A Phase 3, Open-label, Randomized Study of Nivolumab Combined With Ipilimumab, or With Standard of Care Chemotherapy, Versus Standard of Care Chemotherapy in Participants With Previously Untreated Unresectable or Metastatic Urothelial Cancer
Phase: PHASE3
Conditions: Urothelial Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 3, Open-label, Randomized Study of Nivolumab Combined with Ipilimumab, or with 
Standard of Care Chemotherapy, versus Standard of Care Chemotherapy in Participants with 
Previously Untreated Unresectable or Metastatic Urothelial Cancer 
 
NCT Number: NCT03036098 
Document Date (Date in which document was last revised): 27 Apr 2023 
 
 
 

Page:
1
Protocol Number:
CA209901
IND Number:
122,840
EUDRACT Number
2016-003881-14
Date
14-Nov-2016
Revised Date
27-Apr-2023
CLINICAL PROTOCOL CA209901
A Phase 3, Open-label, Randomized Study of Nivolumab Combined with Ipilimumab, or with 
Standard of Care Chemotherapy, versus Standard of Care Chemotherapy in Participants with 
Previously Untreated Unresectable or Metastatic Urothelial Cancer
(CheckMate 901: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 901)
Protocol Amendment Number: 05
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 
to partners to which BMS has transferred obligations, e.g., a Contract Research 
Organization (CRO).
© 2023 Bristol-Myers Squibb Company
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
Protocol Amendment No.: 05
Date: 27-Apr-2023
2
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 
05
27-Apr-2023
This amendment updates the substudy final analysis strategy for progression 
free survival (PFS) to coincide with the overall survival (OS) final analysis, 
regardless of the number of PFS events reached at this time.
This change is being made due to the actual substudy PFS event rate being 
lower than initially anticipated with a projected delay of approximately 
3 years. Therefore, it is not possible for the originally planned number of PFS 
events to be reached simultaneously with the planned number of OS events as 
currently specified for the final analysis in the protocol. Thus, this amendment 
will allow for the final analysis for OS and PFS to occur after only the 
required number of OS (at least 356) events have been reached in the 
substudy.
There is no update of OS endpoint or corresponding analysis.
Administrative 
Letter 16
11-Jul-2022
The purpose of this letter is to notify regarding change/addition in study 
personnel.
Administrative 
Letter 15
07-Dec-2021
The purpose of this letter is to notify regarding change/addition in study 
personnel.
Administrative 
Letter 14
11-Nov-2021
The purpose of this letter is to notify regarding change/addition in study 
personnel.
Administrative 
Letter 13
29-Oct-2021
The purpose of this letter is to notify regarding change/addition in study 
personnel.
Administrative 
Letter 12
15-Jan-2021
The purpose of this letter is to notify regarding change/addition in study 
personnel.
Revised 
Protocol 04
20-Mar-2020
This revision, solely limited to substudy, elevates overall survival (OS) as a 
primary endpoint with progression free survival (PFS), OS interim analysis 
has been added, and PFS interim analysis has been removed. To ensure 
sufficient power for the primary endpoints, 300 cisplatin-eligible participants 
have been added to the substudy.
Administrative 
Letter 11
20-May-2019
The purpose is to clarify that an error was discovered in Rev Prot 03 (dated 09 
APR 2019) such that Table 9.8.1, Biomarker Sampling Schedule (All 
Participants) is incorrect because the KEY superscript “c” was incorrectly 
applied in the table to the “Whole blood (gene expression)” column instead of 
the intended “PBMC” column. Key “c” notes “Not collected in China, 
Argentina, Brazil, Chile, Peru, or Australia for Whole Blood (Gene 
Expression)”. As indicated in the Lab Manual, there should be no restrictions 
to Whole blood (gene expression) collection, and therefore no Key for the 
“Whole Blood for gene expression” column
Revised 
Protocol 03
09-Apr-2019
This revision removes PFS as a co-primary objective and endpoint and adds 
OS in PD-L1 positive (≥1%) as a primary population, adds 100 cisplatin-
ineligible participants to the primary study, and revises the timing of the OS 
interim analysis for the primary study. The timing of the interim analysis for 
the substudy is revised as well.
Administrative 
Letter 09
06-Aug-2018
The purpose is to update nivolumab dosing information in revised protocol 02 
to be consistent with Investigator Brochure v17; to align Section 7.1.3.1 with 
Tables 2.4 and 2.5 with respect to allowing additional cycles of gemcitabine if 
local practice and to address a typographical error.
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CA209901
BMS-936558
Nivolumab
Protocol Amendment No.: 05
Date: 27-Apr-2023
3
Document
Date of Issue
Summary of Change
Administrative 
Letter 03
14-Sep-2017
This letter serves to update Study Director information, clarify statements in 
the protocol to ensure alignment across the protocol sections and correct 
typographical errors within the current CA209901 Revised Protocol 02.
Administrative 
Letter 01
10-Jul-2017
A typographical error was discovered in an exploratory endpoint for PD-L1 
expression in the substudy in Revised Protocol 02 for Study CA209901. The 
investigational treatment to be assessed in this substudy is “nivolumab 
combined with SOC chemotherapy”, not “nivolumab combined with 
ipilimumab.”
Revised 
Protocol 02
21-Apr-2017
Incorporates Amendment 03
Amendment 
03
21-Apr-2017
1.
Added substudy, Arms C and D. 
2.
Updated tumor tissue requirement 
3.
Updated treatment duration to 24 months
4.
Section added regarding BICR assessments
5.
Appendix 3, RECIST criteria updated.
Amendment 
02
21-Apr-2017
Country specific amendment
Revised 
Protocol 01
19-Dec-2016
Incorporated Amendment 01
Amendment 
01
19-Dec-2016
1.
Added procedures to be collected on Day 8 (prior to gemcitabine dosing)
2.
Added details regarding requests for optional archive tissue sample 
(radical cystectomy)
3.
Revised renal function criteria for cisplatin-eligible participants. 
4.
Added Appendix 9 for country specific requirements for Germany
5.
Additional clarifications for consistency throughout.
Original 
Protocol
14-Nov-2016
Not Applicable
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 05:
This amendment updates the substudy final analysis strategy to be overall survival (OS) events-
driven, with the progression free survival (PFS) final analysis being conducted at the same time as 
the OS final analysis based on the available PFS events at that time (time-driven).
This change is being made due to the actual substudy PFS event rate being lower than initially 
anticipated with a projected delay of approximately 3 years. This is mainly due to the high 
percentage of subjects censored for PFS. The reason for censoring was mainly due to subsequent 
anti-cancer therapy prior to progression. This high percentage of censoring is related to the
treatment landscape change for this patient population during the conduct of this study with the 
introduction of avelumab maintenance therapy after initial platinum-based chemotherapy.
Therefore, it is not possible for the originally planned number of PFS events to be reached 
simultaneously with the planned number of at least 356 OS events as currently specified for the 
final analysis in the protocol. Thus, this amendment will allow for the final analysis for OS and 
PFS to occur after only the required number of OS events have been reached in the substudy.
This amendment incorporates the changes from the approved Administrative Letter 16, which are 
detailed in the Document History, but not listed in the Summary of Key Changes below.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.1.3.1: 
Progression Free 
Survival
Updated description of progression free 
survival (PFS) statistical analysis and
added PFS power table corresponding 
to the expected number of PFS events 
at the time of final OS analysis.
To align with the updated substudy final 
analysis testing strategy. Only general 
power estimates are kept in the updated 
sentences.
Section 10.1.3.2: Overall 
Survival
Updated numbers of cure fraction for 
Arm C and Arm D from 0.20 to 0.234 
and 0.234 to 0.20, respectively. 
To update a mismatch of the cure rates in 
the protocol.
Section 10.1.4: Analysis 
Timing Projections
Table 10.1.4-1: 
Populations and 
Projected Timing for 
Analysis of Primary 
Endpoints: Primary 
Study and Secondary 
Study
Added description of substudy OS and 
PFS final analysis.
In Table 10.1.4-1:
•
For the Substudy OS and PFS 
(Final Analysis) endpoint, 
changed the criterion from “At 
least 460 PFS and 356 OS 
events” to “At least 356 OS 
events.”
To align with the updated substudy final 
analysis testing strategy.
In Table 10.1.4-1:
•
To align with the updated 
substudy final analysis testing 
strategy.
Appendix 8
Updated text for investigator oversight 
in subsection: Institutional Review 
Board/Independent Ethics Committee.
For clarification.
Added additional requirements in 
Informed Consent Process subsection.
Clarified the investigator’s obligations in 
the informed consent process.
Protocol Amendment No.: 05
Date: 27-Apr-2023
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & 
Title
Description of Change
Brief Rationale
Added new sections: BMS 
Commitment to Diversity in Clinical 
Trials and Data Protection, Data 
Privacy, and Data Security.
Added to align with BMS commitment to 
diversity in clinical trials and to comply 
with European Union Clinical Trials 
Regulation (EU-CTR) requirement.
Updated text for Source Documents.
Clarified definition of source data.
Updated first paragraph to Case Report 
Forms subsection.
Updated description of terms “participant” 
and “subject.”
Updated description of monitoring plan 
in Monitoring subsection.
The COVID-19 pandemic resulted in the 
need to revise site monitoring language to 
specifically allow for remote monitoring.
Defined duration of records storage 
within Records Retention subsection.
Clarified duration of records storage.
Added instructions for partially used 
study interventions/empty containers 
within Return of Study Treatment 
subsection.
Clarified instructions for study intervention 
reconciliation and disposal. 
Added new sections for Study and Site 
Closure and Dissemination of Clinical 
Study Data.
To define study and site closure and 
describe BMS policy for dissemination of 
study data.
All
Minor formatting and typographical 
corrections.
Minor, therefore not been summarized.
Protocol Amendment No.: 05
Date: 27-Apr-2023
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 05: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 Research Hypothesis ................................................................................ 
 
3.1.1.1 Research Hypothesis for Primary Study ......................................... 
 
3.1.1.2 Research Hypothesis for Substudy .................................................. 
 
3.1.2 Rationale for Immunotherapy in UC ....................................................... 
 
3.1.3 Rationale for Cisplatin-ineligible Subpopulation being a Primary 
Analysis Population .................................................................................... 
 
3.1.4 Rationale for PD-L1 Positive Subpopulation being a Primary Analysis 
Population ................................................................................................... 
 
3.1.5 Rationale for Arm B and Arm D: Gemcitabine-Cisplatin/Gemcitabine-
Carboplatin Combination Chemotherapy................................................... 
 
3.1.6 Rationale For Exclusion Of ECOG Performance Status ≥2 ................... 
 
3.1.7 Rationale For Shorter Infusion Times Of Nivolumab And Ipilimumab 
Dosing In Part 1.......................................................................................... 
 
3.1.8 Rationale For Shorter Infusion Times With Nivolumab 480 Mg Flat Dose 
In Part 2 ...................................................................................................... 
 
3.1.9 Rationale for 360 mg Flat Dose Nivolumab plus Gemcitabine-Cisplatin 
Chemotherapy (Substudy, Arm C) .............................................................. 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Bladder Cancer ........................................................................................ 
 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
 
3.2.3 Ipilimumab Mechanism of Action ............................................................ 
 
3.2.4 Nivolumab plus Ipilimumab Evidence ..................................................... 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
3.3.1 Benefit/Risk Assessment for Primary Study ............................................. 
 
3.3.2 Benefit/Risk Assessment for Substudy ...................................................... 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
 
5.1.1.1 Blinded Independent Central Review Committee ........................... 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.4.1 Rationale for Duration of Treatment with Nivolumab and Ipilimumab .. 
 
5.5 Justification for Dose ........................................................................................ 
 
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Clinical Protocol
BMS-936558
CA209901
Nivolumab
Protocol Amendment No.: 05
Date: 27-Apr-2023
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5.5.1 Rationale for Nivolumab and Ipilimumab Dose and Schedule ................ 
 
5.5.2 Rationale for Flat Dose 480 mg Nivolumab every 4 weeks in Part 2 of 
Arms A and C (Nivolumab Monotherapy) .................................................. 
 
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 ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Nivolumab and Ipilimumab ...................................................................... 
 
7.1.1.1 Arm A: Part 1 Study Drug Administration - Nivolumab and 
Ipilimumab Combination Therapy (Cycles 1-4) ................................... 
 
7.1.1.2 Arm A and C: Part 2 Study Drug Administration - Nivolumab 
Monotherapy ......................................................................................... 
 
7.1.2 Study Drug Preparation and Infusion...................................................... 
 
7.1.3 Arm B: Platinum Doublet Chemotherapy ................................................ 
 
7.1.3.1 Gemcitabine/Cisplatin .................................................................... 
 
7.1.3.2 Gemcitabine/Carboplatin ............................................................... 
 
7.1.4 Arm C: Nivolumab plus Platinum-Doublet Chemotherapy ..................... 
 
7.1.5 Arm D: Platinum-Doublet Chemotherapy (Cisplatin-Eligible) ............... 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Dose reductions ....................................................................................... 
 
7.4.1.1 Nivolumab or Ipilimumab Dose Modification ................................ 
 
7.4.1.2 Platinum Doublet Chemotherapy Dose Reductions ....................... 
 
7.4.1.3 Platinum Doublet Chemotherapy - Dose Reductions for 
Hematologic Toxicity ............................................................................ 
 
7.4.1.4 Platinum Doublet Chemotherapy - Dose Reductions for Non-
Hematologic Toxicities ......................................................................... 
 
7.4.2 Dose Delay Criteria ................................................................................. 
 
7.4.2.1 Nivolumab or Ipilimumab Dose Delay Criteria ............................. 
 
7.4.2.2 Platinum Doublet Chemotherapy Dose Delay ................................ 
 
7.4.2.3 Dose Delay Criteria for Nivolumab plus Platinum-Doublet 
Chemotherapy ....................................................................................... 
 
7.4.3 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ...... 
 
7.4.4 Management Algorithms for Immuno-Oncology Agents ......................... 
 
7.4.5 Treatment Beyond Progression ................................................................ 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
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Clinical Protocol
BMS-936558
CA209901
Nivolumab
Protocol Amendment No.: 05
Date: 27-Apr-2023
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7.7.3 Permitted Therapy ................................................................................... 
 
7.7.3.1 Imaging Restriction and Precautions ............................................. 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Dose Discontinuation............................................................................... 
 
8.1.1.1 Discontinuation of Nivolumab or Ipilimumab ................................ 
 
8.1.1.2 Platinum Doublet Chemotherapy Dose Discontinuation ............... 
 
8.1.2 Criteria to Resume Treatment .................................................................. 
 
8.1.2.1 Criteria to Resume Nivolumab or Ipilimumab ................................ 
 
8.1.2.2 Criteria to Resume Treatment with Platinum Doublet 
Chemotherapy ....................................................................................... 
 
8.1.3 Post Study Treatment Follow-up ............................................................. 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Overall Survival ....................................................................................... 
 
9.1.2 Progression-Free Survival ....................................................................... 
 
9.1.3 Objective Response Rate .......................................................................... 
 
9.1.4 Imaging Assessment for the Study............................................................ 
 
9.1.4.1 BICR Assessment Of Progression ................................................... 
 
9.1.5 Patient Report Outcomes ......................................................................... 
 
9.2 Adverse Events ................................................................................................. 
 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Electrocardiograms ................................................................................. 
 
9.4.2 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.3 Imaging Safety Assessment ...................................................................... 
 
9.5 Pharmacokinetic ................................................................................................ 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Additional Research Collection ............................................................... 
 
9.8.2 Immunogenicity Assessments ................................................................... 
 
9.8.3 Tumor Tissue Specimens .......................................................................... 
 
9.8.4 Peripheral Blood Markers ....................................................................... 
 
9.8.5 Single Nucleotide Polymorphisms (SNPs) ............................................... 
 
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Clinical Protocol
BMS-936558
CA209901
Nivolumab
Protocol Amendment No.: 05
Date: 27-Apr-2023
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9.8.6 Serum-Soluble Factors ............................................................................ 
 
9.8.7 Peripheral Blood Mononuclear Cells (PBMCs) ...................................... 
 
9.8.8 Plasma...................................................................................................... 
 
9.8.9 Whole Blood Gene Expression................................................................. 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.1.1 Sample Size Justification for the Primary Overall Survival Endpoints in 
the Primary Study ....................................................................................... 
 
10.1.1.1 Overall Survival in Cisplatin-ineligible Participants ................... 
 
10.1.1.2 Overall Survival in PD-L1 Positive (≥ 1%) Participants ............. 
 
10.1.2 Sample Size Justification for the Secondary Overall Survival Endpoint 
in All Randomized Participants in the Primary Study ................................ 
 
10.1.3 Sample Size Justification for the Dual Primary Endpoints of 
Progression Free Survival and Overall Survival in Cisplatin-eligible 
Randomized Participants in the Substudy................................................... 
 
10.1.3.1 Progression Free Survival ............................................................ 
 
10.1.3.2 Overall Survival ............................................................................ 
 
10.1.4 Analysis Timing Projections .................................................................. 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.1.1 Primary Endpoints ........................................................................ 
 
10.3.1.2 Secondary Endpoints .................................................................... 
 
10.3.1.3 Exploratory Endpoints .................................................................. 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.3 Other Analyses ....................................................................................... 
 
10.3.3.1 Pharmacokinetic Analyses ............................................................ 
 
10.3.3.2 Immunogenicity Analyses.............................................................. 
 
10.3.3.3 Biomarker Analyses ...................................................................... 
 
10.3.3.4 Outcome Research Analyses ......................................................... 
 
10.3.4 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 PERFORMANCE STATUS SCORES ................................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 RECIST 1.1 GUIDELINES (WITH BMS MODIFICATIONS) .......... 
 
APPENDIX 5 MANAGEMENT ALGORITHIMS ..................................................... 
 
APPENDIX 6 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 7 NYHA FUNCTIONAL CLASSIFICATION ....................................... 
 
APPENDIX 8 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
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Clinical Protocol
BMS-936558
CA209901
Nivolumab
Protocol Amendment No.: 05
Date: 27-Apr-2023
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APPENDIX 9 COUNTRY SPECIFIC REQUIREMENTS ......................................... 
 
