nivolumab 480 mg flat dose
infused over 30 minutes every four weeks in Part 2 until progression or unacceptable toxicity.
Subjects who advance to Part 2 will be treated until progression or unacceptable toxicity whichever 
comes first.
Safety of subjects will be monitored on an ongoing basis by the study team. The BMS medical 
monitor is a physician who is responsible for reviewing the safety of patients in this study in a 
systematic and continuous manner. This includes a review of serious and non-serious adverse 
events including all hematological and non-hematological events.
In addition, study safety is evaluated on an ongoing basis by representatives of BMS Global 
Pharmacovigilance and the BMS medical safety team (MST), who operate independently from 
the clinical team and monitor safety across all nivolumab protocols, identify potential safety 
signals, notify appropriate stakeholders of relevant findings, and implement risk management 
plans.
Number of Participants: 
Enrolled: Approximately 129 participants 
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Randomized: 102 (to yield 100 treated, assuming 1.5% attrition)
Screen Failure Rate: It is expected that  approximately 129 participants will need to be enrolled 
in order to randomize 102, assuming a screen failure rate of 21%.
This number of treated participants was chosen to achieve a sufficient level of precision for a 
descriptive analysis to estimate the difference in rates of AEs in the Broad Scope MedDRA
Anaphylactic Reaction SMQ between the two treatment arms. Fifty treated participants per arm 
will allow estimation of the rate difference within 95% confidence limits of 20% or less and will 
be supplemented by a qualitative clinical assessment of the type and severity of events to evaluate 
benefit-risk. The 20% limit represents what is considered to be a clinically meaningful difference 
in the rates of infusion-related reactions.
Treatment Arms and Duration:
Study treatment: This trial is a two-arm, open-label, randomized study:
Part 1:
Treatment Arm A: FRC single infusion (mix of nivolumab and ipilimumab in 3:1 ratio in 
that order) administered intravenously over 60 minutes
Treatment Arm B: nivolumab (3 mg/kg infused over 60 minutes) followed by ipilimumab 
(1 mg/kg infused over 30 minutes) administered intravenously with a 30-minute interval 
waiting period between the two separate infusions
Note: Cycles will be defined as three weeks in the combination period, Part 1
Part 2:
Following four doses of the combination participants will switch to nivolumab 480 mg flat 
dose infused over 30 minutes q 4 weeks. There will be a 6-week interval wait time after the 
completion of the 4 combination doses prior to beginning the nivolumab monotherapy.
Note: Cycles will be defined as four weeks in the flat dosing period, Part 2
Discontinuation of Participants from Treatment:
Participants who advance to Part 2 will be treated for up to disease progression or unacceptable 
toxicity, whichever comes first.  Once a patient has discontinued from treatment, he or she will 
continue to be followed for overall survival (OS) for approximately 5 years. All reasonable effort 
will be made to maintain contact with participants during this follow-up period via phone calls, 
faxes, or emails.
If investigator’s use of a third-party representative to assist in locating participants that have been 
lost to follow up 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, 
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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.
Post Study Drug Access to Therapy:
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to BMS supplied study drug if any of the following occur: a) the marketing application is rejected 
by a responsible health authority; b) the study is terminated due to safety concerns; c) the 
participant can obtain medication from a government sponsored or private health program; or 
therapeutic alternatives become available in the local market.
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
The fixed ratio combination drug product is formulated by combining the nivolumab drug 
substance and ipilimumab drug substance at a nivolumab/ipilimumab protein-mass ratio of 3 to 1. 
The composition and manufacturing process of these 2 drug substances are the same as those used 
for the nivolumab and ipilimumab commercial drug products.
The Sponsor has conducted quality testing to demonstrate that no interaction occurs between the 
two antibodies. The table below provides the composition of the three products.
Nivolumab/Ipilimumab 3:1 for Renal Cell Carcinoma
Component
Nivolumab
Ipilimumab
Fixed Combination
Nivolumab
10 mg/mL
8.57 mg/mL
Ipilimumab
5 mg/mL
2.85 mg/mL
Sodium Citrate
20 mM
8.57 mM
Tris Hydrochloride
20 mM
11.43 mM
Sodium Chloride
50 mM
100 mM
78.57 mM
Mannitol
3% w/v
1% w/v
1.86% w/v
Pentetic Acid
20 μM
100 μM
65.7 μM
Polysorbate 80 
0.02% w/v
0.01% w/v
0.023% w/v
The study design schematic is presented in the figure below. The duration of the trial is expected 
to be 6 months of accrual and approximately 60 months of follow-up after the last participant has 
received the first study drug dose. The primary analysis is only for safety related endpoint and will 
be conducted when all participants who remain on-treatment have completed Part 1. The final 
analysis will be for efficacy related endpoints and be conducted after all participants have at least 
9 months of follow-up.
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA209800)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Prior to any screening procedures register in IRT to obtain participant
number
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and 
confirmed prior to randomization
Medical History
X
Including concomitant medications and prior medications for 
collection of prior cancer therapy
Tumor Tissue Samples
X
Sufficient tumor tissue, archival or recent acquisition, (block or a 
minimum of 20 slides is requested with a minimum of 10 slides 
required; obtained from core biopsy, punch biopsy, excisional biopsy 
or surgical specimen) confirmed to be available at Central Laboratory.
Safety Assessments
Physical Examination
X
Vital Signs
X
BP, HR, temperature, within 14 days prior to randomization
Physical Measurements (including performance
status)
X
Height, weight, IMDC score, BSA and Karnofsky Performance 
Status.
Assessment of Signs and Symptoms
X
For screening, within 14 days prior to 1st dose
Serious Adverse Events Assessment
Continuously
Serious Adverse Events from time of consent
Review of Concomitant Medications
X
Within 14 days prior to randomization
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Table 2-1:
Screening Procedural Outline (CA209800)
Procedure
Screening
Visit
Notes
Laboratory Tests
X
CBC with differential, Chemistry panel including: LDH, AST, ALT, 
ALP, ALB, T.Bili, BUN or serum urea level, creatinine, corrected Ca, 
Na, K, Cl, Glucose, amylase, lipase, phosphate, TSH, Free T4, Free 
T3, within 14 days of randomization; hepatitis B surface antigen 
(HBVsAg), and hepatitis C antibody (HCV Ab) or hepatitis C RNA 
(HCV RNA), within 28 days of randomization
Pregnancy Test (WOCBP only)
X
Serum or urine (minimum sensitivity equivalent units
25IU/L or equivalent units of HCG) to be done at screening visit and 
repeated within 24 hours prior to first dose of study treatment.
Screening/Baseline Tumor Assessment
X
Chest, Abdomen, Pelvis, and Brain within 28 days prior to first dose. 
Head MRI is required in participants with known history of brain 
metastases; participants without known history of brain metastases 
may have head CT or MRI
Contrast enhanced CT scan of the chest, abdomen and pelvis and all 
other known/suspected sites of disease.  Should a participant have 
contraindication for CT intravenous contrast, a non-contrast CT scan 
of the chest and a contrast enhanced MRI of the abdomen and pelvis 
and all other known/suspected sites of disease.
For participants with known brain metastasis, an MRI brain without 
and with gadolinium is required at Screening. A brain CT is not 
allowed for participants with a history or evidence of known brain 
metastasis at Screening.
Clinical Drug Supplies
Randomize
X
First dose to be administered within 72 hours following 
randomization.
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Table 2-2:
On-Study Assessments Part 1 (CA209800) 
Procedure
For Part 1, Study treatment Every 3 Weeks for 
4 Doses
(Both Arm A and Arm B)
Notes
Cycle 1, 2, 3, 4
(Day 1)
Safety Assessments
Targeted Physical Examination
X
To be performed only as clinically indicated within 72 hours 
prior to dosing
Vital Signs 
X
Including BP, HR, and temperature within 72 hours prior to 
dosing
Physical Measurements (including
performance status)
X
Weight and KPS within 72 hours prior to dosing
Adverse Events Assessment
Continuously
For 48 hours, pay close attention to any hypersensitivity, 
anaphylaxis or any infusion related reactions.
Review of Concomitant 
Medications
X
Laboratory Tests
X
Within 72 hrs prior to dosing to include CBC w/ differential, 
LFTs, BUN or serum urea level, creatinine, corrected Ca, Na, 
K, Cl, LDH, Glucose, amylase, lipase, phosphate, TSH 
(+ reflex Free T4 and Free T3)
Pregnancy Test (WOCBP only)
X
Serum or urine (minimum sensitivity equivalent units
25 IU/L or equivalent units of HCG) within 24 hours prior to 
administration of first dose and every 3 weeks thereafter in Part 
1 of the study. A negative pregnancy test should be documented 
within 24 hours prior to start of each dose of investigational 
product.
Pharmacokinetic and 
Immunogenicity Assessments
Immunogenicity blood sample
X
Refer to Table 9.5-1
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nivolumab
Table 2-2:
On-Study Assessments Part 1 (CA209800) 
Procedure
For Part 1, Study treatment Every 3 Weeks for 
4 Doses
(Both Arm A and Arm B)
Notes
Cycle 1, 2, 3, 4
(Day 1)
PK Samples
X
Refer to Table 9.5-1
 
 
 