APPENDIX 10 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
 
 
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Clinical Protocol
BMS-936558
CA209901
Nivolumab
Protocol Amendment No.: 05
Date: 27-Apr-2023
10
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930107916
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
1
SYNOPSIS
Protocol Title: A Phase 3, Open-label, Randomized Study of Nivolumab Combined with 
Ipilimumab, or with Standard of Care Chemotherapy, versus Standard of Care 
Chemotherapy in Participants with Previously Untreated Unresectable or Metastatic 
Urothelial Cancer
(CheckMate 901: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 901)
Study Phase: Phase 3 
Rationale:
Urothelial carcinoma (UC) of the bladder is the ninth most common cancer in the world, and the 
fifth most common malignancy in the United States. Approximately 20% to 25% of all patients 
with UC of the bladder develop metastatic disease, resulting in an estimated 15,580 deaths in 2014
in the US.
Cisplatin is among the most active agents in urothelial carcinoma and cisplatin-based combination 
chemotherapy is the treatment of choice for patients with metastatic urothelial bladder cancer. Of 
the commonly used regimens such as gemcitabine plus cisplatin or MVAC (methotrexate, 
vinblastine, doxorubicin, plus cisplatin) gemcitabine and cisplatin treatment was associated with a 
better safety profile and improved tolerability and has become a standard regimen for patients with 
metastatic UC. 
Management guidelines therefore support the use of cisplatin-based regimens in the treatment of 
unresectable or metastatic UC.1,2 However, in clinical practice, more than 50% of all patients with 
unresectable or metastatic UC have contraindications for treatment with cisplatin. Renal 
dysfunction (usually defined as a creatinine clearance of < 60 ml/minute), poor performance status 
and advanced age are relatively common and preclude cisplatin chemotherapy. While no standard 
treatment has been defined for cisplatin-unfit patients, carboplatin-containing regimens are 
considered appropriate alternatives vs cisplatin-based therapy, based on performance status and 
kidney function defined by glomerular filtration rate (GFR).
Although the combination of gemcitabine plus carboplatin is commonly used in cisplatin-ineligible 
patients, to date, combination regimens that do not include cisplatin have never been shown to 
improve survival. Median survival with gemcitabine plus carboplatin in cisplatin-ineligible 
subjects is only 8 to 9 months either due to lower efficacy of carboplatin compared with cisplatin 
or due to these patients’ lower state of general health. In fact, patients who are not candidates for 
cisplatin-containing chemotherapy regimens have significantly worse outcomes with regard to 
response to treatment and overall survival (OS), and there is no consensus on the standard 
chemotherapy treatment for cisplatin-unfit patients. 
Despite the initial chemosensitivity of UC of the bladder, responses generally are short-lived; the 
median survival of patients with metastatic disease is approximately 14 months. Visceral 
metastases and poor performance status are adverse prognostic factors associated with a lower 
likelihood of response to chemotherapy and shorter survival. 
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CA209901
BMS-936558
Nivolumab
While the tolerability of treatment has improved over the past 30 years, improvement in efficacy 
has not kept pace, underscoring the urgent need for novel approaches in the treatment of metastatic 
UC of the bladder. Optimally, novel agents with improved efficacy and tolerability may eliminate 
the need to evaluate patients with metastatic bladder cancer in separate cisplatin-eligible and 
cisplatin-ineligible cohorts in the future.
Research Hypothesis for the Primary Study: The study aims to demonstrate that treatment with 
nivolumab combined with ipilimumab will improve efficacy in cisplatin-ineligible participants 
with previously untreated unresectable or metastatic UC. 
Research Hypothesis for Substudy
The study aims to demonstrate that treatment with nivolumab combined with SOC chemotherapy 
will improve efficacy in cisplatin-eligible participants with previously untreated, unresectable or 
metastatic UC. 
Study Population: Males and females, age ≥18 years, with previously untreated unresectable or 
metastatic UC are eligible for inclusion. Eligible subjects may either have de novo unresectable or 
metastatic UC, or previously diagnosed localized muscle invasive bladder cancer (MIBC) with 
radical cystectomy and treatment with chemotherapy in the neo-adjuvant or adjuvant setting 
following radical cystectomy, who experience progression ≥12 months following chemotherapy. 
Key Inclusion/Exclusion
Inclusion: 
•
Histological or cytological evidence of metastatic or surgically unresectable transitional cell 
carcinoma (TCC) of the urothelium involving the renal pelvis, ureter, bladder or urethra. Minor 
histologic variants (< 50% overall) are acceptable (TCC must be the dominant histology). 
Measurable disease by CT or MRI per RECIST 1.1 criteria. 
•
No prior systemic chemotherapy for metastatic or surgically unresectable UC with the 
following exceptions: (i) Prior intravesical therapy completed at least greater than 4 weeks 
prior to the initiation of study treatment. (ii) Prior neoadjuvant chemotherapy, radiation or prior 
adjuvant platinum-based chemotherapy following radical cystectomy with recurrence 
≥12 months from completion of therapy.
•
Cisplatin-ineligible participants will be defined by any one of the following criteria:3
i.
Impaired renal function 
ii.
Common Terminology Criteria for Adverse Events (CTCAE) version 4, ≥Grade 2 
audiometric hearing loss
iii.
CTCAE version 4, ≥Grade 2 peripheral neuropathy
Participants eligible for Cisplatin-based chemotherapy must exhibit adequate renal 
function 
•
Participants must have an evaluable tumor tissue (fresh biopsy [within 2 years]) prior to 
enrollment period. In order to be treated, a participants must be classified as PD-L1 ≥1% or 
PD-L1 < 1% as determined by a central laboratory during the screening period.
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BMS-936558
Nivolumab
•
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. See Appendix 
2 for ECOG Performance Status scale
•
Adequate hematologic and liver function
Exclusion
•
ECOG PS ≥2
•
Disease that is suitable for local therapy administered with curative intent.
•
Active brain metastases or leptomeningeal metastases
•
Active, known or suspected autoimmune disease
•
Participants may not have received live/attenuated vaccines within 30 days prior to first study 
treatment.
Objectives and Endpoints:
Table 1:
Objectives and Endpoints: Primary Study
Objectives
Endpoints
Primary
•
To compare Overall Survival (OS) of nivolumab 
combined with ipilimumab versus standard of care 
(SOC) chemotherapy in cisplatin-ineligible 
participants with previously untreated, unresectable or 
metastatic urothelial carcinoma (UC).
•
Primary endpoint of OS in cisplatin-
ineligible randomized participants 
•
To compare OS of nivolumab combined with 
ipilimumab versus standard of care (SOC) 
chemotherapy in PD-L1 positive (≥1%) participants 
with previously untreated, unresectable or metastatic 
UC.
•
Primary endpoint of OS in PD-L1 positive 
(≥1%) randomized participants by
immunohistochemistry (IHC)
Secondary
•
To compare OS of nivolumab combined with 
ipilimumab versus SOC chemotherapy in all 
randomized participants with previously untreated,
unresectable or metastatic UC.
•
OS in all randomized participants 
•
To evaluate Progression-Free Survival (PFS) of 
nivolumab combined with ipilimumab versus SOC 
chemotherapy in cisplatin-ineligible randomized 
participants, in PD-L1 positive (≥1%) randomized 
participants and in all randomized participants with 
previously untreated, unresectable or metastatic UC.
•
PFS by blinded independent central review 
(BICR) (using RECIST 1.1) in cisplatin-
ineligible randomized participants, in PD-
L1 positive (≥1%) randomized participants
and in all randomized participants
•
To evaluate changes from baseline in Health-Related 
QOL (HRQoL) of nivolumab combined with 
ipilimumab versus SOC chemotherapy in all 
randomized participants with previously untreated,
unresectable or metastatic UC.
•
European Organisation for Research and 
Treatment of Care (EORTC)  QLQ-C30 
Global Health Status score in all 
randomized participants
Protocol Amendment No.: 05
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Clinical Protocol
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BMS-936558
Nivolumab
Table 1:
Objectives and Endpoints: Primary Study
Objectives
Endpoints
Exploratory
•
To estimate objective response rate (ORR) (using 
RECIST 1.1) of nivolumab combined with 
ipilimumab versus SOC chemotherapy. 
•
ORR by BICR (using RECIST 1.1)
•
To assess the efficacy (OS, PFS, and ORR) of 
nivolumab combined with ipilimumab versus SOC 
chemotherapy in cisplatin-eligible participants with 
previously untreated,
•
OS, PFS, and ORR by BICR (using 
RECIST 1.1) in cisplatin-eligible 
participants with previously untreated, 
unresectable or metastatic UC
•
To assess the safety and tolerability of nivolumab 
combined with ipilimumab versus SOC 
chemotherapy.
•
AEs, clinical laboratory values, vital signs,
or other safety biomarkers
•
To assess changes in reported global health outcomes 
based on EuroQol’s EQ-5D-5L.
•
EQ-5D-5L index score, EQ-5D-5L
dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety), 
and EQ-5D-5L visual analog scale (VAS).
•
To evaluate HRQoL as assessed by EORTC QLQ-
C30.
•
QLQ-C30 Functional scales; QLQ-C30 
Symptom scales
•
To evaluate whether PD-L1 expression is a predictive 
biomarker of efficacy (ORR) of nivolumab combined 
with ipilimumab as first-line therapy in participants 
with previously untreated, unresectable or metastatic 
UC.
•
ORR by BICR (using RECIST 1.1) by PD-
L1 expression at ≥1% expression by 
immunohistochemistry (IHC)
•
To characterize the pharmacokinetics of nivolumab 
combined with ipilimumab as first-line therapy in
participants with previously untreated, unresectable or 
metastatic UC.
•
PK parameters, exposure-response 
relationship between select PK measures of 
exposure and safety and efficacy endpoints, 
if applicable
•
To characterize the immunogenicity of nivolumab 
combined with ipilimumab as first-line therapy in
participants with previously untreated, unresectable or 
metastatic UC.
•
Incidence of anti-nivolumab and anti-
ipilimumab antibody levels and their 
potential relationship with safety and 
efficacy endpoints 
•
To evaluate the pharmacodynamic and 
immunomodulatory activity of nivolumab combined 
with ipilimumab.
•
Including but not limited to correlative 
analyses between gene expression profiling, 
flow cytometric analyses of peripheral 
blood mononuclear cells (PBMCs), myeloid 
derived suppressor cells  and serum soluble 
factor analysis in peripheral blood samples 
and ORR, PFS, and OS
•
To investigate the association between biomarkers in 
the peripheral blood and tumor tissue with efficacy.
•
Including but not limited to correlative 
analyses between baseline and on-treatment 
soluble factors (eg, CXCL9, CXCL10, 
gamma interferon signature, baseline PD-
L1/PD-L2, mutational analyses in tumor 
tissue) with ORR, PFS, and OS
Protocol Amendment No.: 05
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2:
Objectives and Endpoints: Substudy
Objectives
Endpoints
Primary
•
To compare PFS of nivolumab combined with SOC 
chemotherapy versus SOC chemotherapy in 
cisplatin-eligible participants with previously 
untreated, unresectable or metastatic urothelial 
carcinoma (UC) 
•
PFS by BICR (using RECIST 1.1) in 
cisplatin-eligible participants with  previously 
untreated, unresectable or metastatic UC
•
To compare OS of nivolumab combined with SOC 
chemotherapy versus SOC chemotherapy in 
cisplatin-eligible participants with previously 
untreated, unresectable or metastatic UC 
•
OS in cisplatin-eligible participants with 
previously untreated, unresectable or 
metastatic UC
Secondary
•
To evaluate changes from baseline in Health-
Related QOL (HRQoL) of nivolumab combined 
with SOC chemotherapy versus SOC chemotherapy 
in cisplatin-eligible participants with previously 
untreated, unresectable or metastatic UC.
•
European Organisation for Research and 
Treatment of Care (EORTC)  QLQ-C30 
Global Health Status score
•
To evaluate whether PD-L1 expression is a 
predictive biomarker of efficacy (PFS and OS) of 
nivolumab combined with SOC chemotherapy as 
first-line therapy in cisplatin-eligible participants 
with previously untreated, unresectable or 
metastatic UC.
•
PFS by BICR (using RECIST 1.1) and OS by 
PD-L1 expression at ≥1% expression by 
immunohistochemistry (IHC)
Exploratory
•
To estimate ORR (using RECIST 1.1) of nivolumab 
combined with SOC chemotherapy versus SOC 
chemotherapy. 
•
ORR by BICR (using RECIST 1.1)
•
To assess the safety and tolerability of nivolumab 
combined with SOC chemotherapy versus SOC 
chemotherapy.
•
AEs, clinical laboratory values, vital signs, or 
other safety biomarkers
•
To assess changes in reported global health 
outcomes based on EuroQol’s EQ-5D-5L.
•
EQ-5D-5L index score, EQ-5D-5L
dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety), and 
EQ-5D-5L VAS.
•
To evaluate HRQoL as assessed by EORTC QLQ-
C30.
•
QLQ-C30 Functional scales; QLQ-C30 
Symptom scales
•
To evaluate whether PD-L1 expression is a 
predictive biomarker of efficacy (ORR) of 
nivolumab combined with SOC chemotherapy as 
first-line therapy in participants with previously 
untreated, unresectable or metastatic UC.
•
ORR by BICR (using RECIST 1.1) by PD-L1 
expression at ≥1% expression by 
immunohistochemistry (IHC)
•
To characterize the pharmacokinetics of nivolumab 
combined with SOC chemotherapy as first-line
therapy in participants with previously untreated, 
unresectable or metastatic UC.
•
PK parameters, exposure-response 
relationship between select PK measures of 
exposure and safety and efficacy endpoints, if 
applicable
Protocol Amendment No.: 05
Date: 27-Apr-2023
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v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2:
Objectives and Endpoints: Substudy
Objectives
Endpoints
•
To characterize the immunogenicity of nivolumab 
combined with SOC chemotherapy as first-line
therapy in participants with previously untreated, 
unresectable or metastatic UC.
•
Incidence of anti-nivolumab antibody levels 
and their potential relationship with safety and 
efficacy endpoints 
•
To evaluate the pharmacodynamic and 
immunomodulatory activity of nivolumab 
combined with SOC chemotherapy.
•
Including but not limited to correlative 
analyses between gene expression profiling, 
flow cytometric analyses of PBMCs, myeloid 
derived suppressor cells  and serum soluble 
factor analysis in peripheral blood samples 
and ORR, PFS, and OS
•
To investigate the association between biomarkers 
in the peripheral blood and tumor tissue with 
efficacy.
•
Including but not limited to correlative
analyses between baseline and on-treatment 
soluble factors (eg, CXCL9, CXCL10, gamma 
interferon signature, baseline PD-L1/PD-L2, 
mutational analyses in tumor tissue) with 
ORR, PFS, and OS
Overall Design: This will be a randomized, open-label, Phase 3 study comparing combination 
therapy of nivolumab (1 mg/kg 30 minute IV infusion) plus ipilimumab (3 mg/kg 30 minute IV 
infusion) administered every 3 weeks for up to four doses, followed by nivolumab monotherapy 
(480 mg 30 minute IV infusion) administered every 4 weeks, versus the standard of care (SOC; 
gemcitabine-cisplatin or gemcitabine-carboplatin) in participants with previously untreated 
unresectable or metastatic UC. 
In addition a substudy of treatment with nivolumab 360 mg in combination with SOC 
(cisplatin-gemcitabine) every 3 weeks for up to 6 cycles followed by nivolumab monotherapy 
(480 mg every 4 weeks) versus SOC alone (up to 6 cycles) will be evaluated in cisplatin-eligible 
participants with previously untreated unresectable or metastatic UC.
Primary Study:
Prior to initiation of the substudy, participants will be randomized 1:1 to treatment Arm A or B 
and stratified by PD-L1 status < 1%, cisplatin-eligibility, and liver metastasis.
•
Arm A (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg [N1 + I3], followed by nivolumab 
monotherapy) 
•
Arm B (standard of care [SOC] platinum chemotherapy doublet, 3 week cycles, up to 6 cycles). 
Participants in Arm A will receive combination therapy (N1+I3) for up to 4 doses (Part 1), 
followed by nivolumab monotherapy (480 mg every 4 weeks; Part 2). Monotherapy will begin 
6 weeks following the last dose of combination therapy and continue until confirmed disease 
progression, unacceptable toxicity, or participant withdrawal of consent, or 24 months, whichever 
comes first. Participants randomized to Arm B, may receive SOC treatment (6 cycles of 
Protocol Amendment No.: 05
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
gemcitabine/cisplatin) or gemcitabine/carboplatin (only cisplatin-ineligible participants). 
Participants in Arm B will receive up to 6 cycles of SOC chemotherapy.
In Part 1 of Arm A, a minimum of 1 combination cycle of nivolumab and ipilimumab is required 
before participants can proceed to monotherapy. Participants in Arm A experiencing AEs related 
to combination dose therapy that do not meet dose discontinuation criteria, may proceed to 
nivolumab monotherapy dosing (Part 2) without completing all 4 combination doses, after 
consultation with BMS Medical Monitor, on a case-by-case basis. In Arm B, participants assigned 
to receive cisplatin-gemcitabine, may be eligible to switch to carboplatin-gemcitabine following a 
minimum of 1 cycle of cisplatin-gemcitabine, and after consultation with the medical monitor. 
Substudy
Once the substudy begins (following IRT configuration), cisplatin-eligible participants will be 
randomized across Arms A through D, and stratified by PD-L1 status < 1%, cisplatin-eligibility, 
and liver metastasis. Cisplatin-ineligible participants will continue to be randomized 1:1 to Arms 
A or B.
The substudy consists of Arms C and D: 
•
Arm C: Nivolumab (360 mg + Gemcitabine-cisplatin) every 3 weeks for up to 6 cycles, 
followed by nivolumab monotherapy (480 mg) every 4 weeks. Monotherapy will begin 
3 weeks following the last dose of combination therapy and continue until confirmed disease 
progression, unacceptable toxicity, or participant withdrawal of consent, or 24 months, 
whichever comes first.
•
Arm D: Gemcitabine- cisplatin for 6 cycles. 
Once at least 445 cisplatin-ineligible participants and 235 PD-L1 positive (≥1%) participants are 
enrolled, enrollment of the primary study (Arms A and B) will stop (see Section 10.1). Only 
cisplatin-eligible will continue to be enrolled into the substudy (Arms C and D).
The study design schematic is presented in Figure 1.
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
Figure 1:
Study Design Schematic
a Arm A and Arm C: In Part 1, a minimum of 1 cycle of combination therapy is required before proceeding to nivolumab monotherapy dosing (Part 2). Participants
should be dosed no less than 19 days between combination treatment cycles (Arm A), 
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
b In Arm A, monotherapy should begin 6 weeks following the last combination dose. In Arm C, monotherapy will begin 3 weeks following the last
combination therapy. During monotherapy participants should be dosed no less than 26 days between monotherapy treatments. Participants in Arms A and C 
will be treated until confirmed progression of disease, unacceptable toxicity, withdrawal of consent, or up to 24 months of treatment, whichever occurs first. 
c Arms B and D participants will receive up to a maximum of 6 cycles per protocol. Additional optional cycles of SOC may be given per local guidelines. See
Section 7.1.3.1.
NOTES: All participants will be randomized 1:1 to Arms A or B during the primary study, prior to substudy initiation. Following initiation of the substudy, 
cisplatin-eligible patients will be randomized to Arms A, B, C or D. Cisplatin-ineligible patients are not eligible for Arms C and D treatment. 
Protocol Amendment No.: 05
Date: 27-Apr-2023
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
Once at least 445 cisplatin-ineligible participants and at least 235 PD-L1 positive (≥1%) 
participants by IHC are enrolled into Arms A or B of the primary study, the primary study will 
cease enrollment (Arms A and B). Cisplatin-eligible participants will continue enrollment into 
Arms C and D. 
Randomized participants will be evaluated for progression beginning at Week 9 (± 1 week) and 
then every 8 weeks (± 1 week) for 48 weeks, followed by evaluations every 12 weeks thereafter, 
until progression or end of treatment, whichever occurs later.
Primary endpoints in the primary study: Overall Survival in cisplatin-ineligible participants and in 
PD-L1 positive (≥1%) participants by IHC; key secondary endpoint: Overall Survival in all
randomized participants (hierarchical testing procedure) and Progression Free Survival.
Primary endpoints in the substudy: Progression Free Survival and Overall Survival in cisplatin-
eligible participants.
Number of Participants: 
Approximately 1290 previously untreated unresectable or metastatic UC participants will be 
randomized:
•
445 cisplatin-ineligible participants will be randomized in a 1:1 ratio to receive nivolumab plus 
ipilimumab vs SOC chemotherapy;
•
245 cisplatin-eligible participants will be randomized in a 1:1 ratio to receive nivolumab plus 
ipilimumab vs SOC chemotherapy;
−
Of these 690 primary study participants, 235 PD-L1 positive (≥1%) participants by IHC 
are expected to be randomized
•
600 cisplatin-eligible participants will be randomized in a 1:1 ratio to receive nivolumab plus 
SOC chemotherapy vs SOC chemotherapy.
Overall, approximately 445 cisplatin-ineligible participants (per eligibility criteria see Section 6.1) 
and 545 cisplatin-eligible participants will be randomized. Enrollment assumptions are a fixed 
accrual rate of 5 participants per month (2 cisplatin-ineligible participants per month) during the 
first 6 months, 14 participants per month (8 cisplatin-ineligible participants per month) between 6 
and 12 months, and 30 participants per months between 12 and 18 months (19 cisplatin-ineligible 
participants per month) and 37 participants per months thereafter (26 cisplatin-ineligible 
participants per month). In addition, as of month 11, cisplatin-eligible participants are equally 
randomized to both primary study and substudy. Therefore once enrollment in the primary study 
is closed, the accrual rate in the substudy is assumed to be 21 cisplatin-eligible participants per 
month.
Assuming a 28% screen failure rate, it is estimated that approximately 1792 participants will be 
enrolled in order to have 445 cisplatin-ineligible participants randomized in the primary study and 
600 cisplatin-eligible participants randomized in the sub study.
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
Treatment Arms and Duration:
Participants in Arm A (combination therapy [N1+I3], followed by nivolumab monotherapy) will 
be treated until confirmed progression of disease, unacceptable toxicity, withdrawal of consent, or 
up to a maximum of 24 months, whichever comes first. 
Participants in Arm B or Arm D will be treated until confirmed progression of disease, 
unacceptable toxicity, withdrawal of consent, or up to 6 cycles of SOC therapy, whichever occurs 
first. 
Participants in Arm C will be treated with up to 6 cycles of nivolumab (360 mg) in combination 
with gemcitabine-cisplatin. Beginning 3 weeks following the last dose of combination therapy, 
participants will be treated with nivolumab monotherapy (480 mg Q4W) until confirmed 
progression of disease, unacceptable toxicity, withdrawal of consent, or up to a maximum of 
24 months, whichever comes first. 
Study treatment: 
Study Drug for CA209901
Medication
Potency
IP/Non-IP
BMS-936558-01 (Nivolumab) Solution for Injectiona
100 mg (10 mg/mL)
IP
Ipilimumab Solution for Injection
200 mg (5 mg/mL)
IP
Carboplatin Solution for Injection
450 mg/vial (10 mg/mL)b
IP
Gemcitabine Powder for Solution for Infusion
1000 mg/vialb
IP
Cisplatin
100 mg/vial (1 mg/mL)b
IP
a May be labeled as either ͆BMS-936558-01͇ or ͆Nivolumab”.
b These products may be obtained by the investigational sites as local commercial product in certain countries if 
allowed by local regulations. In these cases, products may be a different pack size/potency than listed in the table. 
These products should be prepared/stored/administered in accordance with the package insert or summary of 
product characteristics (SmPC).
Protocol Amendment No.: 05
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
REFERENCES
1
Witjes JA, Comperat E, Cowan NC, De Santis M et al. Guidelines on muscle-invasive and 
metastatic bladder cancer. EAU European Association of Urology 2014, www.uroweb.org.
2
NCCN Clinical Practice guidelines in Oncology. Bladder Cancer Version 2.2014. 
www.nccn.org.
3
Galsky MD, Hahn NM, Rosenberg J, et al. A consensus definition of patients with metastatic 
urothelial carcinoma who are unfit for cisplatin-based chemotherapy.  Lancet Oncol. 2011 
Mar;12(3):211-4. 
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline for All Participants (CA209901)
Procedure
Screening Visit
(within 45 days)a
Notes
Informed Consent
X
Must be obtained prior to performing any screening procedures. 
Register in Interactive Response system to obtain participant number.
Study allows for re-enrollment of a participant that has discontinued the study as a pre-
treatment failure. If re-enrolled, the participant must be re-consented and assigned a new 
participant number from IRT.
Inclusion/Exclusion Criteria
X
Assessed during screening period and (re-enrollment if applicable).
Must be confirmed prior to randomization
Medical History
X
Previous anti-cancer treatment
X
Includes chemotherapy, radiotherapy, surgery, intravesical BCG, targeted therapy
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization
Physical Examination, Measurements, 
Vital Signs and ECOG Performance 
Status
X
Height, weight, and ECOG Performance Status (Appendix 2), and hearing assessment 
(per local standard of care) within 14 days prior to randomization. BP, HR, temperature 
at screening and within 72 hours prior to first dose.
Serious Adverse Event Assessment
X
Serious Adverse Events from time of consent. See Section 9.2 and Appendix 3
Laboratory Tests
X
Must be performed within 14 days prior to randomization
CBC w/differential; Chemistry panel including: AST, ALT, ALP, total bilirubin, blood 
urea nitrogen (BUN) or serum urea level, creatinine, phosphate, Ca, Na, K, Cl, Mg, 
LDH, glucose, albumin, amylase, lipase
Thyroid panel including TSH, Free T4, Free T3 (if not available, total T3 and T4 
acceptable)
Hepatitis B/C (HBV sAG, HCV antibody or HCV RNA)
(sites in Germany see Appendix 9)
Chemotherapy eligibility
X
Local evaluation of participant status for cisplatin treatment must be determined before 
randomization
ECG
X
Within 14 days prior to randomization
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-1:
Screening Procedural Outline for All Participants (CA209901)
Procedure
Screening Visit
(within 45 days)a
Notes
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of
HCG) to be done at screening visit and within 24 hours of first dose of study treatment.
Concomitant Medication Collection
X
Within 14 days prior to randomization
Tumor Tissue Sample 
X
Participants must have PD-L1 status from immunohistochemistry (IHC) testing 
performed by the central laboratory during the screening period. Results may take up to 
14 days. 
Sufficient tumor tissue must be obtained and sent to central laboratory (tissue block or a 
minimum of 15 formalin-fixed, paraffin-embedded (FFPE) slides, obtained from core 
biopsy, punch biopsy, excisional biopsy or surgical specimen).
Participants must provide a fresh tumor biopsy from the primary disease site or a 
metastatic site. If fresh tissue cannot be provided, a tissue block (or at least 15 FFPE 
slides) from the latest surgical resection (eg, radical cystectomy) can be accepted if 
collected within 2 years prior to enrollment period and the participant did not receive 
systemic anticancer agents or radiotherapy (except prior to palliative radiotherapy) since 
collection of sample. Samples received must be suitable for testing to verify PD-L1 
status.
For exploratory purposes, an additional block of archival tissue (or 15 FFPE slides) from 
prior radical cystectomy (if available) will be requested.
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Date: 27-Apr-2023