 
Efficacy Assessment
Tumor Assessment
See Notes
FIRST tumor assessment should be performed at 12 weeks 
(± 1 week) following randomization (until disease progression
or treatment discontinuation, whichever occurs later).
Contrast enhanced CT Chest, CT (or MRI with and without 
contrast) abdomen, pelvis and all known sites of disease. Use 
same imaging method as was used at screening/baseline. 
Participants with a history of brain metastasis should have 
surveillance MRI (with and without gadolinium approximately 
every 12 weeks, or sooner if clinically indicated (until disease 
progression or treatment discontinuation, whichever occurs 
later)
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Date: 02-Aug-2017
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nivolumab
Table 2-2:
On-Study Assessments Part 1 (CA209800) 
Procedure
For Part 1, Study treatment Every 3 Weeks for 
4 Doses
(Both Arm A and Arm B)
Notes
Cycle 1, 2, 3, 4
(Day 1)
Outcomes Research Assessments
FACT-G, EQ-5D-3L, and FKSI-19
X
To be completed at the start of the clinic visit every 6 weeks. 
First questionnaire should be completed after randomization but 
before dosing. 
(Cycle 1, 3)
Health Care Utilization
X
Health Care Utilization will be collected at each visit
Clinical Drug Supplies
IRT Drug Vial Assignment
X
Within 24 hours prior to dosing
Administer Study Treatment
X
First dose to be administered within 72 hours following 
randomization.
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nivolumab
Table 2-3:
On-Study Assessments - Part 2 (CA209800)
Procedure
For Part 2, Study treatment is 
Administered Every 4 Weeks
(Both Arm A and Arm B)
Notes
Cycle 5 will begin 6 weeks after Cycle 4
Cycle 5 and beyond
(Day 1)
Safety Assessments
Targeted Physical Examination
X
To be performed only if clinically indicated within 72 hours prior to dosing
Vital Signs 
X
Including BP, HR, and temperature within 72 hours prior to dosing
Physical Measurements (including 
performance status)
X
Weight and KPS within 72 hours prior to dosing
Adverse Events Assessment
Continuously
Review of Concomitant 
Medications
X
Laboratory Tests
X
Beginning at Cycle 5 and every alternate dose thereafter (Cycle 7, 9, 11, 13, etc.), 
on-study local laboratory assessments should be done within 72 hours prior to 
dosing and include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase), BUN or serum urea level, creatinine, corrected Ca, Na, K, Cl, LDH, 
glucose, amylase, lipase, phosphate, TSH with reflexive Free T4, Free T3.
Beginning at Cycle 6 and every alternate dose thereafter (Cycle 8, 10, 12, 14, 
etc.), on-study local laboratory assessment should be done within 72 hours prior to 
dosing and include: LFTs (ALT, AST, total bilirubin, alkaline phosphatase) and 
creatinine.
Pregnancy Test (WOCBP only)
X
Serum or urine (minimum sensitivity equivalent units
25IU/L or equivalent units of HCG) every 4 weeks. A negative pregnancy test 
should be documented within 24 hours prior to start of each dose of 
investigational product.
Outcomes Research Assessments
FACT-G, EQ-5D-3L, and FKSI-19
X
To be completed at the start of the clinic visit every 4 weeks from Cycle 5 
onwards
Health Care Utilization
X
Health Care Utilization will be collected at each visit from Cycle 5 onwards
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nivolumab
Table 2-3:
On-Study Assessments - Part 2 (CA209800)
Procedure
For Part 2, Study treatment is 
Administered Every 4 Weeks
(Both Arm A and Arm B)
Notes
Cycle 5 will begin 6 weeks after Cycle 4
Cycle 5 and beyond
(Day 1)
Pharmacokinetic and 
Immunogenicity Assessments
Immunogenicity blood sample
X
Refer to Table 9.5-1
PK Samples
X
Refer to Table 9.5-1
Efficacy Assessment
Tumor Assessment
See Notes
First tumor assessment during Part 2 should occur after 8 weeks (± 1 week) 
relative to previous tumor assessment performed at Week 12.
Subsequent tumor assessments should occur every 8 weeks (± 1 week) for the first 
12 months from randomization.
From the second year from randomization, tumor assessments should occur every 
12 weeks (± 2 weeks) until disease progression or treatment discontinuation, 
whichever occurs later.
Contrast enhanced CT Chest, CT (or MRI with and without contrast)) abdomen, 
pelvis and all known sites of disease. Use same imaging method as was used at 
screening/baseline.
Participants with a history of brain metastasis should have surveillance MRI brain 
with and without gadolinium approximately every 12 weeks, or sooner if 
clinically indicated (until disease progression or treatment discontinuation, 
whichever occurs later).
Clinical Drug Supplies
IRT Drug Vial Assignment
X
Administer Study Treatment
X
Note: Within 72 hours from vial assignment, the participant must receive the dose 
of study medication.
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Table 2-4:
Follow-up Assessments (CA209800)
Procedure
Follow Up,a
Visits X1 and 
X2
Survival,b
Follow-up Y 
Visits
Notes
Safety Assessments
Targeted Physical Examination
X
To assess for potential late emergent study treatment related issues
Adverse Event Assessments
X
X
Laboratory Tests
X
On site/local CBC w/differential, LFTs, BUN, creatinine, amylase, lipase 
and TSH (+ reflex Free T4 and Free T3) for X1, repeat at X2 if study 
treatment related toxicity persists.
Pregnancy Test (WOCBP Only)
X
Serum or urine
Review of Concomitant Medications
X
Pharmacokinetic Samples  and 
Immunogenicity Assessments
PK Samples
X
Refer to Table 9.5-1
Immunogenicity blood sample
X
Refer to Table 9.5-1
Survival Status
Participant Status
X
X
Every 3 months, Survival Follow up Visits may be accomplished by visit or 
phone contact, to include subsequent anti-cancer therapy
Efficacy Assessments
Tumor Assessments
See Notes
Only for participants without progression on study therapy.
SUBSEQUENT tumor assessments should continue to occur every 8 weeks 
(± 1 week) thereafter for the first 12 months, then every 12 weeks
(± 2 weeks) until disease progression or treatment discontinuation, 
whichever occurs later.
Contrast enhanced CT Chest, CT (or MRI with and without contrast) 
abdomen, pelvis and all known sites of disease. Use same imaging method 
as was used at screening/baseline.
Participants with a history of brain metastasis should have surveillance MRI
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Date: 02-Aug-2017
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nivolumab
Table 2-4:
Follow-up Assessments (CA209800)
Procedure
Follow Up,a
Visits X1 and 
X2
Survival,b
Follow-up Y 
Visits
Notes
Brain without and with gadolinium approximately every 12 weeks, or sooner 
if clinically indicated (until disease progression or treatment discontinuation, 
whichever occurs later).
Outcomes Research Assessments
FACT-G and FKSI-19
X
Collection done at X1 and X2 only
EQ-5D-3L
X
X
Collection done during X1 and X2. Survival follow-up every 3 months for 
the first year and 6 months thereafter
Health Care Utilization
X
Collection done at X1 and X2 only
a X visits occur as follows - X1 = 30 days from the last dose (7 days) or coincide with the date of discontinuation (7 days) if date of discontinuation is greater 
than 37 days after last dose, X2 = 84 days (7 days) from follow-up visit 1. Follow up visits X1 and X2 will occur only after participant completes all study 
treatment. Participants must be followed for at least 100 days after last dose of study treatment. 
b Y Survival visits = every 3 months from X2 (7 days). Survival Follow-up visits to occur every 3 months from Follow-up Visit 2. BMS may request that 
survival data be collected on all treated participants outside of the 3 month specified window. At the time of this request, each participant will be contacted to 
determine their survival status unless the participant has withdrawn consent for all contacts.
For responders (CR, PR or SD) on study beyond 2 years an extension of the frequency of scans from every 12 weeks to every 24 weeks until disease progression 
or treatment discontinuation, whichever occurs later, is permitted. Participants who discontinue study therapy for reasons other than progression should continue 
to be scanned until disease progression is documented. 
If a dose is delayed, the procedures scheduled for that same timepoint should also be delayed to coincide with when that timepoint’s dosing actually occurs.
Revised Protocol No.: 02
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BMS-936558
nivolumab
 
 
 
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objective
Endpoint
Primary
To evaluate the difference in safety between co-
administered FRC nivolumab 3 mg/kg and 
ipilimumab 1 mg/kg relative to sequentially 
administered nivolumab 3 mg/kg and ipilimumab 
1 mg/kg as measured by the incidence of AEs in the 
Broad Scope MedDRA Anaphylactic Reaction SMQ 
occurring within 2 days after dosing during the 
combination, Part 1 period.
The primary endpoint of the study is the incidence of AEs 
in the Broad Scope MedDRA Anaphylactic Reaction 
SMQ occurring within 2 days after dosing during the 
combination, Part 1 period. This incidence rate is defined 
as the number of participants who experienced at least 
1 AE in the MedDRA Anaphylactic Reaction broad scope 
SMQ with onset on the day of or within 2 days after any 
study therapy infusion during the combination period 
(Part 1) divided by number of treated participants. The 
analysis of the primary endpoint will occur at the time of 
first (primary) analysis when all participants who are still 
on-treatment have had at least Part 1 period completed.
Secondary
To evaluate incidence of AEs in the Narrow Scope 
MedDRA Anaphylactic Reaction SMQ
The first secondary endpoint is the incidence of AEs in 
the MedDRA Anaphylactic Reaction narrow scope SMQ 
occurring within 2 days after any study therapy infusion 
during the combination period (Part 1). This incidence 
rate will be defined similarly to the primary endpoint 
except that the event rate will be based on terms within 
the narrow scope SMQ rather than the broad scope.
To evaluate drug-related Grade 3 - 5 AE incidence 
rate  defined using National Cancer Institute 
Common Terminology Criteria for Adverse Events 
(NCI CTCAE) version 4.0 criteria
The second secondary endpoint is the drug-related 
Grade 3 - 5 AE incidence rate defined using NCI CTCAE 
version 4.0 criteria. The drug-related Grade 3 - 5 AE rate 
is defined as number of participants who experienced at 
least 1 AE of Grade 3 or higher, judged to be related to 
study treatment by the investigator, with onset on or after 
the first dose of study treatment and within 30 days of the 
last dose of study treatment, divided by number of treated 
participants.
To evaluate all causality Grade 3 - 5 AE incidence 
rate defined using NCI CTCAE version 4.0 criteria
The third secondary endpoint is the all causality 
Grade 3 - 5 AE incidence rate defined using NCI CTCAE 
version 4.0 criteria. The all causality Grade 3 - 5 AE rate 
is defined as number of participants who experienced at 
least 1 AE of Grade 3 or higher with onset on or after the 
first dose of study treatment and within 30 days of the last 
dose of study treatment, divided by number of treated 
participants.
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Table 4-1:
Objectives and Endpoints
Objective
Endpoint
To determine PK comparisons of nivolumab and 
ipilimumab administered as FRC to that of 
sequentially administered nivolumab and 
ipilimumab.
The fourth secondary endpoint is PK comparisons of 
nivolumab and ipilimumab administered as FRC to that of 
sequentially administered nivolumab and ipilimumab. PK 
will be measured using serum concentration-time data.
To evaluate the objective response rate (ORR), as 
determined by investigators
The fifth secondary endpoint is ORR as determined by 
investigators. The ORR is defined as the number of 
participants with a BOR of CR or PR divided by the 
number of treated participants. The BOR is defined as the 
best response designation, as determined by the 
investigator, recorded between the date of randomization 
and the date of objectively documented progression per 
RECIST 1.1 or the date of first subsequent anti-cancer 
therapy including radiotherapy, tumor-directed surgery, or 
systemic anticancer therapy, whichever occurs first. For 
participants without documented progression or 
subsequent therapy, all available response designations 
will contribute to the BOR assessment.
To evaluate progression free survival (PFS)
The sixth secondary endpoint is PFS. PFS is defined as 
the time between the date of randomization and the first 
date of documented progression, as determined by the 
investigator, or death due to any cause, whichever occurs 
first. Participants who die without a reported progression 
will be considered to have progressed on the date of their 
death. Participants who did not progress or die will be 
censored on the date of their last evaluable tumor 
assessment. Participants who did not have any on study 
tumor assessments and did not die will be censored on 
their date of randomization. Participants who started 
anti-cancer therapy without a prior reported progression 
will be censored on the date of their last evaluable tumor 
assessment prior to the initiation of first subsequent 
anti-cancer therapy including radiotherapy, tumor 
directed surgery, or systemic anticancer therapy.
 