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Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-1:
Screening Procedural Outline for All Participants (CA209901)
Procedure
Screening Visit
(within 45 days)a
Notes
Tumor Assessment
X
CT with IV contrast of the chest/abdomen/pelvis and all other known/suspected sites of 
disease should be imaged during the screening period. If CT iodinated contrast is 
contraindicated, a non-contrast CT of the chest and contrast enhanced MRI abdomen and 
pelvis and all other known or suspected sites of disease should be imaged (See Section
7.7.3.1).
MRI of brain with and without gadolinium is required to rule out brain metastases (CT 
with or without contrast acceptable if prohibited for medical reasons).
RECIST 1.1 criteria (Appendix 4)
Radiographic tumor assessment must be performed within 28 days prior to 
randomization.
Contact IRT
X
IRT contact must occur as follows:
For participant number assignment at the time informed consent is obtained.
Participant must receive the first dose of study medication within 3 days from 
randomization.
Note: 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.
a Screening assessments must be completed ≤ 45 days of signing ICF (or within the timeframes as specified in the table).
Protocol Amendment No.: 05
Date: 27-Apr-2023
25
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-2:
On Treatment Procedural Outline for Arm A, Part 1: Ipilimumab/Nivolumab Combination Treatment 
(CA209901)
Procedure
Day 1 of each cyclea
(Q3 weeks for 4 cycles)
Notes: 
If a dose is delayed, the procedures scheduled for that same time point should also 
be delayed to coincide with when that time point’s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Safety Assessments
Review of Concomitant Medications
Continuously
Record at each visit.
Targeted Physical Examination, 
Physical Measurements, Vital
Signs, ECOG Performance Status
X
Weight, BP, HR, temperature and Performance Status
Obtain vital signs within 72 hours prior to dosing
Serious Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE version 4.
Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE version 4.
Laboratory Tests
X
On site/ local laboratory testing should be done within 72 hours prior to each dose. For 
the first dose visit, labs need not be repeated if they were preformed within 72 hours 
and the results are available and have been reviewed for eligibility.
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, phosphate, glucose, and albumin 
if clinically indicated)
Thyroid Function Testing (TSH with reflexive free T3 and free T4 if TSH is abnormal, 
if free T3 and free T4 are not available then Total T3 and Total T4 are acceptable), to be 
evaluated every 3 weeks during combination cycle (see Section 9.4)
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours prior to first dose and then every 4 weeks (± 1 week) 
regardless of dosing schedule.
Patient Reported Outcomes Assessment 
EORTC QLQ-C30
See notes
Assessed following randomization but prior to dosing on C1D1, and prior to dosing on 
C2D1 and C4D1.
EQ-5D-5L
See notes
Assessed following randomization but prior to dosing on C1D1, and prior to dosing on 
C2D1 and C4D1.
Protocol Amendment No.: 05
Date: 27-Apr-2023
26
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-2:
On Treatment Procedural Outline for Arm A, Part 1: Ipilimumab/Nivolumab Combination Treatment 
(CA209901)
Procedure
Day 1 of each cyclea
(Q3 weeks for 4 cycles)
Notes: 
If a dose is delayed, the procedures scheduled for that same time point should also 
be delayed to coincide with when that time point’s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Efficacy Assessments
Tumor Assessment
See notes
Tumor assessments will occur on Week 9 (± 1 week) and then every 8 weeks (± 1 
week). After 48 weeks, tumor assessments will occur every 12 weeks (± 1 week).
Post-baseline tumor assessments will continue until progression is assessed by the 
investigator and confirmed by BICR or treatment is discontinued (whichever occurs 
later).
CT with IV contrast of the chest, abdomen, pelvis and all other known or suspected 
sites of disease should be imaged.
If CT iodinated contrast is contraindicated, a non-contrast CT of the chest and contrast 
enhanced MRI abdomen, pelvis and all other known or suspected sites of disease should 
be imaged. (See Section 7.7.3.1).
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.
(CT with or without contrast acceptable if prohibited for medical reasons).
If a dose is delayed, the tumor assessments should occur as scheduled.
Pharmacokinetic /Immunogenicity Assessments
PK samples
X
See Table 9.5-1 and Table 9.5-2
Immunogenicity blood samples
X
See Table 9.5-1 and Table 9.5-2
Biomarker Assessments
Serum sample: Soluble Biomarkers
X
See Table 9.8-1
Whole Blood Sample (SNP)
X
See Table 9.8-1
Whole Blood Sample (Gene 
Expression)
X
See Table 9.8-1
Protocol Amendment No.: 05
Date: 27-Apr-2023
27
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-2:
On Treatment Procedural Outline for Arm A, Part 1: Ipilimumab/Nivolumab Combination Treatment 
(CA209901)
Procedure
Day 1 of each cyclea
(Q3 weeks for 4 cycles)
Notes: 
If a dose is delayed, the procedures scheduled for that same time point should also 
be delayed to coincide with when that time point’s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Myeloid Derived Suppressor Cells 
(MDSC)
X
See Table 9.8-1
Peripheral Blood Mononuclear Cells 
(PBMCs)
X
See Table 9.8-1
ctDNA
X
See Table 9.8-1
Collection of tumor tissue for 
biomarker research upon disease 
progression and at C2D15
X
Tumor tissue submission during Cycle 2 (C2D15) and after progression, is highly
recommended, but optional. Biopsy is not required per protocol. See Table 9.8-1
Clinical Drug Supplies
IRT Drug Vial Assignment
X
Dispense Study Drug
X
Nivolumab 1 mg/kg (30 min IV) and ipilimumab 3mg/kg (30 min IV) Q3 weeks for up
to 4 doses.a
The dosing calculations should be based on the body weight. If the participant’s weight 
on the day of dosing differs by > 10% from weight used to calculate the previous dose, 
the dose must be recalculated. All doses should be rounded to the nearest milligram.
a Nivolumab and Ipilimumab Combination Therapy, 1 cycle = 3 weeks. Participants should be dosed no less than 19 days from previous dose in Part 1 of Arm A.
Participants will receive up to 4 doses of combination treatment and then switch to nivolumab monotherapy treatment (to begin 6 weeks following the last 
combination dose received. Participants in Arm A experiencing AEs related to combination dose therapy (Part 1) that do not meet dose discontinuation criteria, 
may proceed to nivolumab monotherapy dosing (Part 2) without completing all 4 combination doses, after consultation with BMS Medical Monitor, on a case-
by-case basis. 
Protocol Amendment No.: 05
Date: 27-Apr-2023
28
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-3:
On Treatment Procedural Outline for Arms A and C, Part 2 Nivolumab Monotherapy Treatment 
(CA209901)
Procedure
Day 1 of each cycle
(Q4 weeks)a
Notes: 
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point’s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Safety Assessments
Review Concomitant Medications 
Continuously
Record at each visit 
Targeted Physical Examination, 
Physical Measurements, Vital Signs, 
ECOG Performance Status
X
Weight, BP, HR, temperature, and ECOG Performance Status
Obtain vital signs within 72 hours prior to dosing
Severe Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE version 4.
Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE version 4.
Laboratory Tests
X
On site/ local laboratory testing should be done within 72 hours prior to each dose. For the 
first dose visit, labs need not be repeated if they were preformed within 72 hours and the 
results are available and have been reviewed for eligibility. 
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, phosphate, glucose (and albumin if 
clinically indicated)
Thyroid Function Testing (TSH with reflexive free T3 and free T4 if TSH is abnormal, if 
free T3 and free T4 are not available then Total T3 and Total T4 are acceptable) to be 
evaluated every 8 weeks during nivolumab treatment (see Section 9.4).
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours prior to first dose and then every 4 weeks (± 1 week) 
regardless of dosing schedule.
Patient Reported Outcomes Assessment 
EORTC QLQ-C30
X
Assessed prior to dosing on Day 1 of each monotherapy dosing cycle for the first 6 months 
of study, then every 12 weeks (every 3 cycles) for the remainder of the treatment period.
EQ-5D-5L
X
Assessed prior to dosing on Day 1 of each monotherapy dosing cycle for the first 6 months 
of study, then every 12 weeks (every 3 cycles) for the remainder of the treatment period.
Protocol Amendment No.: 05
Date: 27-Apr-2023
29
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-3:
On Treatment Procedural Outline for Arms A and C, Part 2 Nivolumab Monotherapy Treatment 
(CA209901)
Procedure
Day 1 of each cycle
(Q4 weeks)a
Notes: 
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point’s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Efficacy Assessments
Tumor Assessment
See Notes
Tumor assessments will occur on Week 9 (± 1 week) and then every 8 weeks (± 1 week). 
After 48 weeks, tumor assessments will occur every 12 weeks (± 1 week). Post-baseline 
tumor assessments will continue until progression is assessed by the investigator and 
confirmed by BICR or treatment is discontinued (whichever occurs later).
CT with IV contrast of the chest, abdomen, pelvis and all other known or suspected sites of 
disease should be imaged.
If CT iodinated contrast is contraindicated, a non-contrast CT of the chest and contrast 
enhanced MRI abdomen, pelvis and all other known or suspected sites of disease should be 
imaged. (See Section 7.7.3.1).
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. (CT 
with or without contrast acceptable if prohibited for medical reasons).
If a dose is delayed, the tumor assessments should occur as scheduled.
Pharmacokinetic /Immunogenicity Assessments
PK samples
X
Table 9.5-1
Immunogenicity blood samples
X
Table 9.5-1
Biomarker Assessments
Serum sample: Soluble Biomarkers
X
See Table 9.8-1
Whole Blood Sample (SNP)
X
See Table 9.8-1
Whole Blood Sample (Gene 
Expression)
X
See Table 9.8-1
Myeloid Derived Suppressor Cells 
(MDSC)
X
See Table 9.8-1
Protocol Amendment No.: 05
Date: 27-Apr-2023
30
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-3:
On Treatment Procedural Outline for Arms A and C, Part 2 Nivolumab Monotherapy Treatment 
(CA209901)
Procedure
Day 1 of each cycle
(Q4 weeks)a
Notes: 
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point’s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Peripheral Blood Mononuclear
Cells (PBMCs)
X
See Table 9.8-1
ctDNA
X
See Table 9.8-1
Collection of tumor tissue for 
biomarker research upon disease 
progression
X
Tumor tissue submission during Cycle 2 (C2D15) and after progression is highly 
recommended, but optional. Biopsy is not required per protocol. See Table 9.8-1
Clinical Drug Supplies
IRT Drug Vial Assignment
X
Dispense Study Drug
X
Nivolumab 480 mg Q4 weeksa (30 min IV) until disease progression
(See Sections 9.1.4 and 7.4.5, and Appendix 4).
a
Participants should be dosed no less than 26 days from previous dose in Part 2 of the study (monotherapy treatment). Monotherapy should begin 6 weeks
following the last combination dose received for Arm A and 3 weeks after the last combination therapy cycle for Arm C.
Protocol Amendment No.: 05
Date: 27-Apr-2023
31
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-4:
On Study Assessments Treatment Arm B and Arm D (Cisplatin-Eligible) Doublet Gemcitabine-
Cisplatin Chemotherapy (CA209901)
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle
Day1
Notes: 1 cycle = 3 weeks, up to 6 cycles maximuma
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point̓s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Safety Assessments
Review of Concomitant 
Medications
Continuously
Record at each visit.
Targeted Physical Examination, 
Physical Measurements, Vital 
Signs, Performance Status
X*
X*
Weight, BP, HR, temperature and Performance Status
Obtain vital signs within 72 hours prior to dosing
*Also to be collected prior to gemcitabine dosing on Day 8 of each cycle, except
Performance Status.
Serious Adverse Event 
Assessments
--------Continuously------
Adverse events will be graded according to the NCI-CTCAE version 4.
Adverse Event Assessments
--------Continuously------
Adverse events will be graded according to the NCI-CTCAE version 4.
Laboratory Tests
X*
X*
On site/ local laboratory testing should be done within 72 hours prior to each dose. For the 
first dose visit, labs need not be repeated if they were preformed within 72 hours and the 
results are available and have been reviewed for eligibility. 
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, phosphate, glucose, amylase, lipase (and 
albumin if clinically indicated)
*CBC required prior to gemcitabine dosing on Day 8 of each cycle.
Pregnancy Test (WOCBP only) 
X
X
Serum or urine within 24 hours prior to first dose and then every 4 weeks (± 1 week) 
regardless of dosing schedule.
Protocol Amendment No.: 05
Date: 27-Apr-2023
32
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-4:
On Study Assessments Treatment Arm B and Arm D (Cisplatin-Eligible) Doublet Gemcitabine-
Cisplatin Chemotherapy (CA209901)
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle
Day1
Notes: 1 cycle = 3 weeks, up to 6 cycles maximuma
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point̓s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Patient Reported Outcomes Assessments
EORTC QLQ-C30
X
See notes 
Assessed following randomization but prior to dosing on Day 1 of treatment, and prior to 
dosing on C2D1, C4D1 and C6D1. For participants who continue with additional treatment 
due to local guidelines, assessments should continue every 2 cycles starting with C8D1.
EQ-5D-5L
X
See notes
Assessed following randomization but prior to dosing on Day 1 of treatment, and prior to 
dosing on C2D1, C4D1 and C6D1. For participants who continue with additional treatment 
due to local guidelines, assessments should continue every 2 cycles starting with C8D1.
Efficacy Assessments
Tumor Assessment
See notes 
Tumor assessments will occur on Week 9 (± 1 week) and then every 8 weeks (± 1 week). 
After 48 weeks, tumor assessments will occur every 12 weeks (± 1 week). Post-baseline 
tumor assessments will continue until progression is assessed by the investigator and 
confirmed by BICR or treatment is discontinued (whichever occurs later).
CT with IV contrast of the chest, abdomen, pelvis and all other known or suspected sites of 
disease should be imaged.
If CT iodinated contrast is contraindicated, a non-contrast CT of the chest and contrast 
enhanced MRI abdomen, pelvis and all other known or suspected sites of disease should be 
imaged. (See Section 7.7.3.1).
Use same imaging method as was used at screening/baseline.
Participants with a history of brain metastasis should have surveillance MRI approximately 
with and without gadolinium every 12 weeks, or sooner if clinically indicated. (CT with or 
without contrast acceptable if prohibited for medical reasons).
If a dose is delayed, the tumor assessments should occur as scheduled.
Biomarker Assessments
Serum sample: Soluble 
Biomarkers
X
See notes
See Table 9.8-1
Whole Blood Sample (SNP)
X
See notes
See Table 9.8-1
Protocol Amendment No.: 05
Date: 27-Apr-2023
33
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-4:
On Study Assessments Treatment Arm B and Arm D (Cisplatin-Eligible) Doublet Gemcitabine-
Cisplatin Chemotherapy (CA209901)
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle
Day1
Notes: 1 cycle = 3 weeks, up to 6 cycles maximuma
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point̓s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Whole Blood Sample (Gene 
Expression)
X
See notes
See Table 9.8-1
Myeloid Derived Suppressor 
Cells (MDSC)
X
See notes
See Table 9.8-1
Peripheral Blood Mononuclear
Cells (PBMCs)
X
See notes
See Table 9.8-1
ctDNA
X
See notes
See Table 9.8-1
Collection of tumor tissue for 
biomarker research upon disease 
progression
See notes
Tumor tissue submission during Cycle 2 (C2D15) and after progression is highly
recommended, but optional. Biopsy is not required per protocol. See Table 9.8-1
Clinical Drug Supplies
IRT Drug Vial Assignment
X
X
Dispense Study Drug
X
X
Gemcitabine at a dose of 1000 mg/m2 for a 30-minute IV infusion on Days 1 and 8 of a 3-
week treatment cycle for up to 6 cycles.
Cisplatin at a dose of 70 mg/m2 as a 30 to 120-minute IV infusion on Day 1 of a 3-week
treatment cycle for up to 6 cycles.a
Dosing calculations should be based on the body surface area calculation and may be capped 
per local standards. The dose may remain the same if the participant’s weight is within 10% 
of the baseline weight or prior dose weight.
a Note that additional cycles may be permitted as per local guidelines.
Protocol Amendment No.: 05
Date: 27-Apr-2023
34
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-5:
On Study Assessments Treatment Arm B (Cisplatin-Ineligible) Doublet Gemcitabine/Carboplatin 
Chemotherapy (CA209901)
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle
Day1
Notes: 1 cycle = 3 weeks, up to 6 cycles maximuma
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point’s dosing actually occurs (with the exception 
of tumor assessments, which should occur as scheduled).
Safety Assessments
Review of Concomitant 
Medications
Continuously
Record at each visit.
Targeted Physical 
Examination, Physical 
Measurements, Vital Signs, 
Performance Status
X*
X*
Weight, BP, HR, temperature, and Performance Status
Obtain vital signs within 72 hours prior to dosing
*Also to be collected prior to gemcitabine dosing on Day 8 of each cycle, except Performance
Status
Serious Adverse Event 
Assessments
-------Continuously------
Adverse events will be graded according to the NCI-CTCAE version 4.
Adverse Event Assessments
-------Continuously------
Adverse events will be graded according to the NCI-CTCAE version 4.
Laboratory Tests
X*
X*
On site/ local laboratory testing should be done within 72 hours prior to each dose. For the first 
dose visit, labs need not be repeated if they were preformed within 72 hours and the results are 
available and have been reviewed for eligibility. 
CBC w/differential , LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum urea 
level, creatinine, Ca, Mg, Na, K, Cl, LDH, phosphate, glucose, amylase, lipase (and albumin if 
clinically indicated)
*CBC required prior to gemcitabine dosing on Day 8 of each cycle
Pregnancy Test (WOCBP 
only) 
X
X
Serum or urine within 24 hours prior to first dose and then every 4 weeks (± 1 week) regardless 
of dosing schedule.
Protocol Amendment No.: 05
Date: 27-Apr-2023
35
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-5:
On Study Assessments Treatment Arm B (Cisplatin-Ineligible) Doublet Gemcitabine/Carboplatin 
Chemotherapy (CA209901)
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle
Day1
Notes: 1 cycle = 3 weeks, up to 6 cycles maximuma
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point’s dosing actually occurs (with the exception 
of tumor assessments, which should occur as scheduled).
Patient Reported Outcomes Assessments
EORTC QLQ-C30
X
See notes
Assessed following randomization but prior to dosing on Day 1 of treatment, and prior to dosing 
on C2D1, C4D1 and C6D1. For participants who continue with additional treatment due to local 
guidelines, assessments should continue every 2 cycles starting with C8D1.
EQ-5D-5L
X
See notes
Assessed following randomization but prior to dosing on Day 1 of treatment, and prior to dosing 
on C2D1, C4D1 and C6D1 For participants who continue with additional treatment due to local 
guidelines, assessments should continue every 2 cycles starting with C8D1.
Efficacy Assessments
Tumor Assessment
See notes
See notes
Tumor assessments will occur on Week 9 (± 1 week) and then every 8 weeks (± 1 week). After 
48 weeks, tumor assessments will occur every 12 weeks (± 1 week). Post-baseline tumor 
assessments will continue until progression is assessed by the investigator and confirmed by 
BICR or treatment is discontinued (whichever occurs later).
If CT iodinated contrast is contraindicated, a non-contrast CT of the chest and contrast enhanced 
MRI abdomen, pelvis and all other known or suspected sites of disease should be imaged. (See 
Section 7.7.3.1)
Use same imaging method as was used at screening/baseline.
CT with IV contrast of the chest, abdomen, pelvis and all other known or suspected sites of 
disease should be imaged. Participants with a history of brain metastasis should have 
surveillance MRI with and without gadolinium approximately every 12 weeks, or sooner if 
clinically indicated. (CT with or without contrast acceptable if prohibited for medical reasons).
If a dose is delayed, the tumor assessments should occur as scheduled.
Biomarker Assessments
Serum sample: Soluble 
Biomarkers
X
See notes
See Table 9.8-1
Whole Blood Sample (SNP)
X
See notes
See Table 9.8-1
Protocol Amendment No.: 05
Date: 27-Apr-2023
36
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-5:
On Study Assessments Treatment Arm B (Cisplatin-Ineligible) Doublet Gemcitabine/Carboplatin 
Chemotherapy (CA209901)
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle
Day1
Notes: 1 cycle = 3 weeks, up to 6 cycles maximuma
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point’s dosing actually occurs (with the exception 
of tumor assessments, which should occur as scheduled).
Whole Blood Sample (Gene 
Expression)
X
See notes
See Table 9.8-1
Myeloid Derived Suppressor 
Cells (MDSC)
X
See notes
See Table 9.8-1
Peripheral Blood Mononuclear
Cells (PBMCs)
X
See notes
See Table 9.8-1
ctDNA
X
See notes
See Table 9.8-1
Collection of tumor tissue for 
biomarker research upon 
disease progression
See notes
Tumor tissue submission during Cycle 2 (C2D15) and after progression is highly recommended, 
but optional. Biopsy is not required per protocol. See Table 9.8-1
Clinical Drug Supplies
IRT Drug Vial Assignment
X
X
Dispense Study Drug
X
X
Gemcitabine at a dose of 1000 mg/m2 for a 30-minute IV infusion on Days 1 and 8 of a 3-week
treatment cycle for up to 6 cycles.a
Carboplatin: AUC4.5/5 (see Section 7.1.3.2) 
Dosing calculations should be based on the body surface area calculation and may be capped per 
local standards. The dose may remain the same if the participant’s weight is within 10% of the 
baseline weight or prior dose weight.
a Note that additional cycles may be permitted as per local guidelines.
Protocol Amendment No.: 05
Date: 27-Apr-2023
37
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Table 2-6:
On Study Assessments Treatment Substudy: (Arm C, Part 1) Nivolumab + Doublet Gemcitabine-
Cisplatin Chemotherapy (CA209901)
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle 
Day 1
Notes: 1 cycle = 3 weeks, for a maximum of 6 cycles. 
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point’s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Safety Assessments
Review of Concomitant 
Medications
Continuously
Record at each visit.
Targeted Physical Examination, 
Physical Measurements, Vital 
Signs, Performance Status
X*
X*
Weight, BP, HR, temperature and Performance Status
Obtain vital signs within 72 hours prior to dosing
*Also to be collected prior to gemcitabine dosing on Day 8 of each cycle, except
Performance Status.
Serious Adverse Event 
Assessments
------Continuously------
Adverse events will be graded according to the NCI-CTCAE version 4.
Adverse Event Assessments
------Continuously------
Adverse events will be graded according to the NCI-CTCAE version 4.
Laboratory Tests
X*
X*
On site/ local laboratory testing should be done within 72 hours prior to each dose. For the 
first dose visit, labs need not be repeated if they were preformed within 72 hours and the 
results are available and have been reviewed for eligibility. 
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, phosphate, glucose, amylase, lipase (and 
albumin if clinically indicated)
Thyroid Function Testing (TSH with reflexive free T3 and free T4 if TSH is abnormal, total 
T3 and T4 acceptable if Free T3 T4 are not available) to be evaluated every 3 weeks during 
treatment with nivolumab (see Section 9.4).
*CBC required prior to gemcitabine dosing on Day 8 of each cycle.
Pregnancy Test (WOCBP only) 
X
X
Serum or urine within 24 hours prior to first dose and then every 4 weeks (± 1 week) 
regardless of dosing schedule.
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Table 2-6:
On Study Assessments Treatment Substudy: (Arm C, Part 1) Nivolumab + Doublet Gemcitabine-
Cisplatin Chemotherapy (CA209901)
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle 
Day 1
Notes: 1 cycle = 3 weeks, for a maximum of 6 cycles. 
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point’s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Patient Reported Outcomes Assessments
EORTC QLQ-C30
X
See notes
Assessed following randomization but prior to dosing on C1D1, and prior to dosing at C2D1 
and C4D1.
EQ-5D-5L
X
See notes
Assessed following randomization but prior to dosing on C1D1, and prior to dosing at C2D1 
and C4D1.
Efficacy Assessments
Tumor Assessment
See notes
Tumor assessments will occur on Week 9 (± 1 week) and then every 8 weeks (± 1 week). 
After 48 weeks, tumor assessments will occur every 12 weeks (± 1 week). Post-baseline 
tumor assessments will continue until progression is assessed by the investigator and 
confirmed by BICR or treatment is discontinued (whichever occurs later).
CT with IV contrast of the chest, abdomen, pelvis and all other known or suspected sites of 
disease should be imaged.
If CT iodinated contrast is contraindicated, a non-contrast CT of the chest and contrast 
enhanced MRI abdomen, pelvis and all other known or suspected sites of disease should be 
imaged. (See Section 7.7.3.1)
Use same imaging method as was used at screening/baseline.
Participants with a history of brain metastasis should have surveillance MRI approximately 
with and without gadolinium every 12 weeks, or sooner if clinically indicated. (CT with or 
without contrast acceptable if prohibited for medical reasons).
If a dose is delayed, the tumor assessments should occur as scheduled.
Biomarker Assessments
Collection of tumor tissue for 
biomarker research upon disease 
progression
See notes
Tumor tissue submission during Cycle 2 (C2D15) and after progression is highly 
recommended, but optional. Biopsy is not required per protocol. See Table 9.8-1
Serum
X
See notes
See Table 9.8-1
Whole Blood Sample (SNP)
X
See notes
See Table 9.8-1
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Table 2-6:
On Study Assessments Treatment Substudy: (Arm C, Part 1) Nivolumab + Doublet Gemcitabine-
Cisplatin Chemotherapy (CA209901)
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle 
Day 1
Notes: 1 cycle = 3 weeks, for a maximum of 6 cycles. 
If a dose is delayed, the procedures scheduled for that same time point should also be 
delayed to coincide with when that time point’s dosing actually occurs (with the 
exception of tumor assessments, which should occur as scheduled).
Whole Blood Sample (Gene 
Expression)
X
See notes
See Table 9.8-1
Myeloid Derived Suppressor 
Cells (MDSC)
X
See notes
See Table 9.8-1
Peripheral Blood Mononuclear
Cells (PBMCs)
X
See notes
See Table 9.8-1
ctDNA
X
See notes
See Table 9.8-1
Clinical Drug Supplies
IRT Drug Vial Assignment
X
X
Dispense Study Drug
X
X
Nivolumab 360 mg Day 1 of each Q 3 weeks (30 min IV)
Gemcitabine at a dose of 1000 mg/m2 for a 30-minute IV infusion on Days 1 and 8 of a 3-
week treatment cycle for up to 6 cycles.
Cisplatin at a dose of 70 mg/m2 as a 30 to 120-minute IV infusion on Day 1 of a 3-week
treatment cycle for up to 6 cycles.
Dosing calculations should be based on the body surface area calculation and may be capped 
per local standards. The dose may remain the same if the participants weight is within 10% of 
the baseline weight or prior dose weight.
3 weeks following the last combination dose (nivolumab + gemcitabine-cisplatin) participants 
will follow assessments and treatment in nivolumab maintenance Table 2-3
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Table 2-7:
Follow-Up Period (All Participants) CA209901
Procedure
Follow Up,
Visits 1 and 2a
Survival Follow-Up 
Visits b
Notes
Safety Assessments
Targeted Physical Examination
X
To assess for potential late emergent study drug related issues
Vital Signs
X
Weight, BP, HR, temperature and Performance Status
Adverse Events Assessment
X
X
In survival period only to include toxicities from study therapy.
Review of Concomitant Medication
X
X
Document Subsequent Cancer Therapy
Laboratory Tests
X
On site/local laboratory testing; CBC w/differential, LFTs, BUN, creatinine, 
amylase, lipase and TSH (+ reflex Free T4 and Free T3 , total T3 and T4 
acceptable if Free T3 T4 are not available) for) for FU 1, repeat at FU 2 if 
study drug related toxicity persists.
Pregnancy Test (WOCBP only)
X
Serum or urine
Exploratory Biomarker Testing
Exploratory Serum Biomarkers
X
Collect serum at Follow-Up Visit 1 and Follow-Up Visit 2 visit. Sample 
collection upon disease progression is optional, but highly recommended. 
See Table 9.8-1
Collection of tumor tissue for 
biomarker research upon disease 
progression
X 
Tumor tissue submission after progression is highly recommended, but 
optional. Biopsy is not required per protocol. See Table 9.8-1
Pharmacokinetic Samples and Immunogenicity Assessments
PK samples
X
See Table 9.5-1 and Table 9.5-2
Immunogenicity blood sample
X
See Table 9.5-1 and Table 9.5-2
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Table 2-7:
Follow-Up Period (All Participants) CA209901
Procedure
Follow Up,
Visits 1 and 2a
Survival Follow-Up 
Visits b
Notes
Efficacy Assessments
Tumor Assessment
X
X
Only for participants without progression, and no longer on study therapy.
Tumor assessments will occur on Week 9 (± 1 week) and then every 8 weeks 
(± 1 week). After 48 weeks, tumor assessments will occur every 12 weeks 
(± 1 week), until disease progression even if the participant has initiated 
subsequent anti-cancer therapy.
CT with IV contrast of the chest, abdomen, pelvis and all other known or 
suspected sites of disease should be imaged.
If CT iodinated contrast is contraindicated, a non-contrast CT of the chest 
and contrast enhanced MRI abdomen, pelvis and all other known or 
suspected sites of disease should be imaged. (See Section 7.7.3.1).
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. (CT with or without contrast acceptable if prohibited for 
medical reasons).
Outcomes Research Assessment 
EORTC QLQ-C30
X
Assessment at clinical visit
EQ-5D-5L
X
X
Assessment at clinical visit, or can be collected over the phone for Survival 
Follow-Up visits.
Participant Status
Survival Status
X
X
Every 3 months after FU 2; may be accomplished by visit, phone contact or 
email, to include assessment of subsequent anti-cancer therapy.
a Follow Up visits 1 (FU1) and 2 (FU2) are in clinic visits. Follow-up visit 1 (FU1) = 30 days from the last dose (± 7 days) or coincides with the date of
discontinuation (± 7 days) if date of discontinuation is greater than 35 days after last dose, Follow-up visit 2 (FU2) = 90 days (± 7 days) from follow-up visit 1
b Survival Follow Up Visits may be conducted in clinic or via telephone contact:  Every 3 Months (± 7 days) from FU2
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3
INTRODUCTION
CA209901 is a Phase 3, open-label, randomized study of nivolumab combined with ipilimumab 
or standard of care chemotherapy, versus standard of care chemotherapy in participants with 
previously untreated unresectable or metastatic urothelial carcinoma (UC). Eligible participants 
may either have de novo previously untreated unresectable or metastatic UC, or previously 
diagnosed localized muscle invasive bladder cancer (MIBC) with radical cystectomy and treatment 
with chemotherapy or radiation therapy in the neo-adjuvant or adjuvant setting and progression 
≥12 months following receiving chemotherapy.
3.1
Study Rationale
UC of the bladder is the ninth most common cancer in the world1 and the fifth most common
malignancy in the United States.2 Approximately 20% to 25% of all patients with UC of the
bladder develop metastatic disease, resulting in an estimated 15,580 deaths in 2014 in the United
States.3
Cisplatin has been used for the treatment of UC since the 1970s, with initial reports describing 
response rates ranging from 30% to 70% for advanced UC treated with cisplatin-containing 
regimens.4,5,6 These response rates were higher than observed with other chemotherapeutic agents 
at the time, establishing cisplatin as a preferred first-line agent in this disease. The M-VAC 
(methotrexate, vinblastine, adriamycin, and cisplatin) regimen, developed in the early 1980’s, 
became a treatment standard based on data from two large randomized trials demonstrating 
improved survival with MVAC compared with single agent cisplatin or CISCA (cisplatin, 
adriamycin, and cyclophosphamide), respectively. 7 , 8 However, the toxicity of MVAC 
(myelosuppression, fever/neutropenia and mucositis)7 limited the widespread use of this regimen 
in elderly patients with comorbidities.
In an effort to improve on the response and toxicity of MVAC, cisplatin-containing doublets 
incorporating other chemotherapeutic agents were tested.9,10 Of the commonly used regimens such 
as gemcitabine plus cisplatin, or MVAC (methotrexate, vinblastine, doxorubicin, plus cisplatin) 
gemcitabine plus cisplatin treatment was associated with a better safety profile and improved 
tolerability and has become a standard regimen for patients with metastatic UC.11,12
Management guidelines therefore support the use of cisplatin-based regimens in the treatment of 
unresectable or metastatic UC.13,14 However, in clinical practice, more than 50% of all patients 
with unresectable or metastatic UC have contraindications for treatment with cisplatin. Renal 
dysfunction, poor performance status, and advanced age are relatively common and preclude 
cisplatin chemotherapy.15 An expert consensus statement was released in 2011 with the goal of 
defining unfit patients.16 According to this definition, unfit patients would meet at least one of the 
following criteria: Eastern Cooperative Oncology Group performance status of 2, creatinine 
clearance less than 60 mL/min, grade ≥2 hearing loss, grade ≥2 neuropathy, and/or New York 
Heart Association Class III heart failure.16
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A randomized study compared two carboplatin-containing regimens, M-CAVI and 
gemcitabine/carboplatin, in this population of cisplatin “unfit” patients. 17 Although median 
survival was comparable, toxicity was significantly lower with gemcitabine/carboplatin, 
establishing it as an appropriate first-line regimen in this patient population.
Although the combination of gemcitabine plus carboplatin is commonly used in cisplatin-ineligible 
patients, to date, combination regimens that do not include cisplatin have never been shown to 
improve survival. Median survival with gemcitabine plus carboplatin in cisplatin-ineligible 
patients is only 8 to 9 months,17 either due to lower efficacy of carboplatin compared with cisplatin 
or due to these patients’ lower state of general health. In fact, patients who are not candidates for 
cisplatin-containing chemotherapy regimens have significantly worse outcomes with regard to 
response to treatment and overall survival (OS). 
Despite the initial chemosensitivity of UC of the bladder, responses generally are short-lived; the 
median survival of patients with metastatic disease is approximately 14 -15 months.12 Visceral 
metastases and poor performance status are adverse prognostic factors associated with a lower 
likelihood of response to chemotherapy and shorter survival.18
While the tolerability of treatment has improved over the past 30 years, improvement in efficacy 
has not kept pace, underscoring the urgent need for novel approaches in the treatment of metastatic 
UC of the bladder. Optimally, novel agents with improved efficacy and tolerability may eliminate 
the need to evaluate patients with metastatic UC in separate cisplatin-eligible and cisplatin-
ineligible cohorts in the future.
3.1.1
Research Hypothesis
3.1.1.1
Research Hypothesis for Primary Study
The study aims to demonstrate that treatment with nivolumab combined with ipilimumab will 
improve efficacy in cisplatin-ineligible and/or PD-L1 positive (PD-L1 ≥ 1%) participants with 
previously untreated, unresectable or metastatic UC. 
3.1.1.2
Research Hypothesis for Substudy
The study aims to demonstrate that treatment with nivolumab combined with SOC chemotherapy 
will improve efficacy in cisplatin-eligible participants with previously untreated, unresectable or 
metastatic UC. 
3.1.2
Rationale for Immunotherapy in UC
UC is an immunogenic malignancy. Immunotherapy has played a major role in the treatment of 
superficial bladder cancer since the introduction of intravesical bacillus Calmette-Guérin (BCG); 
randomized trials have demonstrated treatment with intravesical BCG results in lower recurrence 
rates and significantly superior survival rates.19 While the mechanism of action of BCG remains 
poorly defined, studies support an immunological mechanism including the role of BCG in the 
maturation of dendritic cells by signaling through Toll-like receptors, and secretion of 
inflammatory cytokines such as IL- 12, IFN-γ, and TNF-α.20 Multiple studies have shown that 
bladder cancer specimens harbor tumor infiltrating lymphocytes; 21 , 22 immunohistochemical 
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staining for intratumoral CD8 T cells in tissue samples from 69 patients with bladder cancer (pT2, 
pT3, or pT4) demonstrated that patients with higher numbers of CD8 tumor infiltrating 
lymphocytes within the tumor (8 or more) had better disease-free survival (P < 0.001) and overall 
survival (P = 0.018) than did patients with similar-staged bladder cancer and fewer intratumoral 
CD8 tumor infiltrating lymphocytes.22
Despite the immunogenicity of bladder cancer, patients with bladder cancer also exhibit 
tumor-associated immunologic suppression. Patients with bladder cancer exhibit a tumor-
associated immunologic suppression, particularly evident as an impaired T-cell response, which 
may worsen with advanced tumor stage.23,24,25 Bladder cancer specimens have been shown to be 
infiltrated by T regulatory cells, and to express high levels of inhibitory cytokines.24 In addition, 
aberrant expression of T-cell coregulatory molecules, known to inhibit the immune response, have 
been demonstrated on bladder cancer cells and tumor infiltrating lymphocytes and have correlated 
with clinical outcomes.26
These findings suggest that the balance between CD8+ cytotoxic T cells and negative immune 
regulatory elements in the tumor microenvironment may be critical in determining the host’s 
overall immune response and ultimate clinical outcome. 
Immune checkpoint inhibition blockade has demonstrated intriguing activity in localized 
bladder cancer.
Ipilimumab has been explored pre-cystectomy in a pilot trial of patients with clinically localized 
bladder cancer. In this trial, 12 patients were treated with 2 doses of ipilimumab (n = 6 treated with 
3 mg/kg and n = 6 treated with 10 mg/kg).27 Most drug-related adverse events (AEs) were Grade 
1 or 2, all patients demonstrated an increase in CD4+ ICOShi T cells in tumor tissue and systemic 
circulation, and 8/12 patients had down-staging of their disease on final pathology review. The 
efficacy and safety of first-line gemcitabine, cisplatin plus ipilimumab for metastatic UC is being 
investigated in a Phase 2 trial (NCT01524991). 
High levels of programmed death 1 (PD-1) ligand 1 (PD-L1) expression have been noted in UC, 
suggesting tumor-associated immune tolerance and escape from immune surveillance. PD-L1 
expression has been reported in approximately 20% (5% cutoff) and 30% (1% cutoff) of tumor 
tissue sample (28-30). PD-1 and PD-L1 immune checkpoint inhibitors appear to show benefit in 
patients with disease progression on platinum-based therapy. 28 Recently, atezolizumab 
(anti-PD-L1) was approved in the US to treat metastatic UC in patients whose disease progressed 
during or after platinum-based chemotherapy, based on a 15% response rate in a single-arm study.
In an open-label, multicenter Phase 1/2 expansion cohort in patients with metastatic UC, 
nivolumab elicited a response rate of 24.4% with acceptable safety, regardless of tumor PD-L1 
expression, in patients who had received one or more prior lines of chemotherapy (CheckMate
032; NCT01928394).29 In a larger study in unresectable or metastatic UC, CheckMate 275, 
nivolumab had clinically meaningful efficacy and a manageable safety profile.30 At 7 months of 
median follow-up, 24.4% of patients remain on therapy. Confirmed overall response rate (ORR)
was 19.6% (95% CI 15.0–24.9), with Grade 3-4 treatment-related adverse events occurring in 18% 
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of patients (Grade 5, 1%), mainly fatigue and diarrhea (2% each). The combination of nivolumab 
and ipilimumab demonstrated acceptable safety and high activity in patients with advanced, 
platinum refractory UC in study CA209032. At 7.9 months minimum follow-up, 23.9% of patients
remain on therapy. BICR confirmed overall response rate (ORR) was 37.0% (95% CI 27.1–47.7), 
with Grade 3-4 treatment-related adverse events occurring in 39.1% of patients (no Grade 5 SAE), 
mainly diarrhea (9.8% each) and elevated alanine aminotransferase (6.5%), and only 13% 
discontinuations due to treatment-related AEs (Please see Section 5.5.1).
Taken together, these data suggest that combination therapy with nivolumab and ipilimumab may 
provide the most favorable benefit-risk among the regimens studied and support the further 
development of the N1I3 combination as first-line therapy in metastatic UC.
3.1.3
Rationale for Cisplatin-ineligible Subpopulation being a Primary 
Analysis Population 
Management guidelines support the use of cisplatin-based regimens in metastatic UC.13,14 In real-
world clinical practice, up to 50% of patients with UC are not eligible or are considered unfit for 
cisplatin-based standard chemotherapy because of impaired renal function, performance status, or 
comorbidity.15,16 Hence, evaluation of treatment approaches in all-comer trials with over-
enrollment of cisplatin-eligible patients may not be applicable to the cisplatin unfit population. 
While no standard treatment has been defined for cisplatin-unfit patients, carboplatin-containing 
regimens are considered appropriate alternatives vs cisplatin-based therapy, based on performance 
status and kidney function defined by GFR.17 However, patients who are not candidates for 
cisplatin-containing chemotherapy regimens have significantly worse outcomes with regard to 
response to treatment and OS, and there is no consensus on the standard chemotherapy treatment 
for cisplatin-unfit patients. In view of the limited success of carboplatin-based chemotherapy more 
effective and better tolerated treatments are needed for cisplatin-ineligible patients (a primary 
analysis population in this study). 
3.1.4
Rationale for PD-L1 Positive Subpopulation being a Primary Analysis 
Population 
The treatment options for tumors have been evolving rapidly with new data emerging dramatically.
For locally advanced unresectable and metastatic UC, newly approved immunotherapies have 
recently become available, including Keytruda31 and Tecentriq32 in PD-L1 positive untreated 
metastatic UC. In a second-line setting, data from CA209-032 also provided supportive evidence 
for application in first-line metastatic UC.33 In light of such data, this study CA209-901 was 
revised (revised protocol 03) to remove PFS as a primary endpoint and add OS in PD-L1 positive 
(≥ 1%) patients as a primary population.
The rationale for this revision were based on the available evidence. First, the median PFS of single 
agent immunotherapy were reported as 2.3 months for pembrolizumab31 and 2.7 months for 
atezolizumab34 in untreated cisplatin-ineligible metastatic UC, and 3.55 months for nivolumab in 
study CA209-27535 and 4.86 months for nivolumab in combination with ipilimumab in study 
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CA209-032 in previously platinum-treated metastatic UC,33 which may not be comparable with 
the gemcitabine-carboplatin regimen (7.5 months) in cisplatin-ineligible patients. On the other 
hand, the above mentioned studies presented efficacy of ORR especially in PD-L1 positive 
metastatic UC. In single immunotherapy agent studies, Keynote-052 showed an ORR of 47% for 
PD-L1 CPS ≥ 1031 and IMvigor-210, ORR of 28.1% for PD-L1 ≥ 5% in ICs.32 Furthermore, a 
nivolumab with ipilimumab combined regimen in CA209-032 demonstrated strong incremental 
efficacy in PD-L1 ≥ 1% patients (ORR 54.8%), but limited benefit (ORR 21.4%) in PD-L1 
negative cisplatin pre-treated metastatic UC.33 The clinical efficacy of OS in PD-L1 positive 
metastatic UC was also supported by CA209-032 with OS 24.08 months in PD-L1 positive (14.88 
months in PD-L1 negative).33 The application of pembrolizumab and atezolizumab are restricted 
in PD-L1 positive untreated metastatic UC.31,32 In consideration of this evidence, this current 
revision removed PFS a primary endpoint and added OS in PD-L1 positive (≥1%) as a primary 
endpoint for the primary study.
3.1.5
Rationale for Arm B and Arm D: Gemcitabine-Cisplatin/Gemcitabine-
Carboplatin Combination Chemotherapy
Currently cisplatin, the taxanes and gemcitabine are employed in the management of advanced 
bladder cancer. Combinations of 2 or 3 of these agents have shown clinical benefit, of which 
commonly used combinations include Gemcitabine plus cisplatin and dose-dense MVAC (3). 
While studies have noted the superiority of MVAC over other cisplatin-containing regimens, the 
significant toxicity of MVAC with increased rates of myelosuppression, neutropenic fever, and 
mucositis limits the use of this regimen in the elderly and patients with comorbidities.7
A large Phase 3 trial randomized 405 patients with stage IV UC to gemcitabine plus cisplatin or 
standard MVAC.12 Both arms had similar response rates (RRs) (46%–49%) and OS (13.8–14.8 
months), with improved toxicity profile in the gemcitabine plus cisplatin arm. Fewer deaths were 
noted in the gemcitabine plus cisplatin arm compared to MVAC arm (1% vs. 3%) although this 
did not reach statistical significance. A 5-year update analysis confirmed that gemcitabine plus 
cisplatin was not inferior to MVAC in terms of survival (OS: 13% vs. 15.3%; PFS: 9.8% vs 11.3%,
respectively). The similar disease outcomes and favorable toxicity profile of gemcitabine plus 
cisplatin have established this regimen as an appropriate first-line treatment for patients with 
previously untreated, unresectable or metastatic UC in the US and Europe. Accordingly, to 
maintain homogeneity of treatment in the comparator arm, gemcitabine plus cisplatin was included 
as SOC chemotherapy for cisplatin-eligible patients randomized to SOC arm.
In clinical practice, more than 50% of all patients with unresectable or metastatic UC have 
contraindications for treatment with cisplatin. Renal dysfunction (usually defined as a creatinine 
clearance of < 60 ml/minute), poor performance status, and advanced age are relatively common 
and preclude cisplatin chemotherapy. While no standard treatment has been defined for cisplatin-
unfit patients, carboplatin-containing regimens are considered appropriate alternatives vs cisplatin-
based therapy, based on performance status and kidney function defined by GFR. Hence, 
gemcitabine plus carboplatin was included as SOC chemotherapy for cisplatin-ineligible patients 
randomized to SOC arm.
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3.1.6
Rationale For Exclusion Of ECOG Performance Status ≥2
The relationship between comorbidities, treatment-related toxicities, and efficacy of therapy is 
complex and has not been adequately explored in patients with advanced solid tumors. Poor 
functional status has been associated with increased toxic effects and decreased efficacy in patients 
with metastatic UC who are treated with cisplatin-based chemotherapy.18 Limited to no safety 
information is available with regard to combination of ipilimumab 3 mg/kg with nivolumab 
1 mg/kg in patients with ≥PS 2 across a range of solid tumors evaluated within the nivolumab 
program. 
Accordingly, patients with comorbidities and poor functional status (ECOG PS 2 or greater) will
be excluded from this study out of concern for inability to tolerate combination of higher dose of 
ipilimumab (3 mg/kg) in the combination regimen of the treatment arm.
3.1.7
Rationale For Shorter Infusion Times Of Nivolumab And Ipilimumab 
Dosing In Part 1
Long infusion times place a burden on patients and treatment centers. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of 30-minute duration will 
diminish the burden, provided that there is no change in the safety profile. Nivolumab and 
ipilimumab have been administered at up to 10 mg/kg with infusion duration of 60 minutes and 
90 minutes, respectively.
Establishing that nivolumab can be safely administered using a shorter infusion time (30 minutes) 
is under investigation. Previous clinical studies of nivolumab monotherapy have used a 60-minute 
infusion duration wherein, nivolumab has been safely administered up to 10 mg/kg over long 
treatment periods. Infusion reactions including high-grade hypersensitivity reactions have been 
uncommon across nivolumab clinical program. In CA209010, a dose association was observed for 
infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg, and 
18.5% at 10 mg/kg). All the events were Grade 1-2 and were manageable. An infusion duration of 
30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not expected to 
present any safety concerns compared to the prior experience at 10 mg/kg nivolumab dose infused 
over a 60-minute duration. The safety of nivolumab 3 mg/kg administered as a 30-min infusion 
was assessed in CA209153 in patients (n = 322) with previously treated advanced NSCLC. 
Overall, 
there 
were 
no 
clinically 
meaningful 
differences 
in 
the 
frequency 
of 
hypersensitivity/infusion-related reactions (of any cause or treatment-related) in patients 
administered nivolumab over a 30-minute infusion compared with that reported for patients with 
the 60-minute infusion. Thus, it was shown that nivolumab can be safely infused over 30 minutes. 
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In participants 
with advanced Stage II or Stage IV melanoma (CA184022 study), where ipilimumab was 
administered up to a dose of 10 mg/kg, on-study drug related hypersensitivity events (Grade 1/2) 
were reported in 1 participant (1.4%) in the 0.3 mg/kg and in 2 participants (2.8%) in the 10 mg/kg 
group. There were no drug-related hypersensitivity events reported in the 3 mg/kg group. Across 
the 3 treatment groups, no Grade 3/4 drug-related hypersensitivity events were reported and there 
were no reports of infusion reactions. Ipilimumab 10 mg/kg monotherapy has also been safely 
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administered as a 90-minute infusion in a large Phase 3 study in prostate cancer (CA184043) and 
as adjuvant therapy for Stage III melanoma (CA184029), with infusion reactions occurring in 
participants. Administering 3 mg/kg of ipilimumab represents approximately one-third of the 
10 mg/kg dose. Similarly, shortened infusion duration of 30 minutes for ipilimumab is not expected 
to present additional safety concerns.36
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across clinical studies of nivolumab, ipilimumab, and nivolumab/ipilimumab combinations. 
Furthermore, a 30-minute break after the first infusion for the combination cohort will ensure the 
appropriate safety monitoring before the start of the second infusion. Overall, a change in safety 
profile is not anticipated with 30-minute infusions of nivolumab, ipilimumab, or combination 
treatment.
3.1.8
Rationale For Shorter Infusion Times With Nivolumab 480 Mg Flat Dose 
In Part 2
Long infusion times place a burden on participants and treatment centers. Establishing that 
nivolumab can be safely administered using shorter infusion times of 30 minutes duration in 
participants will diminish the burden provided there is no change in safety profile. Previous clinical 
studies show that nivolumab has been administered safely over 60 minutes at doses ranging up to 
10 mg/kg over long treatment duration. For example, in Study CA209010 (a phase 2, randomized, 
double-blinded, dose-ranging study of nivolumab in participants with advanced/metastatic, clear 
cell RCC), a dose association was observed for infusion site reactions and hypersensitivity 
reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 
1/2 and were manageable. Establishing that nivolumab can be safely administered using a shorter 
infusion time (30 minutes) is under investigation. The safety of nivolumab 3 mg/kg administered 
as a 30-minute infusion was assessed in CA209153 in participants with previously treated 
advanced NSCLC. Overall, there were no clinically meaningful differences in the frequency of 
hypersensitivity/infusion-related reactions (of any cause or treatment-related) in participants 
administered nivolumab over a 30 min infusion compared with that reported for participants with 
the 60 min infusion. An infusion duration of 30 minutes for 1 mg/kg nivolumab and nivolumab 
480 mg (~ 60% of the dose provided at 10 mg/kg) is not expected to present any safety concerns 
compared to the prior experience at 10 mg/kg nivolumab dose infused over a 60-minute duration. 
As of Sep 2016, 4 patients in the nivolumab clinical development programs have received 
nivolumab 480 mg Q4W for at least 1 dose. Clinical evaluation of this dose regimen is in its early 
stages and no safety summary is available. BMS has a clinical safety program that monitors 
symptoms potentially related to infusion-related reactions reported on the day of infusion and the 
following day. For the 4 patients treated with 480 mg nivolumab as a 30-minute infusion, there 
have been no reports of any symptoms that may potentially be linked to infusion reactions on the 
day of infusion or the following day.
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3.1.9
Rationale for 360 mg Flat Dose Nivolumab plus Gemcitabine-Cisplatin 
Chemotherapy (Substudy, Arm C)
The interaction of a tumor with the immune system is complex. Tumors and the tumor 
microenvironment are known to express a variety of factors that impede a robust immune response 
from eliminating the tumor. Soluble and membrane-bound factors have been shown to inhibit the 
cytolytic activity of tumor infiltrating T-cells (e.g., PD-L1 expression; TGF-beta). In addition, 
some tumor-derived factors are able to enhance immune system counter-regulatory systems (e.g., 
increased T-regulatory cells). Finally, suboptimal tumor antigen delivery and presentation has been 
postulated as another mechanism by which tumors can successfully evade immune system 
recognition.
Cancer therapeutics such as chemotherapy may modulate tumor/immune-system interactions in 
favor of the immune system. Chemotherapy can result in tumor cell death with a resultant increase 
in tumor antigen delivery to antigen-presenting cells. Tumor cell death may also lead to a reduction 
in soluble and membrane-bound factors inhibiting tumor-infiltrating T-cells. Chemotherapy may 
also disrupt immune system regulatory networks by decreasing numbers of T-regulatory cells.
Nivolumab added to chemotherapy has been evaluated in several cohorts of chemotherapy-naive 
patients with advanced NSCLC in study CA209012. Nivolumab 10 mg/kg was combined with 
gemcitabine + cisplatin and pemetrexed + cisplatin. Nivolumab 10 mg/kg, and 5 mg/kg, were
combined with paclitaxel and carboplatin. 
The safety profile of nivolumab combined with platinum-doublet chemotherapy reflects additive 
toxicities of the individual agents, which were manageable using established safety guidelines 
(Table 3.1.9-1). The frequency of most immune-related select AEs was higher than what has been 
observed for nivolumab monotherapy. However, these treatment-related AEs, including 
pneumonitis, were effectively managed and did not lead to any deaths.
Table 3.1.9-1:
Treatment-related AEs Reported in ( 10% of all NSCLC Patients
Treated with Nivolumab plus Platinum-based Chemotherapy
Treatment-related AE, n (%)
Total (n=56)
All Grades
Grade 3/4
Patients with any AE
53 (95)
25 (45)
Fatigue
40 (71)
3 (5)
Nausea
26 (46)
1 (2)
Decreased appetite
20 (36)
1 (2)
Alopecia
17 (30)
0
Anemia
15 (27)
2 (4)
Rash
14 (25)
2 (4)
Diarrhea
12 (21)
1 (2)
Arthralgia
12 (21)
0
Constipation
11 (20)
0
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Table 3.1.9-1:
Treatment-related AEs Reported in ( 10% of all NSCLC Patients
Treated with Nivolumab plus Platinum-based Chemotherapy
Treatment-related AE, n (%)
Total (n=56)
All Grades
Grade 3/4
Peripheral neuropathy
11 (20)
0
Dysgeusia
8 (14)
0
Hypersensitivity
8 (14)
1 (2)
Vomiting
8 (14)
0
Mucosal inflammation
7 (12)
0
Myalgia
7 (12)
0
Pneumonitis
7 (12)
4 (7)
Infusion-related reaction
6 (11)
0
Leukopenia
6 (11)
0
Lymphopenia
6 (11)
0
Peripheral sensory neuropathy
6 (11)
0
Pruritus
6 (11)
0
Treatment related AEs leading to discontinuation
11(2)