 
 
 
 
 
 
 
 
 
 
 
 
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nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 2, open-label, randomized 2-arm study of the fixed ratio combination 
(BMS-986237) of nivolumab and ipilimumab in a 3:1 ratio (nivolumab 3 mg/kg and ipilimumab 
1 mg/kg) in participants with previously untreated advanced or metastatic RCC.
Participants meeting all eligibility criteria will be randomized 1:1 ratio and stratified by IMDC 
prognostic score (0 vs 1-2 vs 3-6) to Arm A (BMS-986237) or Arm B (nivolumab and ipilimumab 
administered sequentially).
In Part 1, Arm A, BMS-986237 will be administered as one 60-minute infusion, every 3 weeks for 
up to 4 doses.
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In Part 1, Arm B, nivolumab and ipilimumab will be administered sequentially within the same 
day, as 2 separate infusions, one 60-minute nivolumab infusion and one 30-minute ipilimumab
infusion with a 30 minute break between each infusion, every 3 weeks for up to 4 doses.
Six weeks after the last dose in Part 1, participants will then receive nivolumab 480 mg flat dose 
infused over 30 minutes every four weeks in Part 2 until progression or unacceptable toxicity.
Subjects who advance to Part 2 will be treated until progression or unacceptable toxicity, 
whichever comes first.
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
Physical examinations, vital sign measurements and clinical laboratory evaluations will be 
performed at selected times throughout the dosing interval. Participants will be closely monitored 
for adverse events throughout the study.
5.1.1
Data Monitoring Committee and Other External Committees
Not applicable.
5.2
Number of Participants
It is expected that  approximately 129 participants will need to be enrolled in order to randomize 
102, assuming a screen failure rate of 21%.
This number of 100 treated participants was chosen to achieve a sufficient level of precision for a 
descriptive analysis to estimate the difference in rates of AEs in the Broad Scope MedDRA 
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Anaphylactic Reaction SMQ between the two treatment arms. Fifty treated participants per arm 
will allow estimation of the rate difference within 95% confidence limits of 20% or less and will 
be supplemented by a qualitative clinical assessment of the type and severity of events to evaluate 
benefit-risk. The 20% limit represents what is considered to be a clinically meaningful difference 
in the rates of infusion-related reactions.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. The end of the 
trial is defined as the last scheduled procedure shown in the time and events schedule for the last 
participant who has received combination treatment. 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.
This study will consist of 3 phases: screening, treatment, and follow-up.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
participant care
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests including the completion of quality of life questionnaires and other 
requirements of the study
2) Type of Participant and Target Disease Characteristics
a) Histological confirmation of RCC with a clear-cell component
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b) Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC 
Stage IV) RCC
c) No prior systemic therapy for RCC with the following exception:
i.
One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such 
therapy did not include a checkpoint inhibitor and if recurrence occurred at least 
6 months after the last dose of adjuvant or neoadjuvant therapy.
d) Karnofsky Performance Status (KPS) of at least 70%
e) Measurable disease as per RECIST 1.1
f)
Tumor tissue (formalin-fixed paraffin-embedded (FFPE) archival or recent acquisition) 
must be received   by the central vendor (block or unstained slides) in order to randomize 
a participant to study treatment.  (Note: Fine Needle Aspiration [FNA] and bone 
metastases samples are not acceptable for submission).
i.
If an insufficient amount of tumor tissue from an unresectable or metastatic site is 
available prior to the start of the screening phase, subjects must consent to allow 
the acquisition of additional tumor tissue for performance of biomarker analyses
g) Participants with favorable, intermediate and poor risk categories will be eligible for the 
study. 
i.
To be eligible for the Intermediate-Risk cohort one or two of the following 
prognostic factors as per International Metastatic RCC Database Consortium 
(IMDC) risk factors include:
i. KPS equal to 70%
ii. Less than 1 year from initial diagnosis to randomization
iii. Hemoglobin less than the LLN
iv. Corrected calcium concentration greater than 10 mg/dL
v. Absolute neutrophil count greater than the ULN
vi. Platelet count greater than the ULN
ii.
If more than two factors are present they will be eligible for Poor-Risk cohort. If 
none of the above factors are present, participants are only eligible for the 
Favorable-Risk cohort. 
3) Age and Reproductive Status
a) Males and Females, 18 years of age 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment. Women must not be breastfeeding
c) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception, as indicated in the informed consent form, for a period of 
30 days (duration of ovulatory cycle) plus the time required for the investigational drug to 
undergo approximately five half-lives. WOCBP should therefore use an adequate method 
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to avoid pregnancy for 5 months (30 days plus the time required for nivolumab to undergo 
approximately five half lives) after the last dose of investigational drug (combination or 
monotherapy). 
d) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception, as indicated in the informed consent form, for a period of 
90 days plus the time required for the investigational drug to undergo approximately five 
half-lives. Men who are sexually active with WOCBP must continue contraception for 
7 months (90 days plus the time required for nivolumab to undergo approximately five 
half-lives) after the last dose of investigational drug (combination or monotherapy). In 
addition, male participants must be willing to refrain from sperm donation during this time.
e) Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, (Appendix 4 
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Active brain metastases or leptomeningeal metastases. Participants with brain metastases 
are eligible if these have been treated and there is no magnetic resonance imaging (MRI -
except where contraindicated in which CT scan is acceptable) evidence of progression for 
at least 8 weeks after treatment is complete and within 28 days prior to first dose of study 
treatment administration.
b) Ocular melanoma
c) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.
d) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally
e) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative)
f)
Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) 
that, in the investigator’s opinion, would increase the risk associated with study 
participation or study treatment administration or interfere with the interpretation of safety 
results.
g) Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study treatment.
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h) Anti-cancer therapy less than 28 days prior to the first dose of study treatment or palliative, 
focal radiation therapy less than 14 days prior to the first dose of study treatment.
i)
Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that 
have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study 
treatment.
2) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways
b) Any active or recent history of a known or suspected autoimmune disease or recent history 
of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) 
or immunosuppressive medications except for syndromes which would not be expected to 
recur in the absence of an external trigger. Participants with vitiligo or type I diabetes 
mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone 
replacement are permitted to enroll.
c) Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 14 days prior to first dose of 
study treatment. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune disease.
d) Uncontrolled adrenal insufficiency.
3) Physical and Laboratory Test Findings
a) Any of the following laboratory test findings:
i.
WBC < 2000/μL
ii.
Neutrophils < 1500/μL
iii.
Platelets < 100*103/μL
iv.
Hemoglobin < 9.0 g/dL
v.
Serum creatinine  >1.5 x ULN or calculated creatinine clearance 
< 40 mL/min (using the Cockcroft-Gault formula)
vi.
AST/ALT: > 3.0 x ULN
vii.
Total bilirubin > 1.5 x ULN (participants with Gilbert Syndrome who must 
have a total bilirubin level of < 3.0x ULN)
viii.
Any positive test result for hepatitis B virus or hepatitis C virus indicating 
presence of virus, eg Hepatitis B surface antigen (HBsAg, Australia antigen) 
positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA 
negative).
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study treatment components
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required).
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b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) 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 or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / 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 or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
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).
In this protocol, investigational products are:

Nivolumab

Ipilimumab
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
Nivolumab/Ipilimumab Fixed Ration Combination (FRC).
The fixed ratio combination drug product is formulated by combining the nivolumab drug 
substance and ipilimumab drug substance at a nivolumab/ipilimumab protein-mass ratio of 3 to 1. 
The Sponsor has conducted quality testing to demonstrate that no interaction occurs between the 
two antibodies. The table below provides the composition of the three products.
Table 7-1:
Nivolumab/Ipilimumab 3:1 for Renal Cell Carcinoma
Component
Nivolumab
Ipilimumab
Fixed Combination
Nivolumab
10 mg/mL
8.57 mg/mL
Ipilimumab
5 mg/mL
2.85 mg/mL
Sodium Citrate
20 mM
8.57 mM
Tris Hydrochloride
20 mM
11.43 mM
Sodium Chloride
50 mM
100 mM
78.57 mM
Mannitol
3% w/v
1% w/v
1.86% w/v
Pentetic Acid
20 μM
100 μM
65.7 μM
Polysorbate 80 
0.02% w/v
0.01% w/v
0.023% w/v
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products.
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Table 7-2:
Study treatments for CA209800
Product Description / 
Class and Dosage 
Form
Potency
Primary Packaging 
(Volume)/Label Type
Secondary Packaging 
(Qty)/Label Type
Packaging / 
Appearance
Storage Conditions
(per label)
Nivolumab Solution for 
Injection
100 mg (10 mg/mL)
or
40 mg (10 mg/mL)
10 mL per vial 
Or
4 mL vial/Open label
5 or 10 vials per carton/ 
Open-label
Or 
240 mg kits (2 - 100 mg 
vials & 1 - 40 mg vial)
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
2°C to 8°C. Protect 
from light and freezing
Ipilimumab
200 mg (5 mg/mL)
40 mL per vial/Open-
label
4 vials per 
carton/Open-label
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
2°C to 8°C. Protect 
from light and freezing
BMS-986237 Solution 
for Injection
(Nivolumab/Ipilimumab 
FRC)
240 mg Nivolumab/ 
80 mg Ipilimumab
28 mL per vial/Open-
label
(vial with booklet 
label - first page in 
ORANGE)
6 vials per 
carton/Open-label
Clear to opalescent, 
colorless to pale yellow 
liquid. Light (few) 
particulates may be 
present
2°C to 8°C. Protect 
from light and freezing
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7.1
Treatments Administered
7.1.1
Part 1 Study Treatment Administration
In Part 1 of the study there will be two treatment arms:
Arm A BMS-986237 (nivolumab 3 mg/kg/ipilimumab 1 mg/kg as a single infusion) will be 
administered as one 60-minute infusion on Day 1 of each treatment cycle every 3 weeks for 4 doses 
or until progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever 
occurs first.
Arm B nivolumab and ipilimumab will be administered sequentially, as two separate infusions, 
one 60 minute nivolumab infusion and one 30-minute ipilimumab infusion with a 30-minute break 
between each infusion. Nivolumab is to be administered first. Participants should receive 
nivolumab at a dose of 3 mg/kg as a 60-minute IV infusion, on Day 1 of each treatment cycle every 
3 weeks for 4 doses or until progression, unacceptable toxicity, withdrawal of consent, or the study 
ends, whichever occurs first. Participants should begin study treatment within 3 calendar days of 
randomization.
The second infusion will always be ipilimumab, and the time in between infusions is expected to 
be approximately 30 minutes but may be more or less depending on the situation. Participants 
should receive ipilimumab at a dose of 1 mg/kg as a 30-minute IV infusion, on Day 1 of each 
treatment cycle every 3 weeks for 4 doses or until progression, unacceptable toxicity, withdrawal 
of consent, or the study ends, whichever occurs first. 
Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to 
re-calculate subsequent doses if the participant weight is within 10% of the weight used to calculate 
the previous dose. All doses should be rounded up or to the nearest milligram per institutional 
standard.
The nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab 
before starting the next infusion.
Both agents given as single agents are uncommonly associated with infusion reactions, incidence 
less than 1% for ipilimumab (YervoyFDA Label) and for nivolumab 3% (OpdivoFDA Label). 
In the CA209069 study, hypersensitivity/infusion reactions were listed as 3.2% for the 
combination and 2.2% for ipilimumab. No Grade 3 or Grade 4 hypersensitivity/infusion reactions 
were observed in either the combination or single agent ipilimumab treatment groups.28
Participants should be carefully monitored for infusion reactions during study treatment
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.4.5.
The pharmacy manual includes detailed instructions for study medication preparation.
During Part 1, participants may be dosed no less than 19 days between doses. If dosing is delayed, 
both nivolumab and ipilimumab must be delayed together. If dosing is resumed after a delay, both 
nivolumab and ipilimumab must be resumed on the same day.
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In extenuating circumstances in which the participant cannot make the dosing schedule within the 
3-day window, BMS Medical Monitor should be contacted.
Detailed instructions for dilution and infusion of study treatment injection are provided in the 
pharmacy binder, pharmacy reference sheet and current investigator brochures. Care must be taken 
to assure sterility of the prepared solution as the product does not contain any antimicrobial 
preservative or bacteriostatic agent. 
7.1.2
Part 2 Study Treatment Administration
Starting 6 weeks after the last co-administered dose in Part 1, participants will be administered a 
flat dose 480 mg nivolumab 30-minute infusion every 4 weeks (Q4W) until unacceptable toxicity 
or disease progression is reached, whichever comes first.
Participants may be dosed up to 3 days after the scheduled date if necessary. Subsequent dosing 
should be based on the actual date of administration of the previous dose of drug. Every effort 
should be made to adhere to protocol treatment schedule of administration of nivolumab every 
4 weeks in the maintenance phase. In extenuating circumstances in which the participant cannot 
make the dosing schedule within the 3-day window, BMS Medical Monitor should be contacted. 
Note: Subjects who advance to Part 2 will be treated until progression or unacceptable 
toxicity, whichever comes first.
For details on prepared drug storage, preparation, and administration, please refer to the 
nivolumab, ipilimumab and BMS-986237 IBs and/or pharmacy reference sheets. The selection 
and timing of dose for each participant is as follows:
7.1.3
Selection and Timing of Dose
Table 7.1.3-1:
Selection and Timing of Dose Part 1 (Arm A) (Administered as one 
60-minute infusion, every 3 weeks for up to 4 doses).
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
BMS-986237
4 mg/kg
Every 3 Weeks
(4 total doses)
IV
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Table 7.1.3-2:
Selection and Timing of Dose Part 1 (Arm B) - (Administered 
sequentially within the same day, as two separate infusions, one 
60-minute nivolumab infusion and one 30-minute ipilimumab 
infusion with a 30 minute break between each infusion, every 
3 weeks for up to 4 doses)
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
nivolumab
3 mg/kg
Every 3 Weeks
(4 total doses)
IV
ipilimumab
1 mg/kg
Every 3 Weeks
(4 total doses)
IV
Table 7.1.3-3:
Selection and Timing of Dose Part 2 (All Participants) -
(Administered as infusion over 30 minutes every four weeks in Part 
2 until progression or unacceptable toxicity)
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
nivolumab
480 mg
Every 4 weeks
IV
When nivolumab and ipilimumab are to be administered on the same day, nivolumab is to be 
administered first. Nivolumab infusion must be promptly followed by a saline flush to clear the 
line of nivolumab before starting the ipilimumab infusion. The second infusion will always be the 
ipilimumab study treatment and will start after the infusion line has been flushed, filters changed 
and participant has been observed to ensure no infusion reaction has occurred. The time in between 
infusions is expected to be approximately 30 minutes but may be more or less depending on the 
situation.
There will be no dose escalations or reductions of study treatment allowed. For Q4W dosing 
cycles, participants may be dosed within a 3-day window. Premedications are not recommended 
for the first dose of nivolumab.
Participants should be carefully monitored for infusion reactions during study treatment
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.4.5.
Doses of nivolumab, ipilimumab, and BMS-986237 may be interrupted, delayed, or discontinued 
depending on how well the participant tolerates the treatment. Dosing visits are not skipped, only
delayed.
Nivolumab injection is to be administered as a ~ 60-minute IV infusion through a 0.2-micron to 
1.2-micron pore size, low-protein binding (polyethersulfone membrane) in-line filter at the 
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protocol specified doses and infusion times. It is not to be administered as an IV push or bolus 
injection. Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP to protein concentrations as low as 
0.35 mg/mL. During drug product preparation and handling, vigorous mixing or shaking is to be 
avoided. Instructions for dilution and infusion of nivolumab injection are provided in the clinical 
protocol, pharmacy binder, pharmacy manual, or pharmacy reference sheet. Care must be taken to 
assure sterility of the prepared solution as the product does not contain any antimicrobial 
preservative or bacteriostatic agent. Nivolumab infusions are compatible with polyvinyl chloride 
(PVC) or polyolefin containers and infusion sets, and glass bottles. Vials of nivolumab injection 
must be stored at 2C to 8C (36F to 46F) and protected from light and freezing.
Ipilimumab injection can be used for IV administration without dilution after transferring to a 
PVC, non-PVC/non-DEHP or glass container and is stable for 24 hours at 2° - 8°C or room 
temperature/room light (RT/RL). For ipilimumab storage instructions, refer to ipilimumab IB 
and/or pharmacy reference sheets.
Separate infusion bags and filters should be used when administering nivolumab and ipilimumab 
on the same day.
Ipilimumab is to be administered as a ~30 minute IV infusion, using a volumetric pump with a 
0.2 to 1.2 micron in-line filter at the protocol-specified dose. The drug can be diluted with 0.9% 
normal saline or 5% Dextrose Injection to concentrations between 1 mg/mL and 4 mg/mL. It is 
not to be administered as an IV push or bolus injections. Care must be taken to assure sterility of 
the prepared solutions, since the drug product does not contain any antimicrobial preservatives or 
bacteriostatic agents. At the end of the infusion, flush the line with a sufficient quantity of normal 
saline or 5% dextrose solution.
BMS-986237 injection is to be administered as an IV infusion through a 0.2-micron pore size, 
low-protein binding in-line filter at the protocol-specified doses and infusion times. It is not to be 
administered as an IV push or bolus injection. Prior to infusion, the BMS-986237 injection is 
diluted with 0.9% Sodium Chloride Injection, United States Pharmacopeia (USP) to required 
concentrations.
BMS-986237 is available as a solution at a concentration of 11.4 mg/mL. The volume for 
calculated weight based dose (refer to pharmacy reference sheets) is to be added to 40 mL of 0.9% 
Sodium Chloride (normal saline) USP prior to being administered to the participant as an infusion, 
at a flow rate of less than or equal to 2.5 mL/min over ~ 60 minutes.
During drug product preparation and handling, vigorous mixing or shaking is to be avoided. Vials 
of BMS-986237 injection must be stored at 2to 8C (36to 46F) protected from light and it 
must not be frozen. Further instructions for dilution and infusion of BMS-986237 injection are
provided in the clinical protocol, pharmacy binder, or pharmacy reference sheet. Care must be 
taken to assure sterility of the prepared solution as the product does not contain any antimicrobial 
preservative or bacteriostatic agent. No incompatibilities between BMS-986237 and polyvinyl 
chloride (PVC) and polyolefin containers/IV components have been observed. 
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7.2
Method of Treatment Assignment
All participants will be centrally randomized or using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log in information and directions on how to 
access the IRT.
Once enrolled in IRT, enrolled subjects that have met all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for subject randomization:

Subject number

Date of birth

IMDC prognostic score at screening (0 vs 1-2 vs 3-6)
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to Arm A or Arm B,
stratified by IMDC prognostic score. The randomization procedures will be carried out via 
permuted blocks within each stratum. The exact procedures for using the IRT will be detailed in 
the IRT manual.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
7.3
Blinding
This is an open-label study; however, the specific treatment to be taken by a participant will be 
assigned using an Interactive Response Technology (IRT). The site will contact the Interactive 
Response System prior to the start of study treatment administration for each participant. The site 
will record the treatment assignment on the applicable case report form, if required.
7.4
Dosage Modification
7.4.1
Dose Delay Criteria 
Regardless of whether or not the event is attributed to nivolumab, ipilimumab, or BMS-986237, 
all study treatments must be delayed until treatment can resume. Tumor assessments for all 
participants should continue as per protocol even if dosing is delayed.
Nivolumab, ipilimumab, and BMS-986237 administration should be delayed for the following:

Grade 2 non-skin, drug-related adverse event, with the exception of fatigue

Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities

Grade 3 skin, drug-related adverse event

Grade 3 drug-related laboratory abnormality, with the following exceptions: 
o
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose 
delay
o
Grade 3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section
7.4.3)

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
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Participants who require delay of study treatment should be re-evaluated weekly or more 
frequently if clinically indicated and resume study treatment dosing when re-treatment criteria are 
met.
7.4.2
Criteria to Resume Treatment
Participants may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade 1 or baseline value, with the following exceptions:

Participants may resume treatment in the presence of Grade 2 fatigue

Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity

For participants with Grade 2 AST, ALT and/or Total Bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.

Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 7.4.3) should have treatment permanently discontinued. 

Drug-related pulmonary toxicity, diarrhea or colitis or myocarditis myositis, rhabdomyolysis
must have resolved to baseline before treatment is resumed. Participants with persistent 
Grade 1 pneumonitis after completion of a steroid taper over at least 1 month may be eligible
for retreatment if discussed with and approved by BMS Medical Monitor.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor. 
Adrenal insufficiency requires discontinuation regardless of control with hormone replacement.
7.4.3
Dose Discontinuation
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab. Although there is overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued. In this instance, the patient would be 
considered off part 1 of the study and must have a 6 weeks interval before moving on to part 2 of 
the study (nivolumab monotherapy).
If a participant in any of the nivolumab/ipilimumab combination arms meets criteria for 
discontinuation and investigator is unable to determine whether the event is related to both or one 
study drug, the participant should discontinue both nivolumab and ipilimumab and be taken off 
the treatment phase of the study.
Study treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
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uveitis, pneumonitis, bronchospasm, myositis, myocarditis, rhabdomyolysis, hypersensitivity 
reactions, infusion reactions, and endocrinopathies:

Grade 3 drug-related, diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, myositis, myocarditis, rhabdomyolysis, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation

Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
o
Grade 3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
* In most cases of Grade 3 AST or ALT elevation, study treatment(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.

Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin).

Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. However, dosing must be discontinued for any drug related AE that requires 
treatment with 10mg/day or greater prednisone or equivalent for more than 12 weeks.

Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor. 
Prior to re-initiating treatment in a participant with a dosing delay of >6 weeks, the BMS Medical 
Monitor must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue every 
6 weeks or more frequently if clinically indicated during such dosing delays.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab dosing.
7.4.4
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab, ipilimumab, and BMS-986237 are 
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considered immuno-oncology agents in this protocol. Early recognition and management of AEs 
associated with immuno-oncology agents may mitigate severe toxicity. Management Algorithms 
have been developed to assist investigators in assessing and managing the following groups of 
AEs:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathy

Skin

Neurological

Myocarditis
The above algorithms are found in the Appendix 8 of this protocol.
7.4.5
Treatment of Related Infusion Reactions
Since study treatment contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and reported 
as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(Version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):

Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment [(eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for 
24 hours)]:

Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the 
participant
with 
diphenhydramine 
50 mg 
IV
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant until 
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resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate (for Arm B 
subjects) or to 50% of the original infusion rate (for Arm A subjects) until completion of the 
infusion. Monitor participant closely. If symptoms recur, then no further study treatment will 
be administered at that visit.

For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before infusions. If necessary, corticosteroids (up 
to 25 mg of hydrocortisone or equivalent) may be used
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (eg, renal impairment, 
pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory support indicated):

Immediately discontinue infusion of study treatment. Begin an IV infusion of normal saline 
and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Study treatment will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product 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.
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Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets).

Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2 and Study Reference Manual.
 
 
 
 
 
 
7.6
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and electronic case report form (eCRF).
7.7.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to study treatment administration in the study 
are described below. Medications taken within 4 weeks prior to study treatment administration 
must be recorded on the CRF.
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event):

Immunosuppressive agents

Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.2).

Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of the disease under study). 
 
 
 
7.7.2
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
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daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
7.7.3
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of treatment 
assignment are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration specified in 
the protocol. Study treatment will be provided via an extension of the study, a rollover study 
requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of BMS.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of nivolumab, 
ipilimumab, and/or BMS-986237 is terminated for other reasons, including but not limited to lack 
of efficacy and/or not meeting the study objectives; c) the participant can obtain medication from 
a government sponsored or private health program. In all cases BMS will follow local regulations
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information

Any clinical adverse event (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 Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed
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In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event In most cases, the study treatment will be permanently discontinued 
in an appropriate manner (eg, dose tapering if necessary for participant safety). Please call the 
BMS Medical Monitor 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/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 post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.1.1
Post Study Treatment Study Follow-up
In this study, overall survival 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 collection of 
outcome and/or survival follow-up data as required and in line with Section 5 until death or the 
conclusion of the study.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window. 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.
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.3
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.7
Participants treated with study treatment(s) will be permitted to continue treatment beyond initial 
RECIST 1.1 defined PD in both Part 1 and Part 2, assessed by the investigator, as long as they 
meet the following criteria:

Investigator-assessed clinical benefit

Tolerance of study treatment

Stable performance status

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 treatment. All other 
elements of the main consent including description of reasonably foreseeable risks or 
discomforts, or other alternative treatment options will still apply.
A radiographic assessment/ scan should be performed within 6 weeks of initial 
investigator-assessed progression to determine whether there has been a decrease in the tumor size 
or continued PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the participant is clinically deteriorating and unlikely to receive any benefit from 
continued treatment.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Time and Events Schedule.
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum 5 mm absolute increase from time 
of initial PD. This includes an increase in the sum of diameters of all target lesions and/ or the 
diameters of new measurable lesions compared to the time of initial PD. Nivolumab treatment 
should be discontinued permanently upon documentation of further progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
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8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.

As 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 three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 

The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.

If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities. 

Protocol waivers or exemptions are not allowed.
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
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study treatment related toxicities resolve, return to baseline, or are deemed 
irreversible.
If a participant shows new or worsening cardiac-related signs, symptoms, or findings (eg, dyspnea 
at rest/on exertion, heart block, cardiomyopathy or reduced LV function on imaging) consistent 
with possible cardiac adverse events, the participant should be immediately evaluated to rule out 
myocarditis toxicity, according to the suspected Myotoxicity (myositis, myocarditis, 
rhabdomyolysis) adverse event management algorithm in the BMS-936558 (nivolumab) 
Investigator Brochure.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
Tumor assessment with contrast-enhanced computed tomography (CT) scans acquired on 
dedicated CT equipment is preferred for this study. Contrast-enhanced CT of the chest, abdomen, 
pelvis, and other known/suspected sites of disease should be performed for tumor assessments. 
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained. A contrast-enhanced MRI of the chest may be obtained instead of a 
non-contrast CT of the chest.
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Should a participant have contraindication for both MR and CT intravenous contrasts, a 
non-contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. A non-contrast MRI of the chest, abdomen, 
pelvis, and other known/suspected sites of disease is also acceptable.
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable.
CT and MRI scans should be acquired with slice thickness of 5 mm or less with no intervening 
gap (contiguous). Every attempt should be made to image each participant using an identical 
acquisition protocol on the same scanner for all imaging timepoints. 
For participants with known/suspected brain metastasis, a brain MRI without and with contrast 
(preferred) or a head CT without and with contrast is required at screening to rule out active brain 
metastasis. Participants with a history of brain metastasis should have surveillance MRI/CT 
approximately every 12 weeks, or sooner if clinically indicated until disease progression per 
RECIST 1.1 criteria or treatment discontinuation, whichever occurs later.
Assessments will be performed at baseline and at the timepoints described in Section 2 per 
RECIST v1.1 criteria (see Appendix 5) until disease progression per RECIST v1.1 criteria (see 
Appendix 5) or treatment discontinuation, whichever occurs later.
Tumor assessments at other timepoints may be performed if clinically indicated. Assessments of 
PR and CR must be confirmed at least 4 weeks after initial response. Changes in tumor 
measurements and tumor responses will be assessed by the investigator using RECIST v1.1 
criteria.  Investigators will also report the number and size of new lesions that appear while on 
study. The timepoint of tumor assessments will be reported on the eCRF based on the 
investigator’s assessment using RECIST v1.1 criteria. (See Appendix 5 for specifics of 
RECIST v1.1 criteria to be utilized in this study.)
For participants who are treated beyond RECIST v1.1 defined progression, assessment will be
performed until discontinuation of study treatment (typically triggered when an additional 10% or 
greater increase in tumor burden volume from the time of initial progression [including all target 
lesions and new measurable lesions]). 
9.1.1
Imaging Assessment for the Study
Central assessments are not planned for this study.  However, copies of all scans will be stored at 
sites for possible future analysis. At the Sponsor’s discretion, scans may be collected for possible 
future analysis if determined to be necessary by BMS at any time. 
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE information should begin at initiation of study treatment until 
100 days after the last dose of study therapy, at the timepoints specified in the Schedule of 
Activities (Section 2). Non-serious AE information should also be collected from the start of a 
placebo lead-in period or other observational period intended to establish a baseline status for the 
participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study treatment, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants randomized/assigned to treatment and never treated with 
study treatment, SAEs should be collected for 30 days from the date of randomization.
Admission for administration of anticancer therapy in the absence of any other SAEs (applies to 
oncology protocols)
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
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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 Section Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest will be followed 
until resolution, until the condition stabilizes, until the event is otherwise explained, or until the 
participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3
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 within 
24 hours of awareness of the pregnancy.
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Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Appendix 3 for reporting details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), AND;
2) Total bilirubin > 2 times 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, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, 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.
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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 occurrences of overdose must be reported as SAEs (see Appendix 3).
In the event of an overdose the investigator/treating physician should:
1) Contact the Medical Monitor immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities
3) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities. Safety 
assessments include AEs, physical examinations, vital signs, performance status, assessment of 
signs and symptoms, laboratory tests, and pregnancy tests as outlined in the Schedule of Activities.
9.4.1
Physical Examinations
Refer to Schedule of Activities.
9.4.2
Vital signs
Refer to Schedule of Activities.
9.4.3
Clinical Safety Laboratory Assessments

Investigators must document their review of each laboratory safety report.