The observed response rates of nivolumab and chemotherapy (Table 3.1.9-2) were similar to that 
of platinum-doublet chemotherapy alone, though the duration of responses is longer. The median 
duration of response across all the nivolumab + chemotherapy cohorts was 27.3 weeks. The 1-year 
survival rate for all cohorts combined is 71%.
Table 3.1.9-2:
Efficacy in First-Line Nivolumab + Chemotherapy
Nivo/Gem/Cis
(n=12)
Nivo/Pem/Cis
(n=15)
Nivo/Pac/Carbo
(n=29)
Nivo/Chemo
(n=56)
ORR, n (%)
4 (33%)
7 (47%)
13 (45%)
24 (43%)
Median DOR 
(wks)
45
24.4
27.3
27.3
PFS rate at 24 wks
51%
71%
43%
52%
Median PFS (wks)
24.7
29.7
21.4
24.7
OS rate at 12 mos
50%
87%
72%
71%
OS rate at 18 mos
33%
60%
62%
55%
Median OS (wks)
50.5
83.4
89.6
83.4
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Participants will be evaluated with the combination of nivolumab and chemotherapy 
(gemcitabine+cisplatin) as follows:
•
Cisplatin-eligible metastatic urothelial carcinoma participants (Sub-study, Arm C)
−
nivolumab + gemcitabine with cisplatin (up to 6 cycles), followed by nivolumab 
maintenance therapy for those without disease progression following combination therapy
NOTE: The chemotherapy backbone is as in Arms B and D 
As the PK of nivolumab is linear, the corresponding flat dose of nivolumab for an every 6-week 
schedule is 360 mg. The simulated steady state concentration at trough (Cminss), peak (Cmaxss), and 
average (Cavgss) with 480 mg are less than 10 mg/kg every 2 weeks. Thus, these regimens are 
expected to be safe and tolerable.
3.2
Background
3.2.1
Bladder Cancer
UC of the bladder is the ninth most common cancer in the world (1)1, and the fifth most common 
malignancy in the United States.2 Approximately 20% to 25% of all patients with UC of the 
bladder develop metastatic disease, resulting in an estimated 15,580 deaths in 2014 in the United 
States.3 Nonmuscle-invasive tumors account for 75–85% of bladder neoplasms while the 
remaining 15–25% are muscle-invasive or metastatic at the time of initial presentation.37 In 2015, 
an estimated 74,000 patients were diagnosed with bladder cancer in the USA and approximately 
16,000 patients succumbed to the disease. Bladder cancer is more common in men with nearly a 
3:1 incidence. The vast majority of cases are urothelial carcinoma (previously known as 
transitional cell carcinoma) while mixed histologies and pure variant histologies, such as 
adenocarcinoma and squamous cell carcinoma, comprise a smaller subset.2 While urothelial 
cancers predominantly arise in the bladder, given that the urothelium extends from the renal pelvis 
to the urethra, such cancers can arise from any of these locations in the genitourinary tract. Once 
invasive into the muscularis propria, urothelial cancer of the bladder is an aggressive disease that 
requires multimodal treatment with surgery or radiation therapy with or without chemotherapy. 
Despite multimodality treatment, more than 50% of patients will develop metastatic disease. The 
median survival of patients with metastatic urothelial cancer of the bladder is only 12–14 months.12
Chemotherapy is standard treatment for metastatic UC. Cisplatin is among the most active 
agents in UC and cisplatin-based combination chemotherapy is the treatment of choice for patients 
with metastatic urothelial bladder cancer. Commonly used regimens such as gemcitabine plus 
cisplatin or MVAC (methotrexate, vinblastine, doxorubicin, plus cisplatin) yield objective 
responses in 50% to 60% of patients, with complete responses in 10% to 20%. However, 
gemcitabine and cisplatin treatment was associated with a better safety profile and improved 
tolerability and has become a standard regimen for patients with metastatic UC. 
Treatment of cisplatin-ineligible or “unfit” patients. In clinical practice, more than 50% of all 
patients with unresectable or metastatic UC have contraindications for treatment with cisplatin. 
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Renal dysfunction (usually defined as a creatinine clearance of < 60 ml/minute), poor performance 
status, and advanced age are relatively common and preclude cisplatin chemotherapy. While no 
standard treatment has been defined for cisplatin-unfit patients, carboplatin-containing regimens 
are considered appropriate alternatives vs cisplatin-based therapy, based on performance status 
and kidney function defined by GFR. Although the combination of gemcitabine plus carboplatin 
is commonly used in cisplatin-ineligible patients, patients who are not candidates for cisplatin-
containing chemotherapy regimens have significantly worse outcomes with regard to response to 
treatment and OS, and there is no consensus on the standard chemotherapy treatment for cisplatin-
unfit patients. 
To date, combination regimens that do not include cisplatin have never been shown to improve 
survival. Despite the initial chemosensitivity of UC of the bladder, responses generally are short-
lived; the median survival of patients with metastatic disease is approximately 14 months. Visceral 
metastases and poor performance status are adverse prognostic factors associated with a lower 
likelihood of response to chemotherapy and shorter survival.
3.2.2
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.38,39,40
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor (TCR).41 Collectively, these signals govern 
the balance between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA 4, ICOS, and BTLA. 42 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also been 
noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.43 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-
4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
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of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a CMV 
re stimulation assay with human PBMC, the effect of nivolumab on antigen specific recall response 
indicates that nivolumab augmented IFN-γ secretion from CMV specific memory T cells in a dose-
dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine analog 
of nivolumab enhances the anti-tumor immune response and result in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).44
3.2.3
Ipilimumab Mechanism of Action
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin superfamily that competes with CD28 for B7. CTLA-4 mediated signals are 
inhibitory and turn off T cell-dependent immune responses. 45 Ipilimumab is a fully human 
monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from human 
and nonhuman primates. The proposed mechanism of action for ipilimumab is interference of the 
interaction of CTLA-4 with B7 molecules on APCs, with subsequent blockade of the inhibitory 
modulation of T-cell activation promoted by the CTLA 4/B7 interaction.
3.2.4
Nivolumab plus Ipilimumab Evidence
The combination of nivolumab and ipilimumab was chosen because of preclinical and clinical 
evidence supporting synergy between these two established checkpoint blockade inhibiting 
monoclonal antibodies. 
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN-γ
production 2-fold to 7-fold over either agent alone in a mixed lymphocyte reaction.46 Several 
preclinical syngeneic tumor models showed that combined treatment with anti-murine PD-1 and 
anti-murine CTLA-4 monoclonal antibody (mAb) resulted in increased antitumor responses over 
either mAb alone which were greatest when the antibodies were given together rather than 
sequentially.46 In some instances, combined treatment resulted in tumor-free mice that exhibited 
long-lived tumor immunity when re-challenged with tumor cells.46 In a murine melanoma vaccine 
model, blockade with either CTLA-4 or PD-1 antibodies increased the proportion of CTLA-4 and 
PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and dual blockade increased tumor 
infiltration of T effector cells and decreased intratumoral T regulatory cells, as compared to either 
agent alone.47
The combination of nivolumab and ipilimumab was initially studied in participants with 
unresectable or metastatic melanoma in the Phase 1 dose escalation study CA209004. In this study, 
the 3 mg/kg nivolumab plus 3 mg/kg ipilimumab dosing regimen exceeded the maximum tolerated 
dose (MTD) per protocol.48 In CA209004, while both Cohort 2 (1 mg/kg nivolumab + 3 mg/kg 
ipilimumab) and Cohort 2a (3 mg/kg nivolumab + 1 mg/kg ipilimumab) had similar clinical 
activity, a dose of 1 mg/kg nivolumab every 3 weeks combined with 3 mg/kg of ipilimumab every 
3 weeks for a total of four doses, followed by nivolumab 3 mg/kg every 2 weeks until progression 
was chosen.46 This dose level has been approved in participants with advanced melanoma in the 
US based on the Phase 3 study CA209067 which demonstrated that the combination of nivolumab 
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and ipilimumab had increased benefit compared to either nivolumab or ipilimumab monotherapy 
in participants with advanced melanoma.49
The combination of nivolumab with ipilimumab is being studied in the Phase 1 study CA209016.50
Participants with mRCC (favorable/intermediate MSKCC score; Karnofsky performance 
status > 80%; untreated or any number of prior therapies) were randomized to receive 
•
nivolumab 3 mg/kg + ipilimumab 1 mg/kg (arm N3 + I1) or 
•
nivolumab 1 mg/kg + ipilimumab 3 mg/kg (arm N1 + I3) IV Q3W for 4 doses followed by
nivolumab 3 mg/kg IV Q2W until progression/toxicity.
The primary objective was to assess safety/tolerability; secondary objective was to assess 
antitumor activity. Participants were randomized to N3 + I1 (n = 21) and N1 + I3 (n = 23). Most 
patients (n = 34; 77%) had prior systemic therapy (N3 + I1: 16; N1 + I3: 18). The confirmed ORR 
was 43% (N3 + I1) and 48% (N1 + I3). Duration of response (DOR) was 4.1+ to 42.1+ weeks 
(7 of 9 responses ongoing) in N3 + I1, and 12.1+ to 35.1+ weeks (9 of 11 responses ongoing) in 
N1 + I3. Best response of stable disease (SD) was seen in 5 (24%) patients (N3 + I1) and 8 (35%) 
pts (N1 + I3). Median PFS was 36.6 weeks (N3 + I1) and 38.3 weeks (N1 + I3); these data are still 
immature, with 11 of 21 events reported for N3 + I1 and 10 of 23 events reported for N1 + I3.51
The safety of nivolumab combined with ipilimumab was assessed in study CA209016.
Treatment-related adverse events (AEs) were seen in 83 of 94 patients (88%), including 39 of 
47 (83%) in N3 + I1 and 44 of 47 (94%) in N1 + I3. The most frequently reported drug-related
AEs in participants treated with 3 mg/kg nivolumab + 1 mg/kg ipilimumab included fatigue
(23 participants, 48.9%), rash and pruritus (12 participants, 25.5% each), and diarrhea and
nausea (11 participants, 23.4% each); the majority were Grade 1- 2. The most frequently reported
drug-related AEs in participants treated with 1 mg/kg nivolumab + 3 mg/kg ipilimumab included
fatigue (30 participants, 63.8%); nausea and diarrhea (20 participants, 42.6% each), and lipase
increased (16 participants, 34.0%). The majority were Grade 1-2.
Treatment-related AEs leading to discontinuation (21% vs 11%), and treatment-related SAEs 
(34% vs 21%) all occurred more commonly in participants in the N1 + I3 arm than in the N3 + I1 
arm, respectively.51
In the Phase 1 study CA209004, ascending doses of nivolumab have been studied concomitantly 
with ascending doses of ipilimumab in participants with unresectable or metastatic melanoma.
In each arm in this multi-arm study, ipilimumab was administered once every 3 weeks for 4 doses
with nivolumab administered once every 3 weeks for 8 doses. Starting at week 24, ipilimumab
and nivolumab were administered once every 12 weeks for 8 doses. The 3 initial
dose-escalation cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg plus ipilimumab 3 mg/kg;
n = 14), Cohort 2 (nivolumab 1.0 g/kg plus ipilimumab 3 mg/kg; n = 17) and Cohort 3 (nivolumab 
3.0 mg/kg plus ipilimumab 3 mg/kg; n = 6). Later, the study was amended to include Cohort 2a 
which evaluated nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (n = 16).
As of the 15-Feb-2013 clinical cut-off in CA209004, of the 52 participants evaluable for
response, 21 participants (40%) had an objective response by modified World Health
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Organization (mWHO) criteria. In an additional 2 participants (4%) there was an unconfirmed 
objective response. In Cohort 1 (0.1 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of
14 evaluable participants had an objective response by mWHO (21%); 1 complete response 
(CR) and 2 participants with a partial response (PR) with an additional PR observed by
immune-related mWHO criteria (irPR). 52 In Cohort 2 (1 mg/kg nivolumab + 3 mg/kg
ipilimumab), 9 out of 17 evaluable participants had an objective response by mWHO (53%;
3 CRs (18%), 6 PRs (35%) with two additional participants experiencing immune-related
SD (irSD). In Cohort 2a (3 mg/kg nivolumab + 1 mg/kg ipilimumab), 6 out of 15 response
evaluable participants had an objective response rate by mWHO (40%; 1 CR (7%), 5 PRs
(33%) with 2 additional uPRs (13%) and 2 irSDs and 1 irPR). In Cohort 3 (3 mg/kg nivolumab 
+ 3 mg/kg ipilimumab), 3 out of 6 evaluable participants had an objective response by mWHO
(50%; 3 PRs (50%) with 1 additional irPR and 1 irSD.
Preliminary analysis revealed 16 of the 52 evaluable participants (31%) had > 80% reduction in
the size of target tumor lesions by the week 12 evaluation. This is compared to < 2% for
3 mg/kg ipilimumab monotherapy based on CA184020 (N = 540) and < 3% for nivolumab
monotherapy based on CA209003 (N = 94, 0.1-10 mg/kg).
The following DLTs were observed in Cohort 1 - Grade 3 elevated AST/ALT (1 participant);
in Cohort 2 - Grade 3 uveitis (1 participant) and Grade 3 elevated AST/ALT (1 participant)
and
in Cohort 3 - Grade 4 elevated lipase (2 participants) and Grade 3 elevated lipase
(1 participant). Based on these data, Cohort 2 was identified as the maximum tolerated dose 
(MTD) and Cohort 3 exceeded the MTD.
A total of 53 melanoma participants were treated with nivolumab combined with ipilimumab in
CA209004 across cohorts 1, 2, 2a, and 3. At least one AE regardless of causality has been
reported in 98% of participants treated. The most common (reported at > 10% incidence)
treatment related AEs (any Grade %; Grade 3-4 %: 93; 53) are rash (55; 4), pruritus (47; 0), 
vitiligo (11; 0), fatigue (38; 0), pyrexia (21, 0), diarrhea (34; 6), nausea (21, 0), vomiting (11, 2), 
ALT increased (21; 11), AST increased (21; 13), lipase increased (19; 13), amylase increased 
(15, 6), headache (11, 0), and cough (13, 0).
The majority of AEs
leading to discontinuation (regardless of causality) were Grade 3 or 4 
(reported in 11 of 53 participants, 21%). Grade 3 events included lipase increased, ALT
increased, AST increased, troponin I increased, colitis, diverticular perforation, pancreatitis,
tachycardia, renal failure acute, choroiditis, autoimmune disorder, and pneumonitis. One
participant each discontinued due to Grade 4 events of blood creatinine increased and AST
increased. No drug-related deaths were reported.53
3.3
Benefit/Risk Assessment
3.3.1
Benefit/Risk Assessment for Primary Study
Metastatic UC is an aggressive disease; patients have a median survival of approximately
15 months when treated with modern chemotherapy regimens. While objective response rates to 
frontline therapy are generally high, nearly all patients with metastatic, unresectable UC will 
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progress. Therefore, new therapeutic options that will result in durable responses are urgently 
needed in metastatic UC. Several lines of evidence, as outlined in Section 3.1.2, strongly support 
the investigation of immunotherapy agents to improve outcomes for patients with metastatic,
unresectable UC.
Safety and efficacy have been demonstrated with both single agent nivolumab and ipilimumab. 
The combination of dual check-point blockade with both of these agents administered together has 
an efficacy advantage over either single agent alone. Same day sequential administration of 
nivolumab (1 mg/kg) followed by ipilimumab (3 mg/kg) was initially evaluated in 
advanced/metastatic melanoma in 2 studies, the Phase 2 study CA209069 and the Phase 3 study 
CA209067, and demonstrated statistically significant and clinically meaningful improvements in 
progression-free survival (PFS) and objective response rate (ORR) compared to nivolumab or 
ipilimumab monotherapy.51,54 and served as the basis for an application to extend the indication 
of Opdivo® to include the use of nivolumab and ipilimumab in combination for the treatment of 
advanced melanoma (United States Packaging Insert [USPI] for nivolumab and Summary of 
Product Characteristics [SmPC] for nivolumab). Subsequently, nivolumab plus ipilimumab has 
also demonstrated clinical activity in several tumor types, including renal cell cancer (RCC),55
NSCLC,56 small cell lung cancer (SCLC),57 and gastric cancer.58
Results to date suggest that the safety profile of nivolumab plus ipilimumab combination therapy 
is consistent with the mechanisms of action of nivolumab and ipilimumab. The nature of the AEs 
is similar to that observed with either agent used as monotherapy; however, both frequency and 
severity of most AEs are increased with the combination. The adverse event profile of nivolumab 
1 mg/kg combined with ipilimumab 3 mg/kg characterized by immune-related toxicities, such as 
diarrhea, rash, pneumonitis, liver toxicity, and endocrinopathies. These events were mostly low 
grade and manageable with well-established treatment algorithms that included the use of 
corticosteroids.
Extensive details on the safety profile of nivolumab are available in the Investigator Brochure, and 
will not be repeated herein.
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical trials with no MTD 
reached at any dose tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively 
few related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level.
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 5. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed 
in these algorithms. 
Additional details on the safety profile of nivolumab, and ipilimumab, including results from other 
clinical studies, are also available in the nivolumab IB51 and ipilimumab IB,59 respectively.
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3.3.2
Benefit/Risk Assessment for Substudy
The potential benefit of nivolumab, (which was recently approved by FDA for advanced or 
metastatic UC patients who progressed on first line or recent peri-operative platinum therapy) in 
combination with platinum-doublet chemotherapy over standard-of-care platinum-based first-line 
chemotherapy is supported by both CheckMate 012 as well as data with other PD-1 inhibitors, eg 
pembrolizumab in Keynote 021. The response rate observed from the two studies ranges from 33% 
to 55% regardless of PD-L1 expression levels. In KN021, which to date is the only randomized 
study, albeit with a very small sample size, the addition of a PD-1 inhibitor significantly increased 
ORR and prolonged PFS. All published data to date indicate that a similar magnitude of benefit is 
observed with IO/chemo combinations regardless of PD-L1 expression level. Together, these data 
suggest that addition of nivolumab to platinum-doublet chemotherapy could provide benefit over 
doublet alone in a broad population of patients. The platinum-based chemotherapy regimens have 
similar clinical activity and well described safety profiles, characterized by myelosuppression and 
other 
regimen-specific 
non-hematologic 
toxicities, 
such 
as 
peripheral 
neuropathy, 
nausea/vomiting, and renal impairment. The safety profile of PD-1 agent plus platinum-doublet 
chemotherapy reflects additive toxicities of the individual agents, which were manageable using 
established safety guidelines. The frequency of most immune-related, select AEs was higher with 
nivolumab/pembrolizumab plus platinum-doublet chemotherapy compared to platinum-doublet. 
However, these treatment-related AEs, including pneumonitis, were effectively managed and did 
not lead to any deaths.
The potential benefit of nivolumab combined with platinum-doublet chemotherapy in the 
treatment of cisplatin-eligible metastatic UC patients compared to SOC platinum-based first-line 
chemotherapy, will be evaluated in Arms C and D of the sub-study as follows: nivolumab 
combined with platinum-doublet chemotherapy (Arm C), or platinum doublet chemotherapy (Arm
D), stratified by PD-L1 status < 1%, cisplatin-eligibility, and liver metastasis.
To assure an ongoing favorable risk/benefit assessment for participants enrolled onto CA209901, 
an independent Data Monitoring Committee (DMC) will be utilized to monitor the safety and 
clinical activity of the treatments throughout the conduct of the trial, until the primary end-point 
for the sub-study is reached (See Section 5.5.1).
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints: Primary Study
Objectives
Endpoints
Primary
•
To compare Overall Survival (OS) of nivolumab combined 
with ipilimumab versus standard of care (SOC) chemotherapy 
in cisplatin-ineligible participants with previously untreated, 
unresectable or metastatic urothelial carcinoma (UC).
•
Primary endpoint of OS in 
cisplatin-ineligible randomized 
participants 
•
To compare OS of nivolumab combined with ipilimumab 
versus standard of care (SOC) chemotherapy in PD-L1 positive 
(≥1%) participants with previously untreated, unresectable or 
metastatic UC.
•
Primary endpoint of OS in PD-L1 
positive (≥1%) randomized
participants by
immunohistochemistry (IHC)
Secondary
•
To compare OS of nivolumab combined with ipilimumab 
versus SOC chemotherapy in all randomized participants with 
previously untreated, unresectable or metastatic UC.
•
OS in all randomized participants 
•
To evaluate Progression-Free Survival (PFS) of nivolumab 
combined with ipilimumab versus SOC chemotherapy in 
cisplatin-ineligible randomized participants, in PD-L1 positive 
(≥1%) randomized participants and in all randomized 
participants with previously untreated, unresectable or 
metastatic UC.
•
PFS by blinded independent 
central review (BICR) (using 
RECIST 1.1) in cisplatin-ineligible 
randomized participants, in PD-L1 
positive (≥1%) randomized 
participants and in all randomized 
participants
•
To evaluate changes from baseline in Health-Related QOL 
(HRQoL) of nivolumab combined with ipilimumab versus 
SOC chemotherapy in all randomized participants with 
previously untreated, unresectable or metastatic UC.
•
European Organisation for 
Research and Treatment of Care 
(EORTC) QLQ-C30 Global Health 
Status score in all randomized 
participants
Exploratory
•
To estimate objective response rate (ORR) (using RECIST 1.1) 
of nivolumab combined with ipilimumab versus SOC 
chemotherapy. 
•
ORR by BICR (using RECIST 1.1)
•
To assess the efficacy (OS, PFS, and ORR) of nivolumab 
combined with ipilimumab versus SOC chemotherapy in 
cisplatin-eligible participants with previously untreated, 
unresectable or metastatic UC.
•
OS, PFS, and ORR by BICR 
(using RECIST 1.1) in cisplatin-
eligible participants with 
previously untreated, unresectable 
or metastatic UC
•
To assess the safety and tolerability of nivolumab combined
with ipilimumab versus SOC chemotherapy.
•
AEs, clinical laboratory values, 
vital signs, or other safety 
biomarkers
•
To assess changes in reported global health outcomes based on 
EuroQol’s EQ-5D-5L.
•
EQ-5D-5L index score, EQ-5D-5L
dimensions (mobility, self-care, 
usual activities, pain/discomfort, 
and anxiety), and EQ-5D-5L visual 
analog scale (VAS).
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Table 4-1:
Objectives and Endpoints: Primary Study
Objectives
Endpoints
•
To evaluate HRQoL as assessed by EORTC QLQ-C30.
•
QLQ-C30 Functional scales; QLQ-
C30 Symptom scales
•
To evaluate whether PD-L1 expression is a predictive 
biomarker of efficacy (ORR) of nivolumab combined with 
ipilimumab as first-line therapy in participants with previously 
untreated, unresectable or metastatic UC.
•
ORR by BICR (using RECIST 1.1)
by PD-L1 expression at ≥1% 
expression by 
immunohistochemistry (IHC)
•
To characterize the pharmacokinetics of nivolumab combined 
with ipilimumab as first-line therapy in participants with 
previously untreated, unresectable or metastatic UC.
•
PK parameters, exposure-response 
relationship between select PK 
measures of exposure and safety 
and efficacy endpoints, if 
applicable
•
To characterize the immunogenicity of nivolumab combined 
with ipilimumab as first-line therapy in participants with 
previously untreated, unresectable or metastatic UC.
•
Incidence of anti-nivolumab and 
anti-ipilimumab antibody levels 
and their potential relationship 
with safety and efficacy endpoints 
•
To evaluate the pharmacodynamic and immunomodulatory 
activity of nivolumab combined with ipilimumab.
•
Including but not limited to 
correlative analyses between gene 
expression profiling, flow 
cytometric analyses of peripheral 
blood mononuclear cells (PBMCs), 
myeloid derived suppressor cells
and serum soluble factor analysis 
in peripheral blood samples and 
ORR, PFS, and OS
•
To investigate the association between biomarkers in the 
peripheral blood and tumor tissue with efficacy.
•
Including but not limited to 
correlative analyses between 
baseline and on-treatment soluble 
factors (eg, CXCL9, CXCL10, 
gamma interferon signature, 
baseline PD-L1/PD-L2, mutational 
analyses in tumor tissue) with 
ORR, PFS, and OS
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Table 4-2:
Objectives and Endpoints: Substudy
Objectives
Endpoints
Primary
•
To compare PFS of nivolumab combined with SOC 
chemotherapy versus SOC chemotherapy in cisplatin-
eligible participants with previously untreated, 
unresectable or metastatic urothelial carcinoma (UC) 
•
To compare OS of nivolumab combined with SOC 
chemotherapy versus SOC chemotherapy in cisplatin-
eligible participants with previously untreated,
unresectable or metastatic UC
•
PFS by BICR (using RECIST 1.1) in 
cisplatin-eligible participants with
previously untreated, unresectable or 
metastatic UC
•
OS in cisplatin-eligible participants with 
previously untreated, unresectable or 
metastatic UC
Secondary
•
To evaluate changes from baseline in Health-Related 
QOL (HRQoL) of nivolumab combined with SOC 
chemotherapy versus SOC chemotherapy in cisplatin-
eligible participants with previously untreated,
unresectable or metastatic UC.
•
European Organisation for Research and 
Treatment of Care (EORTC) QLQ-C30 
Global Health Status score
•
To evaluate whether PD-L1 expression is a predictive 
biomarker of efficacy (PFS and OS) of nivolumab 
combined with SOC chemotherapy as first-line
therapy in cisplatin-eligible participants with 
previously untreated, unresectable or metastatic UC.
•
PFS by BICR (using RECIST 1.1) and OS 
by PD-L1 expression at ≥1% expression by 
immunohistochemistry (IHC)
Exploratory
•
To estimate ORR (using RECIST 1.1) of nivolumab 
combined with SOC chemotherapy versus SOC 
chemotherapy. 
•
ORR by BICR (using RECIST 1.1)
•
To assess the safety and tolerability of nivolumab 
combined with SOC chemotherapy versus SOC 
chemotherapy.
•
AEs, clinical laboratory values, vital signs,
or other safety biomarkers
•
To assess changes in reported global health outcomes 
based on EuroQol’s EQ-5D-5L.
•
EQ-5D-5L index score, EQ-5D-5L
dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety), 
and EQ-5D-5L VAS.
•
To evaluate HRQoL as assessed by EORTC QLQ-
C30.
•
QLQ-C30 Functional scales; QLQ-C30 
Symptom scales
•
To evaluate whether PD-L1 expression is a predictive 
biomarker of efficacy (ORR) of nivolumab combined 
with SOC chemotherapy as first-line therapy in
participants with previously untreated, unresectable or 
metastatic UC.
•
ORR by BICR (using RECIST 1.1) PD-L1 
expression at ≥1% expression by 
immunohistochemistry (IHC)
•
To characterize the pharmacokinetics of nivolumab 
combined with SOC chemotherapy as first-line
therapy in participants with previously untreated, 
unresectable or metastatic UC.
•
PK parameters, exposure-response 
relationship between select PK measures of 
exposure and safety and efficacy endpoints, 
if applicable
•
To characterize the immunogenicity of nivolumab 
combined with SOC chemotherapy as first-line
therapy in participants with previously untreated, 
unresectable or metastatic UC.
•
Incidence of anti-nivolumab antibody levels 
and their potential relationship with safety 
and efficacy endpoints 
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Table 4-2:
Objectives and Endpoints: Substudy
Objectives
Endpoints
•
To evaluate the pharmacodynamic and 
immunomodulatory activity of nivolumab combined 
with SOC chemotherapy.
•
Including but not limited to correlative 
analyses between gene expression profiling, 
flow cytometric analyses of PBMCs, 
myeloid derived suppressor cells and serum 
soluble factor analysis in peripheral blood 
samples and ORR, PFS, and OS
•
To investigate the association between biomarkers in 
the peripheral blood and tumor tissue with efficacy.
•
Including but not limited to correlative 
analyses between baseline and on-treatment 
soluble factors (eg, CXCL9, CXCL10, 
gamma interferon signature, baseline PD-
L1/PD-L2, mutational analyses in tumor 
tissue) with ORR, PFS, and OS
5
STUDY DESIGN
5.1
Overall Design
This will be a randomized, open-label, Phase 3 study comparing combination therapy of nivolumab 
(1 mg/kg 30 minute IV infusion) plus ipilimumab (3 mg/kg 30 minute IV infusion) administered 
every 3 weeks for up to four doses, followed by nivolumab monotherapy (480 mg 30 minute IV 
infusion) administered every 4 weeks, versus the standard of care (SOC; gemcitabine-cisplatin or 
gemcitabine-carboplatin) in participants with previously untreated unresectable or metastatic UC. 
In addition a substudy of treatment with nivolumab (360 mg) in combination with SOC (cisplatin-
gemcitabine) for up to 6 cycles followed by nivolumab monotherapy (480 mg) versus SOC alone
(up to 6 cycles) will be evaluated in cisplatin-eligible participants with previously untreated 
unresectable or metastatic UC will be evaluated.
Primary Study:
Prior to initiation of the substudy, participants will be randomized 1:1 to treatment Arm A or B
and stratified by PD-L1 status < 1%, cisplatin-eligibility, and liver metastasis.
•
Arm A (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg [N1 + I3], followed by nivolumab 
monotherapy) 
•
Arm B (standard of care [SOC] platinum chemotherapy doublet, 3 week cycles, up to 6 cycles). 
Participants in Arm A will receive combination therapy (N1+I3) for up to 4 doses (Part 1), 
followed by nivolumab monotherapy (480 mg every 4 weeks; Part 2). Monotherapy will begin 
6 weeks following the last dose of combination therapy and continue until confirmed disease 
progression, unacceptable toxicity, or participant withdrawal of consent, or 24 months from first 
dose, whichever comes first. Participants randomized to Arm B may receive up to 6 cycles of SOC 
treatment (gemcitabine/cisplatin for cisplatin-eligible participants or gemcitabine/carboplatin for
cisplatin-ineligible participants, additional cycles may be permitted as per local guidelines). 
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In Part 1 of Arm A, a minimum of 1 combination cycle of nivolumab and ipilimumab is required 
before participants can proceed to monotherapy. Participants in Arm A experiencing AEs related 
to combination dose therapy that do not meet dose discontinuation criteria, may proceed to 
nivolumab monotherapy dosing (Part 2) without completing all 4 combination doses, after 
consultation with BMS Medical Monitor, on a case-by-case basis. In Arm B, participants assigned 
to receive cisplatin-gemcitabine, may be eligible to switch to carboplatin-gemcitabine following a 
minimum of 1 cycle of cisplatin-gemcitabine, and after consultation with the Medical Monitor. 
Substudy
The substudy consists of Arms C and D: 
•
Arm C: Nivolumab (360 mg) in combination with gemcitabine-cisplatin) every 3 weeks for up 
to 6 cycles, followed by nivolumab monotherapy (480 mg) every 4 weeks. Monotherapy will 
begin 3 weeks following the last dose of combination therapy and continue until confirmed 
disease progression, unacceptable toxicity, participant withdrawal of consent, or 24 months
from first dose, whichever comes first.
•
Arm D: Gemcitabine-cisplatin for up to 6 cycles (additional cycles may be permitted as per 
local guidelines).
Once the substudy is initiated, cisplatin-ineligible participants will continue to be randomized 1:1 
to Arms A or B. Cisplatin-eligible participants will be randomized across Arms A through D, and 
stratified by PD-L1 status < 1%, cisplatin-eligibility, and liver metastasis. Once approximately 445 
cisplatin-ineligible participants and 235 PD-L1 positive participants are enrolled into Arms A and 
B, enrollment of the primary study (Arms A and B) will stop (see Section 5.2). Only cisplatin-
eligible will continue to be enrolled into the substudy (Arms C and D).
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
a Arm A and Arm C: In Part 1, a minimum of 1 cycle of combination therapy is required before proceeding to nivolumab monotherapy dosing (Part 2). Participants
should be dosed no less than 19 days between combination treatment cycles for Arm A combination therapy.
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b In Arm A, monotherapy should begin 6 weeks following the last combination dose. In Arm C, monotherapy will begin 3 weeks following the last combination
therapy. During monotherapy participants should be dosed no less than 26 days between monotherapy treatments. Participants in Arms A and C will be 
treated until confirmed progression of disease, unacceptable toxicity, withdrawal of consent, or up to 24 months of treatment, whichever occurs first. 
c Arms B and D participants will receive up to a maximum of 6 cycles per protocol. Additional optional cycles of SOC may be given per local guidelines. See
Section 7.1.3.1.
NOTES: All participants will be randomized 1:1 to Arms A or B during the primary study, prior to substudy initiation. Following initiation of the substudy, 
cisplatin-eligible patients will be randomized to Arms, A, B, C or D. Cisplatin-ineligible patients are not eligible for Arms C and D treatment. 
Once at least 445 cisplatin-ineligible participants and at least 235 PD-L1 positive (≥1%) participants by IHC are randomized into Arms A and B of the primary 
study, the primary study will cease enrollment (Arms A and B). Cisplatin-eligible participants will continue enrollment into Arms C and D.
Randomized participants will be evaluated for progression beginning at Week 9 (± 1 week) and then every 8 weeks (± 1 week) for 48 weeks, followed by evaluations 
every 12 weeks thereafter, until progression or end of treatment, whichever occurs later.
Primary endpoints in the primary study: Overall Survival in cisplatin-ineligible participants and in PD-L1 positive (≥1%) participants by IHC; key secondary
endpoint: Overall Survival in all randomized participants (hierarchical testing procedure) and Progression Free Survival.
Primary endpoints in the substudy: Progression Free Survival and OS primary endpoints in cisplatin-eligible participants.
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5.1.1
Data Monitoring Committee and Other External Committees
A Data Monitoring Committee (DMC) will be established to provide oversight of safety and 
efficacy considerations in protocol CA209901. Additionally, the DMC will provide advice to the 
sponsor regarding actions the committee deems necessary for the continuing protection of 
participants enrolled in the study. The DMC will be charged with assessing such actions in light 
of an acceptable benefit/risk profile for nivolumab. The DMC will act in an advisory capacity to 
BMS and will monitor participant safety and evaluate the available efficacy data for the study. 
Details regarding the responsibilities of the DMC including frequency of meetings will be included 
in the DMC charter. The oncology therapeutic area of BMS has primary responsibility for design 
and conduct of the study.
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
5.1.1.1
Blinded Independent Central Review Committee
A blinded independent central review (BICR) will be utilized in this study for determination of 
BICR-assessed PFS and ORR endpoints. All available tumor assessment scans for all randomized
participants will be reviewed. Details of BICR procedures will be specified in the Imaging Manual.
Additional activities and medical monitoring to ensure participant safety include:
•
Education of investigators and representatives of the sponsor on the nivolumab AE profile and 
management of potential immune-related adverse events through well-defined treatment 
algorithms.
•
Ongoing safety monitoring by the BMS Medical Monitor, as well as assessment and review of 
safety signals across the entire nivolumab program through the BMS medical surveillance team 
(MST).
•
Appropriate contraceptive methods (as outlined in Appendix 6) and pregnancy testing during 
the mandatory contraceptive period.
5.2
Number of Participants
Assuming a 28% screen failure rate, it is estimated that approximately 1792participants with 
previously untreated unresectable or metastatic UC will be enrolled with approximately 1290
participants randomized to the primary study and substudy:
•
445 cisplatin-ineligible participants will be randomized in a 1:1 ratio to receive nivolumab plus 
ipilimumab vs SOC chemotherapy (primary study);
•
245 cisplatin-eligible participants will be randomized in a 1:1 ratio to receive nivolumab plus 
ipilimumab vs SOC chemotherapy (primary study);
−
Of these 690 primary study participants, 235 PD-L1 positive (≥ 1%) participants by IHC 
are expected to be randomized
•
600 cisplatin-eligible participants will be randomized in a 1:1 ratio to receive nivolumab plus 
SOC chemotherapy vs SOC chemotherapy (substudy).
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With revised protocol 04, randomization to the substudy is increased by 300 cisplatin eligible 
participates to ensure adequate power of dual primary endpoints OS and PFS.
Overall, approximately 445 cisplatin-ineligible participants (per eligibility criteria see Section 6.1) 
and 845 cisplatin-eligible participants will be randomized. Enrollment assumptions are a fixed 
accrual rate of 5 participants per month (2 cisplatin-ineligible participants per month) during the 
first 6 months, 14 participants per month (8 cisplatin-ineligible participants per month) between 6 
and 12 months, and 30 participants per months between 12 and 18 months (19 cisplatin-ineligible 
participants per month) and 37 participants per months thereafter (26 cisplatin-ineligible 
participants per month). In addition, as of month 11, cisplatin-eligible participants are equally 
randomized to both primary study and substudy. Therefore once enrollment in the primary study 
is closed, the accrual rate in the substudy is assumed to be 18 cisplatin-eligible participants per 
month.
Based on the above information, it will take approximately 28 months to randomize 690 
participants in the primary study (including 445 cisplatin-ineligible participants and 235 PD-L1 
positive (≥1%) participants), given that an estimated 34% of the participants randomized in the 
primary study would be PD-L1 positive, and 44 months from substudy initiation (ie, 54 months 
from first participants randomized in the study) to randomize 600 cisplatin-eligible participants in 
the substudy.
Details regarding sample size calculation are found in Section 10.1.
Once at least 445 cisplatin-ineligible participants and at least 235 PD-L1 positive (≥ 1%) 
participants by IHC are randomized into Arms A and B of the primary study, the primary study 
will cease enrollment (Arms A and B).
5.3
End of Study Definition
The start of the trial is defined as first participant first screening visit. End of trial is defined as last 
participant last visit on the Schedule of Activities. Study completion is defined as the final date on 
which data for the primary endpoint was or is expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
A 2-arm open-label, randomized study will be employed to hierarchically demonstrate that 
treatment with nivolumab combined with ipilimumab will improve overall survival (OS) in (i) the 
high unmet need, primary population of cisplatin-ineligible, previously untreated, unresectable or 
metastatic UC participants as compared to standard of care (SOC) gemcitabine-plus-carboplatin 
chemotherapy and the high unmet need, primary population of PD-L1 positive (≥ 1%), previously
untreated, unresectable or metastatic UC participants as compared to standard of care (SOC) 
gemcitabine-plus-carboplatin chemotherapy and (ii) all randomized participants as compared to 
SOC chemotherapy. The sample size of the primary study accounts for the comparison of the 
primary endpoint (OS) in the two primary populations (cisplatin-ineligible participants and PD-L1 
positive (≥1%) participants by IHC) followed by all randomized participants.
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5.4.1
Rationale for Duration of Treatment with Nivolumab and Ipilimumab
The optimal duration of immunotherapy is currently unknown. However, because immunotherapy 
engages the immune system to control the tumor, continuous treatment as is required with targeted 
agents or cytotoxic therapy may not be necessary.
Accumulating evidence from different clinical trials in different tumor types with nivolumab or 
nivolumab combined to ipilimumab indicates that most of the responses are generally occurring 
early, with a median time to response of 2-4 months. 60,61 A recent analysis in a melanoma study 
suggests the majority of patients who discontinue nivolumab and/or ipilimumab for toxicity 
maintain disease control in the absence of further treatment.62 Furthermore, a limited duration of 
ipilimumab including only 4 induction doses resulted in long term survival in patients with 
metastatic melanoma, with a sustained plateau in survival starting at around Year 3.63
For these reasons, in study CA209901, treatment with nivolumab will be given for up to 24 months 
in the absence of disease progression or unacceptable toxicity. Chemotherapy will be given as per 
the study dosing schedule. Participants who complete 24 months of nivolumab and have 
subsequent disease progression may reinitiate nivolumab at the same dose and schedule given 
previously on study and continue such treatment for up to 1 additional year provided criteria for 
treatment beyond progression (Section 7.4.5) are met. 
5.5
Justification for Dose
5.5.1
Rationale for Nivolumab and Ipilimumab Dose and Schedule
In CheckMate 032 (NCT01928394), an open-label, multicenter Phase 1/2 study of patients with 
metastatic UC who progressed after prior platinum-based therapy, patients with locally advanced 
or metastatic UC previously treated with platinum-based therapy for metastatic disease were 
included in the study. Patients were treated with either of two combination schedules, nivolumab 
1 mg/kg + ipilimumab 3 mg/kg (N1I3) or nivolumab 3 mg/kg + ipilimumab 1 mg/kg (N3I1) every 
3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 
monotherapy 3 mg/kg (N3) every 2 weeks. All patients were treated until disease progression or 
unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate 
(ORR) by RECIST v1.1. Secondary endpoints included safety, duration of response (DoR), and 
overall survival (OS).
Investigator-assessed ORR was 38.0%, 26.9%, and 25.6% in N1I3, N3I1 and N3 groups, 
respectively after a minimum follow-up of 7.9 months in N1I3 (n=92) group, 38.8 months in the 
N3I1 group (n=104) and 37.7 months in N3 group (n=78).64 The investigator- assessed median 
DOR was 22.93, 22.34, and 30.52 months in N1I3, N3I1, and N3 arms, respectively. The BICR 
assessed ORR was 37.0% and 20.5% in the N1I3 and N3 arms, respectively. The frequency of 
drug-related grade 3-4 adverse events were higher in both combination groups (39.1% in N1I3, 
30.8% in N3I1) than in the N3 group (26.9%). Treatment-related adverse events led to 
discontinuation in 13.0% (N1I3), 12.5% (N3I1), and 3.8% (N3) of patients. One death not related 
to disease progression was reported in the N3I1 group (pneumonitis), one was reported in the N3 
group (pneumonitis and thrombocytopenia), and none reported in the N1I3 group.
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Taken together, these data suggest that combination therapy with nivolumab and ipilimumab may 
provide the most favorable benefit-risk among the regimens studied and support the further 
development of the N1I3 combination as first-line therapy in metastatic UC.
5.5.2
Rationale for Flat Dose 480 mg Nivolumab every 4 weeks in Part 2 of 
Arms A and C (Nivolumab Monotherapy)
Nivolumab monotherapy has been extensively studied in a number of tumor types including 
NSCLC, melanoma, renal cell carcinoma (RCC), and colorectal cancer (CRC) with body weight 
normalized dosing (mg/kg). Nivolumab pharmacokinetics (PK) and exposures of participants in 
these studies have been characterized by population pharmacokinetic (PPK) analysis of data 
collected together with PK data from several Phase 1, 2, and 3 clinical studies of nivolumab 
monotherapy in solid tumors. PPK analyses have shown that the PK of nivolumab are linear, with 
dose proportional exposures over a dose range of 0.1 mg/kg to 10 mg/kg, and are similar across 
tumor types. Nivolumab clearance and volume of distribution were found to increase with 
increasing body weight, but the increase was less than proportional, indicating that a mg/kg dose 
represents an over-adjustment for the effect of body weight on nivolumab PK. Given the 
relationship between nivolumab PK and body weight, a flat dose is expected to lead to lower 
exposures in heavier participants, relative to the exposures in lighter participants. 
Using the PPK model, nivolumab steady-state trough, peak and time-averaged concentration 
(Cminss, Cmaxss, and Cavgss, respectively) were predicted for a flat nivolumab dose of 240 mg 
Q2W and compared to those following administration of 3 mg/kg Q2W in NSCLC, melanoma, 
and RCC participants. A dose of 240 mg nivolumab is identical to a dose of 3 mg/kg for 
participants weighing ~ 80 kg, which is the approximate median body weight of participants in the 
Phase 2 and 3 BMS clinical studies of nivolumab monotherapy. Using a PPK model, the overall 
distributions of nivolumab exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are comparable after 
treatment with either 3 mg/kg or 240 mg nivolumab. The predicted range of nivolumab exposures 
(median and 90% prediction intervals) resulting from a 240 mg flat dose across the 35 to 160 kg 
weight range is maintained well below the corresponding exposures observed with the well 
tolerated 10 mg/kg nivolumab Q2W dosage. Given the similarity of nivolumab PK across tumor 
types and the similar exposures predicted following administration of a 240 mg flat dose compared 
to 3 mg/kg, it is expected that the safety and efficacy profile of nivolumab following a flat dose 
will be similar to that of 3 mg/kg nivolumab dose.
Across the various tumor types in the BMS clinical program, nivolumab has been shown to be safe 
and well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab exposure 
produced by 3 mg/kg and efficacy has been found to be relatively flat. Taken together, the PK, 
safety, and efficacy data indicate that the safety and efficacy profile of flat nivolumab dose every 
2 weeks will be similar to that of a 3 mg/kg nivolumab every 2 weeks.
While 480 mg Q4W is predicted to provide greater (approximately 40%) maximum steady state 
concentrations and lower (approximately 15 to 20%) steady state trough concentrations, these 
exposures are predicted to be within the exposure ranges observed at doses up to 10 mg/kg Q2W 
used in the Phase 1 nivolumab clinical program, and are not considered to put participants at 
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increased risk. Similar to the nivolumab Q2W dosing monotherapy regimen, the exposures 
predicted following administration of nivolumab 480 mg Q4W, are on the flat part of the exposure-
response curves for previously investigated tumors, melanoma and NSCLC, and are not predicted 
to affect efficacy. Based on these data, nivolumab 480 mg Q4W is expected to have similar 
efficacy and safety profiles to nivolumab 3 mg/kg Q2W.
In this study, 6 weeks after the last combination dose is administered, participants will receive flat 
dose 480 mg nivolumab every 4 weeks (Q4W), which provides a more convenient dosing regimen 
for participants. Based on PK modeling and simulations, administration of nivolumab 480 mg 
Q4W will be started after steady state is achieved with the combination regimen.
Hence, doubling the dose of nivolumab from 240 mg to 480 mg would extend the dosing interval 
from 2 weeks to 4 weeks.
Thus, a flat dose of 480 mg every 4 weeks is recommended for investigation in the nivolumab 
monotherapy phase (Part 2) of this study.
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, tumor biopsies, and other requirements of the study.
2) Target Population
a) Histological or cytological evidence of metastatic or surgically unresectable transitional
cell carcinoma (TCC) of the urothelium involving the renal pelvis, ureter, bladder or 
urethra. Minor histologic variants (< 50% overall) are acceptable (TCC must be the 
dominant histology).
b) All participants must have measurable disease by CT or MRI per RECIST 1.1 criteria. See
Appendix 4.
c) Prior systemic chemotherapy for metastatic or surgically unresectable UC is not allowed.
NOTE: (i) Prior intravesical therapy is permitted if completed at least 4 weeks prior to the 
initiation of study treatment. (ii) Prior neoadjuvant chemotherapy, radiation or prior 
adjuvant platinum-based chemotherapy or radiation following radical cystectomy with 
recurrence ≥12 months from completion of therapy is permitted.
d) Participants ineligible for cisplatin-based chemotherapy will be defined by any one of the 
following criteria:
i.
Impaired renal function (glomerular filtration rate [GFR] ≥30 but < 60 mL/min); 
GFR should be assessed by direct measurement (ie, creatinine clearance) or, if not 
available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula)
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ii.
Common Terminology Criteria for Adverse Events (CTCAE) version 4, ≥Grade 2 
hearing loss (assessed per local standard of care) 
iii.
CTCAE version 4, ≥ Grade 2 peripheral neuropathy
Cisplatin-ineligible patients will receive gemcitabine-carboplatin treatment.
e) Participants eligible for Cisplatin-based chemotherapy must exhibit adequate renal 
function as follows:
GFR ≥60 mL/min (assessed by direct measurement (i.e. creatinine clearance) or, if not 
available, by calculation using the Cockcroft-Gault formula):
Female CrCl = [(140 - age in years) × weight in kg × 0.85] / [72 x serum creatinine in 
mg/dL]
Male CrCl = [(140 - age in years) × weight in kg × 1.00] / [72 x serum creatinine in mg/dL]
f)
Participants must provide a fresh tumor biopsy from the primary disease site or a metastatic 
site. If fresh tissue cannot be provided, a tissue block (or at least 15 FFPE slides), from the 
most recent surgical resection (eg, radical cystectomy) can be accepted if collected within 
2 years prior to enrollment period and the participant did not receive systemic anticancer 
agents or radiotherapy since collection of sample. The PD-L1 stained tissue sections will 
be assessed by a pathologist and membranous PD-L1 expression scored in tumor cells if a 
minimum of a hundred (100) evaluable tumor cells are present. Additional information 
regarding biopsy samples see Section 9.8.1. 
g) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1, See 
Appendix 2 for ECOG Performance Status Score
h) Adequate hematologic and liver function (using CTCAE v4). (All baseline laboratory 
requirements will be assessed and should be obtained within 14 days prior to 
randomization)
a)
WBC ≥ 2000/ȣL
b)
Neutrophils ≥ 1500/ȣL
c)
Platelets ≥100 × 103/ȣL
d)
Hemoglobin ≥ 9.0 g/dL
e)
AST ≤3 × ULN
f)
ALT ≤3 × ULN
g)
Total bilirubin ≤1.5 × ULN (except in participants with Gilbert Syndrome, who 
can have total bilirubin < 3.0 mg/dL).
i)
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 treated). If re-enrolled, the 
participant must be re-consented and inclusion/exclusion criteria reassessed.
j)
Prior palliative radiotherapy must have been completed at least 2 weeks prior to study drug 
administration. Participants must have measurable disease outside the radiation field to be 
eligible and the tumor sample be collected before (but not after) palliative RT if it is from 
the irradiated area. Participants with progression in a previously radiated field will also be 
eligible.
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3) Age and Reproductive Status
a) Males and Females, ages ≥18 years or age of majority 
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.
c) Women must not be breastfeeding.
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) plus 5 half-
lives of study treatment, plus 30 days (duration of ovulatory cycle) for a total of 5 months
post-treatment completion.
e) WOCBP must also agree to follow instructions for method(s) of contraception from the 
time of enrollment for the duration of treatment with chemotherapy plus 5 half-lives of 
chemotherapy plus 30 days (duration of ovulatory cycle) for a total of 30 days post 
treatment completion or a duration specified by the local labels of the chemotherapy drugs 
received, whichever is longer.
f)
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 6) for the duration of treatment with study 
treatment(s) plus 5 half-lives of the study treatment plus 90 days (duration of sperm 
turnover) for a total of 7 months post-treatment completion. In addition, male participants 
must be willing to refrain from sperm donation during this time. 
g) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with chemotherapy plus 5 half-
lives of chemotherapy plus 90 days (duration of sperm turnover) for a total of 90 days post 
treatment completion or a duration specified by the local labels of the chemotherapy drugs 
received, whichever is longer.
h) 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 6
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Target Disease Exceptions
a) Has disease that is suitable for local therapy administered with curative intent.
b) 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 4 weeks after treatment is complete and within 28 days prior to first dose of study 
drug administration. Cases must be discussed with the Medical Monitor. Brain lesions are 
not considered measurable disease. 
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c) There must also be no requirement for immunosuppressive doses of systemic 
corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study 
drug administration.
2) Medical History and Concurrent Diseases
a) 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, prostate cancer 
with evidence of undetectable Prostate Specific Antigen (PSA) or carcinoma in situ of the 
prostate, cervix or breast. 
b) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the participant to receive protocol therapy, or interfere with the interpretation 
of study results.
c) Participants must have recovered from the effects of major surgery requiring general 
anesthetic or significant traumatic injury at least 14 days before randomization or treatment 
assignment. 
d) Participants with active, known or suspected autoimmune disease. Participants with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition 
only requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll.
e) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 days 
of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 
10 mg daily prednisone equivalents are permitted in the absence of active autoimmune 
disease.
f)
Uncontrolled adrenal insufficiency.
g) New York Heart Association (NYHA) Functional Classification of Heart Failure: Class III 
or Class IV (Appendix 7)65
h) ECOG PS ≥2
i)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Participants with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as peripheral neuropathy after 
platinum based therapy, are permitted to enroll. 
j)
Dementia, altered mental status, or any psychiatric condition that would prohibit the 
understanding or rendering of informed consent or completing quality of life questionnaire.
k) 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. Sites in Germany see Appendix 9. 
l)
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
unstable angina pectoris, or psychiatric illness/social situations that would limit 
compliance with study requirements.
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m) Participants who have had a history of acute diverticulitis, intra-abdominal abscess, GI 
obstruction and abdominal carcinomatosis which are known risk factors for bowel 
perforation.
n) Participants with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity.
3) Physical and Laboratory Test Findings
a) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
ribonucleic acid (RNA) or hepatitis C antibody (HCV antibody) indicating acute or chronic 
infection.
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
5) Prior Investigational Agents
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) Use of an investigational agent within 4 weeks of Day 1 visit
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
c) Participants may not have received live/attenuated vaccines within 30 days prior to first 