All clinical safety laboratory assessments will be performed locally per the Schedule of 
Activities and Table 9.4.3-1.
Table 9.4.3-1:
Laboratory Assessment Panels
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Creatinine
Blood Urea Nitrogen (BUN) or Serum Urea Level
Glucose
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
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Table 9.4.3-1:
Laboratory Assessment Panels
LDH
Corrected Calcium
TSH (reflex to free T3 and T4 if abnormal)
Lipase
Amylase
Creatinine clearance (CLcr) - (screening only)
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen, HIV-1 and -2 antibody (screening only)
Other Analyses
Pregnancy test (WOCBP only, as described in Section 2).
9.4.4
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.5
Pharmacokinetic
Samples for PK and immunogenicity assessments will be collected for all participants receiving 
nivolumab and ipilimumab as described in Table 9.5-1. All timepoints are relative to the start of 
study treatment administration. All on-treatment timepoints are intended to align with days on 
which study treatment is administered. If it is known that a dose is going to be delayed, then the 
predose sample should be collected just prior to the delayed dose. However, if a predose sample 
is collected but the dose is subsequently delayed, an additional predose sample should not be 
collected. Further details of sample collection, processing, and shipment will be provided in the 
laboratory procedures manual.
Blood samples should be drawn from a site other than the infusion site (ie, contralateral arm) on 
days of infusion. All samples collected pre-dose should be taken just prior to the administration 
from the contralateral arm (ie, the arm not used for the infusion). If the infusion was interrupted, 
the interruption details will also be documented on the CRF. Blood samples will be processed to 
collect serum and stored preferably at -70°C (samples may be stored at -20°C up to 2 months). 
Further details of pharmacokinetic sample collection and processing will be provided to the site in 
the lab manual.
Serum samples will be analyzed for drug (nivolumab and ipilimumab) and ADA (anti-nivolumab 
and anti- ipilimumab antibodies) by validated immunoassays. Samples with a positive ADA 
response may also be analyzed for neutralizing ADA response to nivolumab and/or ipilimumab. 
In addition, selected serum samples may be analyzed by an exploratory method that measures 
nivolumab and ipilimumab, or detect anti-drug antibodies for technology exploration purposes; 
exploratory results will not be reported. The corresponding serum samples designated for either 
PK, immunogenicity or biomarker assessments may also be used for any of those analyses, if 
required (eg, insufficient sample volume to complete testing or to follow up on suspected 
immunogenicity related AE).
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Table 9.5-1:
Pharmacokinetic and Immunogenicity Sample Collections (CA209800 Arms A and B)
Parta
Study Dayb
( 1 Cycle = 3 weeks for Part 1
1 Cycle = 4 Weeks for Part 2)
Time (Event)
Time (Relative to 
Start of Infusion) 
Hours:Min
Pharmacokinetic 
Blood Sample for 
Nivolumab
Immunogenicity 
Blood Sample for 
Nivolumab
Pharmacokinetic 
Blood Sample for 
Ipilimumab
Immunogenic 
Blood Sample for 
Ipilimumab
1
C1D1
(Predose)c
00:00
X
X
X
X
1
C1D1
(EOI-nivo)d
00:60
X
1
C1D1
(EOI-ipi)d
00:60 or 00:30
X
1
C2D1
(Predose)c
00:00
X
X
X
X
1
C2D1
(EOI-nivo)d
00:60
X
1
C2D1
(EOI-ipi)d
00:60 or 00:30
X
1
C4D1
(Predose)c
00:00
X
X
X
X
1
C4D1
(EOI-nivo)d
00:60
X
1
C4D1
(EOI-ipi)d
00:60 or 00:30
X
2
C5D1
(predose)
00:00
X
X
X
X
2
CXD1: Every 16 weeks starting with 
C5D1 (ie, C9D1, C13D1, etc.)
(Predose)
00:00
X
X
First 2 Follow-up Visits (Approximately 
30 days and up to ~ 100 Days from the 
Discontinuation of Study treatment)
NA
X
X
a Part 1 indicates first 12 weeks (or 4 cycles) of combination treatment (nivolumab + ipilimumab). Part 2 indicates nivolumab monotherapy period starting from 
Week 16 (or Cycle 5).
b If a participant discontinues study treatment treatment during the sampling period, they will move to sampling at the follow-up visits.
c Predose: All predose samples for nivolumab and ipilimumab should be taken prior to the start of nivolumab or FRC infusion.
d EOI-nivo and EOI-ipi PK samples: End of Infusion PK samples for nivolumab and ipilimumab, respectively. For sequential dosing, EOI samples for 
nivolumab and ipilimumab should be collected immediately (preferably within 2 - 5 minutes) prior to the end of the 60 minute nivolumab infusion and 
30 minutes ipilimumab infusion, respectively. For the FRC dosing, EOI samples for nivolumab and ipilimumab should be collected immediately 
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(preferably within 2 - 5 minutes) prior to the end of the 60 min FRC co-infusion. If the end of any infusion is delayed, the collection of the EOI samples 
should be delayed accordingly.
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9.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7
Pharmacogenomics
The final disposition of samples will be conducted per local regulations.
Details on processes for collection and shipment of these samples can be found in Section 9.8.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.9
Medical Resource Utilization and Health Economics
Evaluating quality of life (QoL) in oncology clinical studies is becoming increasingly important 
to understand the impact of benefit/risk from the participant perspective. Participant reported 
outcomes will be captured through the use of three validated self-reported questionnaires: the 
Functional Assessment of Cancer Therapy-General (FACT-G), the NCCN Functional Assessment 
of Cancer Therapy- Kidney Symptom Index (FKSI-19) and the EuroQoL Group’s EQ-5D 
(3L version).
The FACT-G is a 27-item questionnaire that measures general cancer health related quality of life. 
It is one of the most widely used HrQoL cancer specific scales and has been validated in numerous 
types of cancer participants, across cultures, and in many languages. The scale is a compilation of 
general questions divided into four primary HrQoL dimensions: Physical Well-Being, 
Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. Summary scores 
can be calculated for each domain in addition to a single overall summary score. 
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The NCCN FKSI-19 is a 19-item scale that measures tumor specific HrQoL in kidney cancer 
participants. The FKSI-19 uses five Likert-type response categories that range from “not at all” to 
“very much”. Participants are asked to circle the response category that best characterizes their 
response over the last 7 days on 19 items that include symptoms such as lack of energy, fatigue, 
appetite, coughing, shortness of breath, pain, nausea and ability to work. General health status will 
be measured using the EQ-5D.
The EQ-5D is a standardized instrument for use as a measure of self-reported general health status. 
The EQ-5D comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety) and a visualanalog rating scale (VAS). The utility data generated from the EQ-5D is 
recommended for and commonly used in cost effectiveness analysis.
Healthcare resource utilization data (eg, hospitalizations, non-protocol specified medical visits, 
etc.) will be collected for all randomized participants. Specifically, healthcare resource utilization 
is evaluated based on the number of medical care encounters such as hospital admissions and their 
duration, outparticipant visits, diagnostic tests and procedures, concomitant medications and 
reasons for the encounters. 
Medical resource utilization associated with medical encounters, will be collected in the CRF by 
the investigator and study-site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inparticipant and outparticipant)

Duration of hospitalization (total days length of stay, including duration by wards; eg, intensive 
care unit)

Number and character of diagnostic and therapeutic tests and procedures

Outparticipant medical encounters and treatments (including physician or emergency room 
visits, tests and procedures, and medications)].
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
Approximately 102 participants will be randomized to the 2 treatment arms in a 1:1 ratio in order 
to target 100 treated participants (50 per arm). This number of treated participants was chosen to 
achieve a sufficient level of precision for estimating the difference in rates of infusion-related 
reactions between the two treatment arms. Fifty treated participants per arm will allow estimation 
of the rate difference within 95% confidence limits of -20% or less and will be supplemented by 
a qualitative clinical assessment of the type and severity of events to evaluate benefit-risk. The 
20% limit represents what is considered to be a clinically meaningful difference in the rates of 
infusion-related reactions.
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In previously submitted Phase 2/3 studies of nivolumab in combination with ipilimumab 
(CA209069 and CA209067), AEs in the MedDRA Anaphylactic Reaction SMQ (broad scope) 
with onset within 2 days after sequential dosing of nivolumab 1 mg/kg combined with ipilimumab 
3 mg/kg were reported in 24% of treated participants. In the current study, if the observed rate of 
infusion reactions is equal to 24% among 50 treated participants in each arm, then the 95% CI for 
the difference in rates of infusion reactions between arms will be (-16.7%, 16.7%).
Table 10.1-1 shows the precision that the sample size of 50 treated participants per arm will 
provide for estimating infusion reaction rates and rate differences between the treatment arms 
under different assumed observed rates.
Table 10.1-1:
95% CI for Rates and Rate Differences when Observed in 
50 Participants per Arm
Observed AE Rate (95% CI)
Observed Rate Difference (95% CI)
Arm A (Co-administration, FRC)
Arm B (Sequential 
administration)
Arm A - Arm B
24% (13.1%, 38.2%)
22% (11.5%, 36.0%)
2% (-14.5%, 18.5%)
24% (13.1%, 38.2%)
24% (13.1%, 38.2%)
0% (-16.7%, 16.7%)
26% (14.6%, 40.3%)
24% (13.1%, 38.2%)
2% (-15.0%, 19.0%)
30% (17.9%, 44.6%)
28% (16.2%, 42.5%)
2% (-15.8%, 19.8%)
30% (17.9%, 44.6%)
30% (17.9%, 44.6%)
0% (-18.0%, 18.0%)
10.2
Populations for Analyses
The first (primary) analysis will be carried out for primary endpoint and safety related secondary 
endpoints when all participants who are still on-treatment complete Part 1 period. The final 
analysis will be carried out for efficacy related secondary endpoints when all participants have at 
least 9 months of follow-up.
Since the primary objective will be addressed by a safety endpoint, the primary endpoint analysis 
will be based on all treated participants. For consistency, the secondary endpoints will use the same 
analysis population as the primary endpoint (ie all treated participants).
Population
Description
All Enrolled Participants
All participants who signed an informed consent form and were 
registered into the IRT. 
All Randomized 
Participants 
All participants who were randomized to any treatment group. 
This is the primary dataset for efficacy listings.
All Treated Participants 
All participants who received at least one dose of any study 
medication. This is the primary dataset for analysis of study 
conduct, study population, efficacy (including secondary 
endpoints), exposure, and safety (including primary endpoint).
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Population
Description
Pharmacokinetic 
Participants
All treated participants with available serum time-concentration 
data.
Immunogenicity 
Participants
All treated participants with available ADA data.
Biomarker Participants
All treated participants with available biomarker data.
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint is related to safety and there are no primary efficacy 
endpoints.
Secondary
One of the secondary endpoint is ORR as determined by investigators. The
ORR is defined as the number of participants with a BOR of CR or PR
divided by the number of treated participants. The BOR is defined as the best 
response designation, as determined by the investigator, recorded between the 
date of randomization and the date of objectively documented progression per 
RECIST 1.1 or the date of subsequent anti-cancer therapy including 
radiotherapy, tumor-directed surgery, or systemic anticancer therapy, 
whichever occurs first. For participants without documented progression or
first subsequent therapy, all available response designations will contribute to 
the BOR assessment. Tumor assessments are scheduled to be performed at 
Week 12 following randomization, every 8 weeks for the first 12 months and 
then every 12 weeks until disease progression.
Another secondary endpoint is PFS. PFS is defined as the time between the 
date of randomization and the first date of documented progression, as 
determined by the investigator, or death due to any cause, whichever occurs 
first. Participants who die without a reported progression will be considered 
to have progressed on the date of their death. Participants who did not 
progress or die will be censored on the date of their last evaluable tumor 
assessment. Participants who did not have any on study tumor assessments 
and did not die will be censored on their date of randomization. Participants 
who started anti-cancer therapy without a prior reported progression will be 
censored on the date of their last evaluable tumor assessment prior to the 
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Endpoint
Statistical Analysis Methods
initiation of first subsequent anti-cancer therapy including radiotherapy, 
tumor-directed surgery, or systemic anticancer therapy.
Efficacy related secondary endpoints will be analyzed at the time of final 
analysis when all participants have at least 9 months of follow-up. Descriptive 
analyses of secondary efficacy endpoints will be performed.
ORRs and corresponding 95% exact CIs will be calculated using the Clopper 
Pearson method for each of the treatment arms. BOR will be tabulated for 
each treatment group. Associated odds ratios and 95% CIs for Arm A relative 
to Arm B will be calculated using Cochran-Mantel-Haenszel (CMH) 
methodology, adjusting for the stratification factors IMDC scores at 
screening. An estimate of the difference in ORRs and corresponding 2-sided 
95% CI will be calculated using CMH methodology, adjusting for the same 
stratification factors as above.
PFS curves for each treatment group will be estimated using the Kaplan-
Meier (KM) product limit method. Median PFS and corresponding two-sided, 
95% confidence intervals will be computed. Descriptive HRs and 
corresponding two sided 95% CIs for Arm A relative to Arm B will be 
estimated using a Cox proportional hazards model, with treatment group as a 
single covariate, stratified by IMDC scores at screening. PFS rates at 6 
months with 95% CIs will be estimated using KM methodology.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.3.2
Safety Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint of the study is the incidence of AEs in the Broad Scope 
MedDRA Anaphylactic Reaction SMQ occurring within 2 days after dosing 
during the combination, Part 1 period. This incidence rate is defined as the 
number of participants who experienced at least 1 AE in the MedDRA 
Anaphylactic Reaction broad scope SMQ with onset on the day of or within 
2 days after any study therapy infusion during the combination period (Part 1) 
divided by number of treated participants. The analysis of the primary 
endpoint will occur at the time of first (primary) analysis when all participants 
who are still on-treatment have had at least complete Part 1 period.
For the primary analysis, the incidence of AEs in the Broad Scope MedDRA 
Anaphylactic Reaction SMQ occurring within 2 days after any dose in Part 1 
dosing by treatment arm, the difference in rates between arms, and the 
corresponding 95% confidence intervals will be reported descriptively. The 
confidence intervals for the rate estimates will be based on the Clopper and 
Pearson method. The estimate and confidence interval for the rate difference 
will be based on CMH method of weighting, adjusting for IMDC scores at 
screening. Descriptive statistics will be presented using NCI CTCAE v 4.0 by 
treatment group. Events will be tabulated using worst grade per NCI CTCAE 
v 4.0 criteria by preferred term.
Secondary
The first secondary endpoint is the incidence of AEs in the MedDRA 
Anaphylactic Reaction narrow scope SMQ occurring within 2 days after any 
study therapy infusion during the combination period (Part 1). This incidence 
rate will be defined similarly to the primary endpoint except that the event 
rate will be based on terms within the narrow scope SMQ rather than the 
broad scope.
The second secondary endpoint is the drug-related Grade 3 - 5 AE incidence 
rate defined using NCI CTCAE v 4.0 criteria. The drug-related Grade 3 - 5 
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Endpoint
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AE rate is defined as number of participants who experienced at least 1 AE of 
Grade 3 or higher, judged to be related to study treatment by the investigator, 
and with onset on or after the first dose of study treatment and within 30 days 
of the last dose of study treatment, divided by number of treated participants.
The third secondary endpoint is the all causality Grade 3 - 5 AE incidence 
rate defined using NCI CTCAE v 4.0 criteria. The all causality Grade 3 - 5 
AE rate is defined as number of participants who experienced at least 1 AE of 
Grade 3 or higher with onset on or after the first dose of study treatment and 
within 30 days of the last dose of study treatment, divided by number of 
treated participants.
Safety related secondary endpoints will be analyzed at the time of the first 
(primary) analysis when all participants who are still on-treatment complete 
Part 1 period. The first secondary endpoint will be summarized using the 
same methods as described above for the primary endpoint analysis. The 
second secondary endpoint, on-treatment drug-related Grade 3 - 5 AEs 
occurring within 30 days after the last dose of study treatment, will be 
tabulated using worst grade per NCI CTCAE v 4.0 criteria by system organ 
class and preferred term by treatment arm.  The third secondary endpoint, all 
causality Grade 3 - 5 AEs, will be summarized using similar methods as 
described for drug-related Grade 3 - 5 AEs. 
 
 
 
 
 
 
 
 
 
 
 
For reference, the terms currently included in the MedDRA Anaphylactic Reaction SMQ based on 
MedDRA version 19.0 are listed in Table 10.3.2-1.
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Table 10.3.2-1:
Preferred Terms Included in the MedDRA Anaphylactic Reaction 
SMQ - Broad and Narrow Scopes
Preferred Term
Term Scope
Acute respiratory failure
Broad
Allergic oedema
Broad
Anaphylactic reaction
Narrow
Anaphylactic shock
Narrow
Anaphylactic transfusion reaction
Narrow
Anaphylactoid reaction
Narrow
Anaphylactoid shock
Narrow
Angioedema
Broad
Asthma
Broad
Blood pressure decreased
Broad
Blood pressure diastolic decreased
Broad
Blood pressure systolic decreased
Broad
Bronchial oedema
Broad
Bronchospasm
Broad
Cardiac arrest
Broad
Cardio-respiratory arrest
Broad
Cardio-respiratory distress
Broad
Cardiovascular insufficiency
Broad
Chest discomfort
Broad
Choking
Broad
Choking sensation
Broad
Circulatory collapse
Narrow
Circumoral oedema
Broad
Cough
Broad
Cyanosis
Broad
Dialysis membrane reaction
Narrow
Diastolic hypotension
Broad
Dyspnoea
Broad
Erythema
Broad
Eye oedema
Broad
Eye pruritus
Broad
Eye swelling
Broad
Eyelid oedema
Broad
Face oedema
Broad
Flushing
Broad
Generalised erythema
Broad
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Table 10.3.2-1:
Preferred Terms Included in the MedDRA Anaphylactic Reaction 
SMQ - Broad and Narrow Scopes
Preferred Term
Term Scope
Hyperventilation
Broad
Hypotension
Broad
Injection site urticaria
Broad
Irregular breathing
Broad
Kounis syndrome
Narrow
Laryngeal dyspnoea
Broad
Laryngeal oedema
Broad
Laryngospasm
Broad
Laryngotracheal oedema
Broad
Lip oedema
Broad
Lip swelling
Broad
Mouth swelling
Broad
Nasal obstruction
Broad
Nodular rash
Broad
Ocular hyperaemia
Broad
Oedema
Broad
Oedema mouth
Broad
Oropharyngeal spasm
Broad
Oropharyngeal swelling
Broad
Periorbital oedema
Broad
Pruritus
Broad
Pruritus allergic
Broad
Pruritus generalised
Broad
Rash
Broad
Rash erythematous
Broad
Rash generalised
Broad
Rash pruritic
Broad
Respiratory arrest
Broad
Respiratory distress
Broad
Respiratory failure
Broad
Reversible airways obstruction
Broad
Sensation of foreign body
Broad
Shock
Narrow
Shock symptom
Narrow
Skin swelling
Broad
Sneezing
Broad
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Table 10.3.2-1:
Preferred Terms Included in the MedDRA Anaphylactic Reaction 
SMQ - Broad and Narrow Scopes
Preferred Term
Term Scope
Stridor
Broad
Swelling
Broad
Swelling face
Broad
Swollen tongue
Broad
Tachypnoea
Broad
Throat tightness
Broad
Tongue oedema
Broad
Tracheal obstruction
Broad
Tracheal oedema
Broad
Type I hypersensitivity
Narrow
Upper airway obstruction
Broad
Urticaria
Broad
Urticaria papular
Broad
Wheezing
Broad
10.3.2.1
Pharmacokinetic Analyses as a Secondary Endpoint
One of the secondary endpoint is to get PK comparisons of nivolumab and ipilimumab 
administered as FRC to that of sequentially administered nivolumab and ipilimumab. PK will be 
measured using serum concentration-time data.
PK comparisons will be summarized using descriptive summary statistics to compare nivolumab 
and ipilimumab predose and EOI concentrations administered as FRC to that of sequentially 
administered nivolumab and ipilimumab.
10.3.2.2
Other Pharmacokinetic Analyses
The nivolumab and ipilimumab concentration vs 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, if needed, to compare model based PK parameters and exposure following administration 
of the FRC and sequential administration. This model will be used to determine measures of 
individual exposure (such as steady state peak, trough and time-averaged concentration). If 
conducted, the results of the population PK analyses will be reported separately.
 