study treatment.
d) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 2 
weeks prior to first study treatment.
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.
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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 (i.e., participant has not been randomized). If re-
enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening 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) and can consist of the following:
•
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.
In this protocol, investigational products are: 
•
Nivolumab
•
Ipilimumab
•
Gemcitabine
•
Cisplatin
•
Carboplatin
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 7-1:
Study Treatments for CA209901 
Product Description / Class and 
Dosage Form
Potency
IP/
Non-IP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
BMS-936558-01 (Nivolumab) 
Solution for Injection
100 mg (10 mg/mL)a
IP
Open-Label
10 mL per vial 
(10 vials/carton)
Store at 2° - 8 °C.
Protect from light and freezing.
Ipilimumab Solution for Injection
200 mg (5 mg/mL)
IP
Open-Label
40 mL per vial 
(4 vials/carton)
Store at 2° - 8 °C.
Protect from light and freezing.
Carboplatin Solution
for Injection
450 mg/vial 
(10 mg/mL)b
IP
Open-label
Clear, colorless or slightly 
yellow solution
As per market conditions
Carboplatin Solution
for Injection
(China Source)
150 mg/vial
(10 mg/mL)
IP
Open-label
Clear, colorless or slightly 
yellow solution
As per market conditions
Gemcitabine Concentrate for 
Solution for Infusion
1000 mg/ vialb
IP
Open-label
Clear, colorless, or light 
straw colored solution
As per market conditions
Gemcitabine Powder for Solution 
for Infusion
1000 mg/vialb
IP
Open-label
White to off-white plug or 
powder
As per market conditions
Cisplatin Concentration for Solution 
for Infusion
100 mg/vial
(1 mg/mL)b
IP
Open-label
Clear, colorless solution
As per market conditions
a May be labeled as either ͆BMS-936558-01͇ or ͆Nivolumab.”
b These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases,
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package 
insert or summary of product characteristics (SmPC).
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Study 
Treatment
Unit Dose Strength(s)/Dosage 
Level(s)
Dosage Formulation
Frequency of Administration
Route of 
Administration
Arm A: 
Part 1
Nivolumab (1 mg/kg)
plus
Ipilimumab (3 mg/kg)
Combination: D1W1 every 3 weeks 
for up to 4 doses
Nivolumab 30 min IV 
infusion
Ipilimumab 30 min IV 
infusion
Arm A: 
Part 2
Nivolumab (480 mg)
Monotherapy beginning 6 weeks 
following last combination dose,
every 4 weeks
Nivolumab 30 min IV 
infusion
Arm B*
Gemcitabine (1000 mg/m2) plus
Cisplatin (70 mg/m2)
Gem: Days 1 and 8 of each 3-week 
cycle
and
Cis: Day 1 of each 3-week cycle
For up to 6 cycles
Gemcitabine: 30 min 
IV infusion
Cisplatin: 30-120 min 
IV infusion
Gemcitabine (1000 mg/m2)
plus
Carboplatin (AUC 4.5/5)
Gem: Days 1 and 8 of each 3-week 
cycle
and
Carb: Day 1 of each 3-week cycle
For up to 6 cycles
Gemcitabine: 30 min 
IV infusion
Carboplatin: 30 min 
IV infusion
Arm C*
Part 1
Nivolumab (360 mg)
plus
Gemcitabine (1000 mg/m2) plus
Cisplatin 70 mg/m2
Nivo: 360 mg Day 1 of each 3-
week cycle
Gem: Days 1 and 8 of each 3-week 
cycle
and
Cis: Day 1 of each 3-week cycle
For up to 6 cycles
Nivolumab 30 min IV 
infusion
Gemcitabine 30 min 
IV infusion
Cisplatin 30-120 min 
IV infusion
Nivolumab should be 
administered first.
Arm C 
Part 2
Nivolumab (480 mg)
Monotherapy beginning 3 weeks 
following last combination dose, 
every 4 weeks
Nivolumab 30 min IV 
infusion
Arm D*
Gemcitabine (1000 mg/m2) plus
Cisplatin (70 mg/m2)
Gem: Days 1 and 8 of each 3-week 
cycle and
Cis: Day 1 of each 3-week cycle
For up to 6 cycles
Gemcitabine: 30 min 
IV infusion
Cisplatin: 30-120 min 
IV infusion
Note: Carboplatin dosing to be calculated per the Calvert formula, see Section 7.1.3.2.
*Only applies to chemotherapy drugs - Infusion duration and premedications may follow local guidelines.
The first treatment in any cohort, will be within 3 days following randomization (see Schedule of 
Activities, Section 2). 
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7.1.1
Nivolumab and Ipilimumab 
7.1.1.1
Arm A: Part 1 Study Drug Administration - Nivolumab and Ipilimumab 
Combination Therapy (Cycles 1-4)
Participants randomized to Arm A, will receive nivolumab plus ipilimumab combination therapy 
for up to 4 cycles. For each infusion, nivolumab is to be administered first. Participants should 
receive nivolumab at a dose of 1 mg/kg as a 30-minute IV infusion, on Day 1 of each treatment 
cycle every 3 weeks for up to 4 doses (Cycles 1-4). In Part 1, a minimum of 1 combination cycle 
of nivolumab and ipilimumab is required, for the participant to proceed to Part 2, nivolumab 
monotherapy. Participants experiencing AEs related to combination dose therapy (Part 1) that do 
not meet dose discontinuation criteria for nivolumab,, may proceed to nivolumab monotherapy 
dosing (Part 2) without completing all 4 combination doses, after consultation with BMS Medical 
Monitor.
During Part 1 in Arm A, 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.
Participants may be dosed up to 2 days before or 3 days after the scheduled date if necessary, so 
long as the dosing intervals are respected (no less than 19 days in Part 1, and no less than 26 days 
in Part 2). Subsequent dosing should be based on the actual date of administration of the previous 
dose of drug.
The nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab 
before starting the ipilimumab infusion.
The second infusion in the combination will always be ipilimumab, and will start after the infusion 
line has been flushed, filters changed and the participant has been observed to ensure no infusion 
reaction has occurred. The time 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 3 mg/kg as a 30-minute IV infusion, on Day 1 of each treatment cycle every 3 weeks for 
4 doses (Cycles 1-4). 
Dosing calculations for the combination phase should be based on the body weight assessed at 
screening. 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 to the nearest 
milligram. The risk/benefit profile for nivolumab has primarily been investigated using a 
60-minute infusion and for ipilimumab a 90-minute infusion. Long infusion times place a burden 
on participants and treatment centers. Establishing that these agents can be safely administered 
using shorter infusion times will diminish some of this burden. Both nivolumab and ipilimumab 
have been administered safely at doses ranging up to 10 mg/kg over these treatment durations. 
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across multiple clinical studies, and all have been managed by following the safety algorithms. 
Infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is 
not expected to present any safety concerns compared with the prior experience at 10 mg/kg 
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nivolumab dose infused over the 60-minute duration. Similarly, a shortened infusion duration of 
30 minutes for ipilimumab is not expected to present additional safety concerns.66
When given as a single agent, there is a low rate of infusion reactions. The incidence is less than 
1% for ipilimumab (Yervoy® FDA Label) and for nivolumab 3%. In the CA209069 study, in 
which nivolumab and ipilimumab were given sequentially, hypersensitivity/infusion reactions 
occurred at 3.2% for the combination and at 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.67
Participants should be carefully monitored for infusion reactions during nivolumab/ipilimumab 
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.4.3.
7.1.1.2
Arm A and C: Part 2 Study Drug Administration - Nivolumab 
Monotherapy 
Starting 6 weeks after the last combination dose in Arm A Part 1, or 3 weeks following the last 
combination dose in Arm C Part 1, participants will be administered a flat dose of 480 mg 
nivolumab on Day 1 of each treatment cycle given IV over approximately 30 minutes every 
4 weeks (Q4W) until unacceptable toxicity or disease progression.
Participants may be dosed up to 2 days before or 3 days after the scheduled date if necessary, 
however participants should be dosed no less than 26 days between treatments. 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 the protocol treatment schedule of administration of nivolumab every 
4 weeks in the monotherapy phase. In extenuating circumstances in which the participant cannot 
make the dosing schedule within the 3-day window, the BMS Medical Monitor should be 
contacted.
Premedications are not recommended for the first dose of nivolumab.
7.1.2
Study Drug Preparation and Infusion
Instructions for dilution of nivolumab injection are provided in the pharmacy manual, or IB. Care 
must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. 
Instructions for dilution of ipilimumab injection are provided in the pharmacy manual or IB.
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. 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.
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Doses of nivolumab and or ipilimumab may be interrupted, delayed, or discontinued depending 
on how well the participant tolerates the treatment. Dosing visits are not skipped, only delayed. In 
the event infusion duration in the SmPC varies from the protocol, the SmPC or local administration 
standards will take precedence.
7.1.3
Arm B: Platinum Doublet Chemotherapy
Participants 
randomized 
to 
Arm 
B, 
may 
receive 
either 
gemcitabine/cisplatin 
or 
gemcitabine/carboplatin. Cisplatin-ineligible participants will only receive gemcitabine/
carboplatin (see Section 6.1). 
Participants may be dosed up to 3 days before or after the scheduled date if necessary. Subsequent 
dosing should be based on the actual date of administration of the previous dose of drug.
7.1.3.1
Gemcitabine/Cisplatin
Participants will receive gemcitabine at a dose of 1000 mg/m2 for a 30-minute IV infusion on 
Days 1 and 8 with cisplatin at a dose of 70 mg/m2 as a 30 to 120-minute IV infusion on Day 1 of 
a 3-week treatment cycle for up to 6 cycles. As noted in Table 2-5, additional cycles may be 
permitted as per local guidelines.
Dosing calculations should be based on the body surface area calculation and may be capped per 
local standards. The dose may remain the same if the participant’s weight is within 10% of the 
baseline weight or prior dose weight.
Cisplatin will be administered to participants following the end of the gemcitabine infusion. 
Pretreatment hydration for cisplatin can follow local standard of care, or 1 to 2 liters of fluid (per 
local standards) infused IV for 8 to 12 hours prior to cisplatin infusion is recommended. Adequate 
hydration and urinary output must be maintained for at least 24 hours following cisplatin 
administration. Administration and monitoring should be performed according to local standards. 
Use of mannitol following the cisplatin infusion should also follow local standards-of-care.
Premedications: Antiemetic premedication will be administered according to local standards. 
Recommended antiemetic treatments are dexamethasone (dosing according to local standards; an 
equivalent dose of another corticosteroid may be substituted) and a 5-HT3 receptor antagonist 
(type per investigator discretion and local standards-of-care). Additional use of antiemetic 
premedications may be employed at the discretion of the Investigator.
Doses of gemcitabine and/or cisplatin may be interrupted, delayed, reduced, or discontinued 
depending on how well the participant tolerates the treatment. See the following sections for more 
details: 7.4.2.2 (dose delays); 7.4.1.2, 7.4.1.3, and 7.4.1.4 (dose reductions); 8.1.2.2 (retreatment), 
and 8.1.1.2 (dose discontinuations).
All participants who will be receiving cisplatin should have audiometric testing performed prior 
to initiation of therapy and prior to subsequent doses of cisplatin, or as per local standards of care.
Participants who discontinue cisplatin alone may, at the investigator’s discretion, be switched to 
gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). 
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Dosing for gemcitabine/carboplatin for such participants should follow the instructions in the 
Gemcitabine/Carboplatin section below.
7.1.3.2
Gemcitabine/Carboplatin
Participants will receive gemcitabine at a dose of 1000 mg/m2 as a 30-minute IV infusion on 
Days 1 and 8 with carboplatin at a dose of AUC 4.5/5 as a 30-minute IV infusion, on Day 1 of a 
3-week cycle, for up to 6 cycles, or at doses per the local prescribing information.
Gemcitabine dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% of the baseline weight or prior dose 
weight.
Carboplatin should be given following gemcitabine on Day 1 of each cycle, and the carboplatin 
dose will be calculated using the Calvert formula as follows:
•
Carboplatin dose (mg) = Target AUC x [CrCl (ml/min) + 25]
•
Creatinine clearance (CrCl) calculation is based on the Cockroft-Gault formula) and should 
include the most recent serum creatinine and most recent weight. NOTE: If calculation of the 
CrCl by the Cockroft-Gault formula yields a result of > 125 mL/min, then a CrCl should be 
calculated by an alternative formula per institutional standards or capped at 125 mL/min.
•
The dose of carboplatin may be capped per local standards.
Premedications: Oral antiemetic premedication will be administered according to local standards. 
Recommended antiemetic treatments are dexamethasone (dosing according to local standards; an 
equivalent dose of another corticosteroid may be substituted) and a 5-HT3 receptor antagonist 
(type per investigator discretion and local standards of care). Additional use of antiemetic 
premedications may be employed at the discretion of the investigator per local standards of care.
Doses of gemcitabine and/or carboplatin may be interrupted, delayed, reduced, or discontinued 
depending on how well the participant tolerates the treatment. See the following sections for more 
details: 7.4.2.2 (dose delays); 7.4.1.2, 7.4.1.3, and 7.4.1.4 (dose reductions); 8.1.2.2 (retreatment), 
and 8.1.1.2 (dose discontinuations).
7.1.4
Arm C: Nivolumab plus Platinum-Doublet Chemotherapy
Participants will receive nivolumab at a dose of 360 mg as 30 minute IV infusion on Day 1, 
followed by gemcitabine at a dose of 1000 mg/m2 for a 30 minute IV infusion with cisplatin at a 
dose of 70 mg/m2 as a 30 to 120-minute IV infusion, of a 3-week treatment cycle for up to 6 cycles. 
Gemcitabine will also be administered at a dose of 1000 mg/m2 for a 30 minute IV infusion on 
Day 8 of each 3-week treatment cycle. In the event infusion duration in the SmPC varies from the 
protocol, the SmPC or local administration standards will take precedence.
At the time of discontinuation of gemcitabine/cisplatin, participants who have not experienced 
disease progression will continue to receive nivolumab at a dose of 480 mg as 30 minute IV 
infusion on Day 1 of a 4 week treatment cycle. Treatment will continue until progression, 
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unacceptable toxicity, withdrawal of consent, or up to a maximum of 24 months, whichever occurs 
first.
Dosing calculations should be based on the body surface area calculation and may be capped per 
local standards. The dose may remain the same if the participant’s weight is within 10% of the 
baseline weight or prior dose weight.
Cisplatin will be administered to patients following the end of the gemcitabine infusion. 
Pretreatment hydration for cisplatin can follow local standard of care, or 1 to 2 liters of fluid 
(per local standards) infused IV for 8 to 12 hours prior to cisplatin infusion is recommended. 
Adequate hydration and urinary output must be maintained for at least 24 hours following cisplatin 
administration. Administration and monitoring should be performed according to local standards. 
Use of mannitol following the cisplatin infusion should also follow local standards-of-care.
Premedications: Antiemetic premedication will be administered according to local standards. 
Recommended antiemetic treatments are dexamethasone (dosing according to local standards; an 
equivalent dose of another corticosteroid may be substituted) and a 5-HT3 receptor antagonist 
(type per investigator discretion and local standards-of-care). Additional use of antiemetic 
premedications may be employed at the discretion of the Investigator.
Doses of gemcitabine and/or cisplatin may be interrupted, delayed, reduced, or discontinued 
depending on how well the participant tolerates the treatment. See the following sections for more 
details: 7.4.2.2 (dose delays); 7.4.1.2, 7.4.1.3, and 7.4.1.4 (dose reductions); 8.1.2.2 (retreatment), 
and 8.1.1.2 (dose discontinuations).
All participants who will be receiving cisplatin should have audiometric testing performed prior 
to initiation of therapy and prior to subsequent doses of cisplatin, or as per local standards of care.
Participants who discontinue cisplatin alone may, at the investigator’s discretion, be switched to 
gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). 
Dosing for gemcitabine/carboplatin for such participants should follow the instructions in the 
Gemcitabine/Carboplatin Section 7.1.3.2.
Beginning 3 weeks following the last combination dose, participants in Arm C will begin 
nivolumab monotherapy as described in Section 7.1.1.2.
7.1.5
Arm D: Platinum-Doublet Chemotherapy (Cisplatin-Eligible)
Dosing for participants randomized to Arm D will be the same as that outlined in Section 7.1.3.1
above. In the event infusion duration in the SmPC varies from the protocol, the SmPC or local 
administration standards will take precedence.
7.2
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log in information and directions on how to 
access the IRT.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
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7.3
Blinding
This is an open-label study; however, the specific treatment to be taken by a participant will be 
assigned using IRT. The site will contact the IRT 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 reductions
7.4.1.1
Nivolumab or Ipilimumab Dose Modification
Dose reductions or dose escalations of nivolumab or ipilimumab are not permitted. 
7.4.1.2
Platinum Doublet Chemotherapy Dose Reductions
Dose reductions of platinum doublet chemotherapy may be required, and will be performed 
according to Table 7.4.1.2-1 or per institutional guidelines. Chemotherapy dose reductions are 
permanent; once the dose of any chemotherapy agent is reduced, it may not be re-escalated in 
subsequent cycles. The dose reductions for each agent in the platinum doublet chemotherapy 
regimen are not linked and may be adjusted independently as summarized below.
Table 7.4.1.2-1:
Dose Modifications of Chemotherapeutic Agents
Dose Level
Gemcitabine
Cisplatin
Carboplatin
Starting dose
1000 mg/m² (with cisplatin) or 
1000 mg/m² (with carboplatin)
70 mg/m²
AUC 4.5/5 with 
gemcitabine
First dose reduction
750 mg/m² (with cisplatin) or 
750 mg/m² (with carboplatin)
56 mg/m²
AUC 4 with gemcitabine
Second dose reduction
500 mg/m² (with cisplatin) or 
500 mg/m² (with carboplatin)
38 mg/m²
AUC 3 with gemcitabine
Third dose reduction
Discontinue
Discontinue
Discontinue
Any participant with two prior dose reductions for one agent who experiences a toxicity that would 
cause a third dose reduction must be discontinued from that agent.
7.4.1.3
Platinum Doublet Chemotherapy - Dose Reductions for Hematologic 
Toxicity 
Dose adjustments are based on nadir blood counts (assessed as per local standards) since the
preceding drug administration. After the first cycle, growth factors may be used to assist 
hematologic recovery. Use local standards of care in the use of these supportive measures. 
Additionally, prophylactic antibiotics may be used according to local standards of care. Please 
report any antibiotic or growth factor use on the eCRF.
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7.4.1.4
Platinum Doublet Chemotherapy - Dose Reductions for Non-
Hematologic Toxicities
All dose reductions should be made based on the worst grade toxicity. Participants experiencing 
toxicity meeting dose-delay criteria during the previous cycle should have their chemotherapy 
delayed until retreatment criteria are met (per Section 8.1.2.2) and then reduced for all subsequent 
cycles by 1 dose level or discontinued as appropriate. Dose levels for the two drugs in the platinum-
doublet chemotherapy regimen are not linked and may be reduced independently.
7.4.2
Dose Delay Criteria
7.4.2.1
Nivolumab or Ipilimumab Dose Delay Criteria
Regardless of whether or not the event is attributed to nivolumab or ipilimumab, both study drugs 
must be delayed until treatment can resume. Tumor assessments for all participants should 
continue as per protocol even if dosing is delayed.
Nivolumab and ipilimumab 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: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see
Section 8.1.1.1)
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Participants who require delay of nivolumab/ipilimumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
7.4.2.2
Platinum Doublet Chemotherapy Dose Delay
Treatment of both drugs in the platinum doublet chemotherapy regimen selected should be delayed 
for any of the following on the Day 1 of each cycle:
•
Absolute neutrophil count (ANC) ≤1500/μL
•
Platelets < 100,000/mm3
•
Any Grade ≥2 non-skin, non-hematologic, drug-related adverse event (excluding Grade 2 
alopecia, Grade 2 fatigue, and Grade 2 laboratory abnormalities other than Grade 2 LFT 
increases if baseline within normal limits)
•
Any Grade ≥ 3 skin, drug-related adverse event
•
Any Grade ≥ 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, AST, ALT, or total bilirubin:
−
Grade 3 lymphopenia does not require dose delay.
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−
If a participant has a baseline AST, ALT or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥2 toxicity. 
−
If a participant has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥3 toxicity. 
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication. Investigators should consult 
local labeling for the chemotherapy drugs being administered to any given participant for 
additional guidance on dose delays.
In addition, participants receiving cisplatin with gemcitabine must discontinue cisplatin if the 
calculated creatinine clearance decreases to < 50 mL/min (based on the Cockroft Gault formula). 
Gemcitabine may be continued, and the platinum agent may, at the investigator’s discretion, be 
switched to carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total) 
when the participant meets retreatment criteria, as specified in Section 8.1.2.2.
Based on institutional guidelines, Day 8 gemcitabine dosing for participants receiving gemcitabine 
with cisplatin or carboplatin may be delayed for any of the following:
•
ANC < 1,000/mm3
•
Platelets < 75,000/mm3
If any adverse event meeting the dose delay criteria above is felt to be related to only one particular 
agent in the platinum doublet chemotherapy regimen, then that agent alone may be omitted for that 
cycle while the other agent is given. In order to maintain synchronized dosing of the regimen, the 
omitted agent should be resumed with the next scheduled cycle once the AE has improved and 
retreatment criteria are met. Please refer to Section 8.1.2.2 to determine if dose reduction of the 
resumed agent is required.
If both drugs in the platinum doublet chemotherapy regimen are delayed, then the participant
should be re-evaluated weekly or more frequently if clinically indicated until re-treatment criteria 
are met (as per Section 8.1.2.2).
7.4.2.3
Dose Delay Criteria for Nivolumab plus Platinum-Doublet 
Chemotherapy
In Arm C, dosing of all drugs should be delayed if any criteria for delay of Arms A
(Section 7.4.2.1) or Arm B (Section 7.4.2.2, Gemcitabine-cisplatin chemotherapy) are met. After 
participants have completed 6 cycles of SOC gemcitabine-cisplatin chemotherapy, and are on 
nivolumab maintenance therapy, dose delay criteria for nivolumab monotherapy (see 
Section 7.4.2.1 should apply.
7.4.3
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, each 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, 
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arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 
or 4 infusion reactions should be reported within 24 hours to the BMS Study Medical Monitor and 
reported as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI 
CTCAE (Version 4) 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 nivolumab 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 nivolumab or ipilimumab 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 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor participant 
closely. If symptoms recur, then no further nivolumab or ipilimumab 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 nivolumab 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 nivolumab or ipilimumab. 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 drug will be 
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permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.4.4
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 and ipilimumab are 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 both the nivolumab and ipilimumab Investigator Brochures,
as well as in Appendix 5. 
7.4.5
Treatment Beyond Progression 
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.68
Participants treated with study drug(s) will be permitted to continue treatment beyond initial 
RECIST 1.1 defined PD in both Part 1 (combination) and Part 2 (monotherapy), assessed by the 
investigator up to a maximum of 24 months from date of first dose as long as they meet the 
following criteria:
•
Investigator-assessed clinical benefit
•
Tolerance of study drug
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
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•
Participant provides written informed consent prior to receiving additional nivolumab 
treatment. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply
•
Radiographic assessment/scan(s) should continue in accordance with the Section 2 Schedule 
of Activities for the duration of the treatment beyond progression and should be submitted to 
the central imaging vendor.
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. 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.
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.
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 infusion preparation are provided in the pharmacy manual
or product specific IB. 
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7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not Applicable.
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. 
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
Treatment with any of the following medications or interventions concomitantly or within 28 days 
of starting nivolumab or ipilimumab:
1. 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
2. Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, non-palliative surgical resection or standard or 
investigational agents for treatment of unresectable or metastatic UC)
3. Use of an investigational agent within 4 weeks of Day 1 visit
4. The following medications are prohibited during the study:
a.
Immunosuppressive agents (except to treat a drug-related adverse event) 
b. Systemic corticosteroids > 10 mg daily prednisone equivalent (except as stated in 
Section 7.7.2 below or to treat a drug-related adverse event)
c.
Intravesical therapy lasting for >1 instillation
d. Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, 
and measles, mumps, rubella) during treatment and until 100 days post last dose
e.
Any botanical preparation (eg herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care. Use of marijuana 
and its derivatives for treatment of symptoms related to cancer or cancer treatment are 
permitted if obtained by medical prescription or if its use (even without a medical 
prescription) has been legalized locally.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune, as is a 
short dose of corticosteroids (< 3 weeks) to prevent a reaction to the IV contrast used for CT scans 
(see Section 7.7.3).
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Palliative (limited-field) radiation therapy and palliative surgical resection are permitted, if the 
following criteria are met:
1) The participant will be considered to have progressed at the time of palliative therapy and must 
meet criteria to continue with treatment beyond progression (Section 7.4.5). Transurethral 
resection of bladder tumors (TURBT) should be discussed on a case by case basis with BMS 