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10.3.2.4
Outcomes Research Analyses
Descriptive summary statistics of Quality of life (QoL) assessments will be presented at baseline 
and each on-study time point, unless otherwise specified. Mean changes from baseline for each of 
the three scales will be calculated for each subject at each on-study time point. In addition, subject 
compliance will be described per time point by the proportion of subjects who filled out the QoL 
assessments over the numbers of subject known to be alive and eligible for assessment at these 
time points.
10.3.2.5
Other Analyses
Methodology for other analyses including pharmacogenomics, immunogenicity, and healthcare 
resource utilization is described in the statistical analysis plan finalized before database lock.
10.3.2.6
Interim Analyses
Not applicable.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ACLS
advanced cardiac life support
AI
accumulation index
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
-HCG
beta-human chorionic gonadotrophin
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
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Term
Definition
CLcr
creatinine clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
minimum observed concentration
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
DMC
Data monitoring committee
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
ESR
Expedited Safety Report
F
bioavailability
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
FRC
Fixed Ratio Combination
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
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Term
Definition
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
L
liter
LAM
Lactation amenorrhea method
LC
liquid chromatography
LDH
lactate dehydrogenase
ln
natural logarithm
mg
milligram
Mg++
magnesium
min
minute
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Term
Definition
mL
milliliter
mmHg
millimeters of mercury
MR
medical research
MS
mass spectrometry
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
UV
ultraviolet
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Term
Definition
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
x g
times gravity
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APPENDIX 2
STUDY GOVERANCE 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 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 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 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 or 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 (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., 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 change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:

IRB/IEC for 

Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
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. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., 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:
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
Provide a copy of the consent form and written information about the study in the language 
in which the participant is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 

Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.

Obtain an informed consent signed and personally dated by the participant or the 
participant's legally acceptable representative and by the person who conducted the 
informed consent discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
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electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
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If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage 
area

amount currently in storage area

label identification number or batch 
number

amount dispensed to and returned by each 
participant, including unique participant
identifiers

amount transferred to another area/site for 
dispensing or storage

nonstudy disposition (e.g., lost, 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 vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing 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.
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CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be used. 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, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
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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 (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (e.g., 
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.
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It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. 
The method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste 
disposal vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
For this study, study treatments (those supplied by BMS or its vendors) such as full or partially 
used study treatment containers, vials, syringes cannot be destroyed on-site.
It is however, the investigator’s or designee’s responsibility to arrange for disposal of all empty 
study treatment containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local, and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. The return of full or partially used study 
treatments supplied by BMS or its vendors will be arranged by the responsible Study Monitor.
CLINICAL STUDY REPORT 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:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Participant recruitment (e.g., among the top quartile of enrollers)

Involvement in trial design
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
Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
For this single site protocol, the Principal Investigator for the site will sign the clinical study report.
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 drug 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 drug, whether or not 
considered related to the study drug.
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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: 
o
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)
o
elective surgery, planned prior to signing consent
o
admissions as per protocol for a planned medical/surgical procedure
o
routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)
o
medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases
o
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)
o
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 8.1.1 for the definition of potential DILI.) 
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Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5
for reporting pregnancies).
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 causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug 
administration and the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
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 drug 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 drug, and pregnancies must be 
reported to BMS (or designee) within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
Surveillance Form (electronic or paper forms).

The preferred method for SAE data reporting collection is through the eCRF.

The paper SAE/pregnancy surveillance forms are only intended as a back-up option 
when the eCRF system is not functioning.
o
In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission 
is the required method for reporting. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms are 
used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment. 
Local laws and regulations may require use of alternative and/or additional contraception methods.
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Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c

Intrauterine device (IUD)c

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
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NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 

Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
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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 1.1 GUIDELINES
1
EVALUATION OF LESIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3. 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).
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. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image 
is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, saggital or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis 10 mm but < 15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
1.2
Non-Measurable
All other lesions are considered non-measurable, 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 is not measurable by reproducible imaging techniques.
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2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
3
RESPONSE CRITERIA
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.
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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 (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
3.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived from 
the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error. To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if it 
is below 5 mm.
3.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
3.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
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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 and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression (see comments below) 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 Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (see examples in Appendix 2 and further details below). A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
3.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
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 patient should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore the increase must be substantial.
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3.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.
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. While FDG-
PET response assessments need additional study, it is sometimes reasonable to incorporate the use 
of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
3.3
Response Assessment
3.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
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3.3.2
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 3.3.2-
1 provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. When patients have non-measurable (therefore non-target) 
disease only, Table 3.3.2-2 is to be used. 
Table 3.3.2-1:
Time Point Response: Patients With Target (+/- Non-Target) 
Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 3.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
3.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
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4 weeks later. In this circumstance, the best overall response can be interpreted as in Table 3.3.3-
1.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 3.3.3-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD durationb met, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration bmet, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
b Minimum criteria for SD duration is 6 weeks.
3.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
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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: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
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APPENDIX 6
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 7
PERFORMANCE STATUS SCALES
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
Normal activity with effort
80
1
Symptoms, but fully 
ambulatory
Cares for self. Unable to carry on normal 
activity or to do active work
70
1
Requires occasional assistance, but able to 
care for most of his needs
60
2
Symptomatic, but in 
bed < 50% of the day
Requires considerable assistance and 
frequent medical care
50
2
Disabled. Requires special care and 
assistance
40
3
Needs to be in bed 
> 50% of the day, but 
not bedridden
Severely disabled. Hospitalization 
indicated though death non imminent
30
3
Very sick. Hospitalization necessary. 
Active supportive treatment necessary
20
4
Unable to get out of 
bed
Moribund
10
4
Dead
0
5
Dead
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APPENDIX 8
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
Revised Protocol No.: 02
Date: 02-Aug-2017
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3.0
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3.0
v

Clinical Protocol
CA209800
BMS-936558
nivolumab
Revised Protocol No.: 02
Date: 02-Aug-2017
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3.0
Approved
930107718
3.0
v

Clinical Protocol
CA209800
BMS-936558
nivolumab
Revised Protocol No.: 02
Date: 02-Aug-2017
122
3.0
Approved
930107718
3.0
v

Clinical Protocol
CA209800
BMS-936558
nivolumab
Revised Protocol No.: 02
Date: 02-Aug-2017
123
3.0
Approved
930107718
3.0
v

Clinical Protocol
CA209800
BMS-936558
nivolumab
Revised Protocol No.: 02
Date: 02-Aug-2017
124
3.0
Approved
930107718
3.0
v

Clinical Protocol
CA209800
BMS-936558
nivolumab
Revised Protocol No.: 02
Date: 02-Aug-2017
125
3.0
Approved
930107718
3.0
v

Clinical Protocol
CA209800
BMS-936558
nivolumab
Revised Protocol No.: 02
Date: 02-Aug-2017
126
3.0
Approved
930107718
3.0
v

Clinical Protocol
CA209800
BMS-936558
nivolumab
Revised Protocol No.: 02
Date: 02-Aug-2017
127
3.0
Approved
930107718
3.0
v

Clinical Protocol
CA209800
BMS-936558
nivolumab
Myotoxicity (Myositis, Myocarditis, Rhabdomyolysis) 
Adverse Event Management Algorithm 
Rule out non-inflammatory causes.  If non-inflammatory, cause, treat accordingly and continue I-O therapy.
Grade of Myotoxicity*
            Management
             Follow UP
Grade 1:
Asymptomatic with laboratory or 
cardiac imaging abnormalities 
(myocarditis)
Mild pain (myositis)
•
Consider delay of I-O therapy
•
Monitor CPK and troponin and emergence of new 
symptoms; EKG
•
Cardiology consultation for abnormal cardiac 
labs/imaging
•
Consider steroids (up to 2 mg/kg/day 
methylprednisolone IV or oral equivalent)
•
Symptomatic therapy (myositis)
•
Close monitoring for new or 
worsening symptoms
•
If worsens: Treat as Grade 2 
or 3/4
Grade 2:
Symptoms with mild to moderate 
activity or exertion (myocarditis)
Moderate pain associated with 
weakness; pain limiting 
instrumental activities of daily 
living (myositis)
•
Delay I-O therapy; consider hospitalization
•
Rule out alternative causes (myocardial ischemia, 
viral infection, nutritional deficiency, thyroid, etc)
•
Prompt cardiology consultation for any cardiac 
signs and/or symptoms, evaluation may include:
•
EKG  ± continuous cardiac monitoring
•
Echocardiogram
•
Troponin and CPK monitoring
•
In absence of cardiac signs and/or symptoms:
•
Monitor CPK and renal function
•
Consider EKG and troponin monitoring
•
Up to 2 mg/kg/day methylprednisolone IV or oral 
equivalent
•
Consider prophylactic antibiotics for opportunistic 
infections
•
If improves to grade 1 or 
baseline, taper steroids after 
cardiac symptoms resolve 
over at least 1 month
•
Retreatment may be 
considered after resolution to 
baseline and completion of 
steroid taper
•
If no improvement observed, 
treat as Grade 3-4 
Revised Protocol No.: 02
Date: 02-Aug-2017
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Clinical Protocol
CA209800
BMS-936558
nivolumab
Grade 3:
Severe with symptoms at rest or 
with minimal activity or exertion 
(myocarditis)
Pain associated with severe 
weakness; limiting self care 
activities of daily living (myositis)
Grade 4:
Life Threatening; urgent 
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic support)
•
Permanently discontinue I-O therapy; hospitalize 
•
Rule out alternative causes (myocardial ischemia, 
viral infection, nutritional deficiency, thyroid, etc)
•
Urgent cardiology consultation for any cardiac 
signs and/or symptoms, evaluation may include:
•
EKG  ± continuous cardiac monitoring
•
Echocardiogram
•
Troponin and CPK monitoring
•
Consider Cardiac MRI and myocardial 
biopsy
•
In absence of cardiac signs and/or symptoms:
•
Monitor CPK and renal function
•
Consider EKG and troponin monitoring
•
2-4 mg/kg/day methylprednisolone IV or 1 g IV 
bolus 
•
Add prophylactic antibiotics for opportunistic 
infections
•
If improves to grade 1 or 
baseline, taper steroids over 
at least 6 weeks
•
If no improvement, consider 
additional 
immunosuppressants
*Patients with clinical signs or symptoms of rhabdomyolysis should be evaluated for myositis/myocarditis per the recommendations in this algorithm.
Revised Protocol No.: 02
Date: 02-Aug-2017
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3.0
v