Medical Monitor as some TURBTs may be allowed without considering the patient as 
progressing (eg, TURBT of lower risk non-muscle invasive lesion).
2) The case is discussed with the BMS Medical Monitor or Study Director.
7.7.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (≤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.
The use of dexamethasone or other steroid as antiemetic premedication is permitted for the 
chemotherapy containing arms as described in Sections 7.1.3.2 and 7.1.4.
Bisphosphonates and RANK-ligand inhibitors for bone metastases are allowed to be initiated while 
on study as per institutional SOC guidelines.
7.7.3.1
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants with renal insufficiency should be assessed as to 
whether or not they should receive contrast and if so, what type and dose of contrast is appropriate. 
Specific to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration 
rate (eGFR) < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI 
contrast should not be given to this participant population. In these participants, an MRI with and 
without gadolinium abdomen and pelvis, and CT without contract. In participants, who are 
excluded from an MRI, a CT (chest, abdomen, and pelvis) without contrast is acceptable. In 
addition, participants are excluded from MRI if they have tattoos, metallic implants, pacemakers, 
etc.
For brain MRI, if MRI is prohibited because of medical reasons (eg. metallic implants), CT with 
or without contrast agents would be acceptable.
Subsequent assessments should use the same imaging method as was used at baseline.
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. Study treatment will be provided via an 
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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 the nivolumab 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
•
Additional protocol specified criteria for discontinuation (see Section 8.1.1)
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.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes pregnant 
during a clinical trial, the study treatment must be discontinued immediately. 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).
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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
Dose Discontinuation 
8.1.1.1
Discontinuation of Nivolumab or Ipilimumab
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.
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 
uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, myocarditis, 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 
require 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 drug(s) will be permanently discontinued. 
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
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study drug(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), except for the following events which do not 
require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
•
Any event that leads to delay in dosing lasting > 8 weeks 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. 
−
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 lasting > 8 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.
For participants in Arm C, if the investigator is unable to determine whether an adverse event is 
due to nivolumab or -to platinum doublet chemotherapy, then all drugs must be discontinued.
8.1.1.2
Platinum Doublet Chemotherapy Dose Discontinuation 
Except where specified below, both chemotherapy drugs in the platinum doublet chemotherapy 
regimen should be discontinued for any of the following:
•
Any Grade ≥3 peripheral neuropathy
•
Grade ≥3 drug-related thrombocytopenia associated with clinically significant bleeding
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
−
AST or ALT > 5-10 × ULN for > 2 weeks
−
AST or ALT > 10 × ULN
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−
Total bilirubin > 5× ULN
−
Concurrent AST or ALT > 3× ULN and total bilirubin > 2 × ULN
•
Any cisplatin-related decrease in creatinine clearance to < 50 mL/min (using the Cockroft 
Gault formula) requires discontinuation of cisplatin.
•
Any drug-related adverse event which recurs after two prior dose reductions for the same drug-
related adverse event (as specified in Sections 7.4.1.3 and 7.4.1.4) requires discontinuation of 
the drug(s) which was/were previously dose reduced.
•
Any Grade ≥3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) felt to be causing the reaction. The drug not felt to be related to 
the hypersensitivity reaction or infusion reaction may be continued.
•
Any Grade 4 drug-related adverse event which the investigator deems is inappropriate to be 
managed by dose reduction(s) requires discontinuation of the drug(s) felt to be causing the 
event. The drug not felt to be related to the event may be continued.
•
Any event that leads to delay in dosing of any study drug(s) for > 6 weeks from the previous 
dose requires discontinuation of that drug(s) with the following exception:
•
Dosing delays lasting > 6 weeks from the previous dose that occur for drug-related 
reasons may be allowed if approved by the BMS Medical Monitor. 
•
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 lasting > 6 weeks, the BMS medical monitor 
must be consulted. 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 platinum 
doublet chemotherapy dosing. Investigators should consult local labeling for the chemotherapy 
drugs being administered to any given participant for additional guidance on dose 
discontinuation.
Note that participants receiving gemcitabine/cisplatin who discontinue cisplatin alone may, at the 
investigator’s discretion, be switched to gemcitabine/carboplatin for the remainder of the platinum 
doublet cycles (up to 6 cycles in total). 
For participants in Arm C, if the investigator is unable to determine whether an adverse event is 
due to nivolumab or to platinum doublet chemotherapy, then all drugs must be discontinued.
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8.1.2
Criteria to Resume Treatment
8.1.2.1
Criteria to Resume Nivolumab or Ipilimumab
Participants may resume treatment with study drug 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 8.1.1) should have treatment permanently discontinued. 
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor.
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.
8.1.2.2
Criteria to Resume Treatment with Platinum Doublet Chemotherapy 
•
Participants may resume treatment with platinum doublet chemotherapy when the ANC returns 
to > 1500/μl, the platelet count returns to ≥100,000/mm3, and all other drug-related toxicities 
have returned to baseline or Grade ≤1 (or Grade ≤2 for alopecia and fatigue).
•
If a participant fails to meet criteria for re-treatment, then re-treatment should be delayed, and 
the participant should be re-evaluated weekly or more frequently as clinically indicated. Any 
participant who fails to recover from toxicity attributable to platinum doublet chemotherapy to 
baseline or Grade ≤1 (except Grade 2 alopecia and fatigue) within 6 weeks from the last dose 
given should discontinue the drug(s) that caused the delay.
8.1.3
Post Study Treatment Follow-up
In this study, PFS and OS are key endpoints 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 randomized participants outside of the 
protocol defined window (Schedule of Activities, Section 2). At the time of this request, each 
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participant will be contacted to determine their survival status unless the participant has withdrawn 
consent for all contacts or is lost to follow-up. 
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of 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 (Section 2).
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•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (e.g., 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.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the Schedule of Activities (Section 2).
9.1.1
Overall Survival
OS is defined as the time between the date of randomization and the date of death from any cause. 
For participants without documentation of death, OS will be censored on the last date the 
participant was known to be alive (“last known alive date”). OS will be censored for participants 
at the date of randomization if they were randomized but had no follow-up. OS will be followed 
continuously while participants are on the study drug and every 3 months via in-person or phone 
contact after participants discontinue the study drug.
The overall survival rate at time T is defined as the probability that a participant is alive at time T 
following randomization.
9.1.2
Progression-Free Survival
PFS will be estimated based on BICR assessments. PFS is defined as the time from the date of 
randomization to the date of first documented disease progression, based on BICR assessments (as 
per RECIST 1.1), or death due to any cause, whichever occurs first. Clinical deterioration in the 
absence of progression per RECIST 1.1 is not considered progression for the purpose of 
determining PFS. Participants who die without a reported prior 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 the date they were randomized. Participants 
who started any subsequent anti-cancer therapy, including tumor-directed radiotherapy and tumor-
directed surgery, without a prior reported progression will be censored at the last evaluable tumor 
assessment prior to/on initiation of the subsequent anti-cancer therapy.
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The progression free survival rate at time T is defined as the probability that a participant has not 
progressed and is alive at time T following randomization.
9.1.3
Objective Response Rate
The ORR is defined as the number of participants with a best overall response (BOR) of a 
confirmed complete response (CR) or partial response (PR) using the RECIST 1.1 criteria based 
on BICR assessments divided by the number of randomized participants for each treatment group. 
The BOR is defined as the best response designation, as determined by BICR, recorded between 
the date of randomization and the date of progression, as assessed by BICR per RECIST 1.1 or the 
date of subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed 
surgery), whichever occurs first. For participants without documented progression or subsequent 
therapy, all available response designations will contribute to the BOR determination.
9.1.4
Imaging Assessment for the Study
Baseline assessments should be performed within 28 days prior to randomization utilizing CT or 
MRI. In addition to chest, abdomen, pelvis, and brain, all known, or suspected, sites of disease 
should be assessed at baseline. 
Participants who cannot receive IV contrast for CT at the start of study should be imaged by MRI 
of abdomen/pelvis with IV contrast and CT of chest without contrast. Subsequent assessments 
should include chest, abdomen, and pelvis, and all known sites of disease and should use the same 
imaging method as was used at baseline. Participants initially imaged with CT of chest, abdomen, 
and pelvis with IV contrast who can no longer receive contrast can be monitored by CT of chest, 
abdomen, and pelvis without IV contrast. Participants in all cohorts will be evaluated for tumor 
response at the following intervals and time points: 
•
First tumor assessment should be performed at Week 9 (± 1 week) following first dose. 
Subsequent tumor assessments should occur every 8 weeks (± 1 week) up to first 48 weeks, 
then every 12 weeks until disease progression or treatment discontinuation, whichever is later
Tumor assessments for all participants should continue as per protocol even if dosing is delayed.
Tumor assessments for ongoing study treatment decisions will be completed by the investigator 
using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria.
Images will be submitted to an imaging core lab. Sites should be trained prior to scanning the first 
study participant. Image acquisition guidelines and submission process will be outlined in the 
CA209901 Imaging Manual to be provided by the core lab. 
9.1.4.1
BICR Assessment Of Progression
Post-baseline tumor assessments will be performed at the time points described above until 
progression assessed by the investigator and confirmed by BICR or treatment is discontinued 
(whichever occurs later). In the case of study drug treatment beyond a BICR confirmed 
progression, scans should continue to be submitted for BICR assessment, but subsequent 
progression does not need to be confirmed by BICR.
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Sites should submit all scans (protocol specified imaging and any additional imaging that may 
demonstrate tumor response or progression, including scans performed at unscheduled time points 
and/or at an outside institution), for BICR on a rolling basis, preferably within 7 days of scan 
acquisition, throughout the duration of the study. BICR will review scans on a rolling basis and 
remain blinded to treatment arm and investigator assessment of submitted scans. 
When progression per RECIST 1.1 criteria is assessed by the investigator, the site will inform the 
imaging core lab, so that the BICR assessment of progression can be expedited. The BICR review 
will be completed and the results provided to the site within approximately 5 business days of 
receipt of the scans, provided there are no pending imaging queries to the site. 
Participants whose progression is not confirmed by the BICR will be required to continue tumor 
assessments (if clinically feasible) according to the protocol-specified schedule or sooner if 
clinically indicated until the BICR confirms progression on a subsequent tumor assessment. Also, 
if participants discontinue treatment without radiographic progression, tumor assessments will 
continue according to the protocol specified schedule, as noted in Section 2, until progression has 
been confirmed by BICR.
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment. The BICR assessment of progression is only relevant for determining 
when tumor assessments for a given participant are no longer required to be submitted to the 
imaging vendor.
9.1.5
Patient Report Outcomes
Outcomes research data including health related quality of life and patient reported symptom 
burden provide a more complete understanding of the impact of treatment by incorporating the 
patients’ perspective. These data offer insights into the patient experience that may not be captured 
through physician reporting. The EQ-5D-5L will be collected in order to assess the impact of 
nivolumab on generic health related quality of life and the data will be used for populating health 
economic models most notably, cost effectiveness analysis. The EORTC QLQ-C30 will be 
collected in order to assess cancer specific health related quality of life. The combination of the 
generic scale for general health status and economic evaluation and the cancer specific scale will 
provide a robust outcomes research package. EORTC QLQ-C30 and the EQ-5D-5L will be 
collected according to the Schedule of Activities. 
The EORTC QLQ-C30 is a 30-item instrument comprising five functional scales (Physical, Role, 
Cognitive, Emotional and Social), three symptom scales (Fatigue, Pain, and Nausea/Vomiting), a 
Global Health Status/QoL scale, and six single items (Constipation, Diarrhea, Insomnia, Dyspnea, 
Appetite Loss, and Financial Difficulties). Except for the overall health status and global QoL
items, responses for all items are 4-point categorical scales ranging from 1 (Not at all) to 4 (Very 
much). The overall health status/QoL responses are 7-point Likert scales. It has gone through 
appropriate psychometric testing and is available in over 81 languages.
General health status will be measured using the EQ-5D-5L. The EQ-5D-5L is a standardized 
instrument for use as a measure of self-reported general health status. The EQ-5D-5L comprises 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety) and a visual 
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analog rating scale (VAS). The utility data generated from the EQ-5D-5L is recommended for and 
commonly used in cost effectiveness analysis.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
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 
[the follow-up contact], at the time points 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 drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later protocol-
specified procedure (eg, a follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
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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.)
9.2.3
Follow-up of AEs and SAEs
•
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
All identified non-serious AEs must be recorded and described on the non-serious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A 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.
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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 drug, SAEs should be collected for 30 days from the date of randomization.
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.
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 non-serious 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 Section 9.2 and Appendix 3 for reporting 
details).
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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, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
At screening, a medical history will be obtained to capture relevant underlying conditions. The 
screening examinations should include weight, height, ECOG Performance Status, blood pressure 
(BP), heart rate (HR), temperature, and hearing assessments (per standard of care). Screening 
assessments should be performed in the time frames as indicated in the Schedule of Activities. 
Screening local laboratory assessments should be done within 14 calendar days prior to first 
treatment and are to include: CBC with differential, Chemistry panel including LFTs (ALT, AST, 
total bilirubin, alkaline phosphatase), BUN or serum urea level, creatinine, Ca, Na, K, Cl, Mg, 
phosphate, LDH, glucose, albumin.
The following screening local laboratory assessments should be done within 28 calendar days prior 
to first treatment: thyroid panel including TSH, free T3, and free T4 (if free T3 and free T4 are not 
available then Total T3 and Total T4 are acceptable) and Hepatitis B and C testing (HBV sAg and 
HCV Ab or HCV RNA). Sites in Germany see Appendix 9. 
While on-study the following local laboratory assessments are to be done within 3 calendar days 
prior to each dose on Day 1: CBC with differential, LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase), BUN or serum urea level, creatinine, Ca, Na, K, Cl, Mg, phosphate, LDH, glucose. 
Albumin will be assessed as clinically indicated in all four treatment arms. Amylase and lipase are 
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to be monitored on-treatment in Arm B and D participants and during Part 1 of Arm C only. CBC 
with differential should be performed prior to gemcitabine dosing on Day 8 (see Section 7.4.2.2).
Thyroid function testing (TSH with reflexive fT3 and fT4 if free T3 and free T4 are not available 
then Total T3 and Total T4 are acceptable) is to be done every 3 weeks (following each 
combination dose infusion) during the on-treatment Part 1 of Arm A (ie, during the period of same 
day sequential dosing with nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg), then every 
8 weeks for participants receiving nivolumab at 480 mg every 4 weeks.
Participants will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase as well as during the first two safety follow-up visits. 
Once participants reach the survival follow-up phase, either in-person visits or documented 
telephone calls/email correspondence to assess the participant’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.
On-study weight, ECOG performance status, and vital signs should be assessed at each on-study 
visit prior to dosing. Vital signs should also be taken as per institutional standard of care prior to, 
during and after infusions. The start and stop time of the study therapy infusions and any 
interruptions or infusion rate reductions should be documented.
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious or serious adverse event page.
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 drug related toxicities resolve, return to baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure and in Appendix 5
of this protocol.
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.
9.4.1
Electrocardiograms
All participants who have met the eligibility criteria are required to have a 12-lead ECG performed 
during Screening. This will serve as a baseline assessment in the event of any on-study cardiac 
events. If clinically indicated, additional ECGs may be obtained during the study.
9.4.2
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
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Please refer to the Schedule of Activities in Section 2 for details related to the required laboratory 
assessments. 
9.4.3
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
Although ECOG status, baseline glomerular filtration rate (GFR), albumin and body weight had 
an effect on nivolumab CL, the effect was not clinically meaningful. When nivolumab is 
administered in combination with ipilimumab 3 mg/kg, the CL of nivolumab was increased by
24%, whereas there was no effect on the clearance of ipilimumab. Additionally, PPK and exposure 
response (ER) analyses have been performed to support use of 240 mg Q2W dosing in addition to 
the 3 mg/kg Q2W regimen. Using the PPK and ER models, exposure, safety and efficacy of 
nivolumab at 240 mg flat dose was identical to a dose of 3 mg/kg. Full details on the clinical 
pharmacology aspects of nivolumab can be found in the Investigator Brochure.
Samples for PK and immunogenicity assessments will be collected for all participants receiving 
nivolumab and ipilimumab as described in Table 9.5-1 and from participants receiving nivolumab 
and platinum doublet chemotherapy as described in Table 9.5-2. All time points are relative to the 
start of study drug administration. All on-treatment time points are intended to align with days on 
which study drug 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.
Blood samples for immunogenicity analyses of nivolumab and/or ipilimumab will be collected 
according to the schedule given in Table 9.5-1 and Table 9.5-2. Samples collected from 
participants will be evaluated for the development of Anti-Drug Antibody (ADA) for nivolumab 
and/or ipilimumab by validated immunoassays. Samples may also be analyzed for neutralizing 
ADA response to nivolumab and/or ipilimumab.
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Table 9.5-1:
Pharmacokinetic and Immunogenicity Sample Collections for Arm A (CA209901)
Parta
Study Dayb
Time (Event)
Time (Relative to 
Start of Nivolumab 
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
00:90
X
1
C1D1
(EOI-ipi)d
00:90
X
1
C2D1
(Predose)c
00:00
X
X
X
X
1
C2D1
(EOI-nivo)d
00:90
X
1
C2D1
(EOI-ipi)d
00:90
X
1
C3D1
(Predose)c
00:00
X
X
X
X
1
C3D1
(EOI-nivo)d
00:90
X
1
C3D1
(EOI-ipi)d
00:90
X
2a
C5D1a
(Predose)c
00:00
X
X
X
X
2
C5D1
(EOI-nivo)d
00:30
X
2
C9D1
(Predose)c
00:00
X
X
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Table 9.5-1:
Pharmacokinetic and Immunogenicity Sample Collections for Arm A (CA209901)
Parta
Study Dayb
Time (Event)
Time (Relative to 
Start of Nivolumab 
Infusion) 
Hours:Min
Pharmacokinetic 
Blood Sample for 
Nivolumab
Immunogenicity 
Blood Sample 
for Nivolumab
Pharmacokinetic 
Blood Sample 
for Ipilimumab
Immunogenic 
Blood Sample 
for 
Ipilimumab
2
CXD1: Every4th 
cycle after C9D1 
in Part 2 (ie, 
C13D1, C17D1, 
etc.)
(Predose)c
00:00
X
X
Follow-up
First 2 Follow-up 
Visits 
(Approximately 
up to 100 Days 
from the 
Discontinuation of 
Study Drug)
NA
X
X
a Cycle numbering is consecutive from start of treatment. Part 1 indicates first 12 weeks (or 4 cycles) of combination treatment (nivolumab + ipilimumab). Part
2, indicates nivolumab monotherapy period beginning 6 weeks following last combination dose. “C5D1” here represents the first dose of nivolumab 
monotherapy, regardless of cycle number. 
b If a participant discontinues study drug 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 infusion. (preferably within 30 minutes). If it is
known that a dose is going to be delayed, then 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.
d EOI-nivo and EOI-ipi: End of Infusion samples for nivolumab and ipilimumab, respectively. For sequential dosing, both EOI samples should be collected
immediately (preferably within 2 - 5 minutes) prior to the end of the ipilimumab infusion (~ 90 min from the start of the nivolumab infusion). If the end 
of infusion is delayed, the collection of the EOI samples should be delayed accordingly. EOI samples may not be collected from the same IV access as drug was 
administered, refer to the laboratory manual for additional instructions.
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Table 9.5-2:
Pharmacokinetic (PK) and Immunogenicity Sample Collections -
Nivolumab + Platinum Doublet Chemotherapy Arm C
Parta
Study Dayb
Time 
(Event)
Time (Relative to 
Start of 
Nivolumab
Infusion) 
Hours:Min
Pharmacokinetic 
Blood Sample for 
Nivolumab
Immunogenicity 
Blood Sample 
for Nivolumab
1
C1D1
Predosec
00:00
X
X
1
C1D1
EOI-nivod
00:30
X
1
C4D1
Predosec
00:00
X
X
1
C6D1
Predosec
00:00
X
X
2a
C7D1a
Predosec
00:00
X
X
2
C12D1
Predosec
00:00
X
X
2
D1 of every 6th Cycle 
after C12D1 (Part 2)
until discontinuation
of study treatment or 
maximum up to 2 
years of treatment
Predosec
00:00
X
X
Follow
-up
First 2 Follow-up 
Visits 
(Approximately up to 
100 Days from the 
Discontinuation of 
Study Drug)
NA
X
X
a Cycle numbering is consecutive from start of treatment. Part 1 indicates first 6 cycles of treatment (nivolumab + 
platinum doublet chemotherapy dosing). Part 2 indicates nivolumab monotherapy period beginning 3 weeks 
following the last combination dose. “C7D1” here represents the first dose of nivolumab monotherapy, 
regardless of cycle number. 
b If a participant discontinues study drug treatment during the sampling period, they will move to sampling at the 
follow-up visits.
c Predose samples should be collected just before the administration of the first drug (preferably within 30 minutes). 
If it is known that a dose is going to be delayed, then 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.
d EOI-nivo End of Infusion samples for nivolumab, EOI samples should be collected immediately (preferably within 
2 - 5 minutes) prior to the end of the nivolumab infusion (~ 30 min from the start of the nivolumab infusion). If the 
end of infusion is delayed, the collection of the EOI samples should be delayed accordingly. EOI samples may not 
be collected from the same IV access as drug was administered, refer to the laboratory manual for additional 
instructions.
9.6
Pharmacodynamics
See Section 9.8.
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9.7
Pharmacogenomics
See Section 9.8.
9.8
Biomarkers
A variety of factors that could potentially predict clinical response and incidence of adverse events 
to Ipilimumab/Nivolumab treatment will be investigated in peripheral blood and in tumor 
specimens taken from all participants prior to treatment. Data from these investigations will be 
evaluated for associations with RFS and safety (adverse event) data. In addition, analyses of 
markers between the treatment arms (nivolumab/ipilimumab vs SOC chemotherapy and 
nivolumab with SOC chemotherapy vs SOC therapy) will provide the necessary data to identify 
and validate biomarkers with predictive vs prognostic value. All samples collected may also be 
used for future exploratory analyses (unless restricted by local requirements and/or institutional 
policies) to assess biomarkers associated with bladder cancer or immunotherapy treatment. 
Complete instructions on the collection, processing, handling and shipment of all samples 
described herein will be provided in a separate procedure manual.
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Table 9.8-1:
Biomarker Sampling Schedule (All Participants)
Collection 
Timinga
Tumor 
Biopsy
MDSCsb
Serum
Whole Blood 
(Gene Expression)
PBMCsc
ctDNA
Whole Blood
(SNP)
Screening
X
C1D1
X
X
X
X
X
X
C2D1
X
C2D15
Xd
C4D1
X
X
X
X
X
C5D1
X
C6D1
X
X
X
X
X
C8D1
X
X
C10D1
X
X
X
X
X
FU 
visit 1 & 2
X
Upon 
Progression
Xe
Xe
Xe
Xe
Xe
Xe
a Biomarker sampling occurs prior to dosing of study drug and can occur up to 5 days prior to dosing.
b Collected in US, Canada, and European countries only.
c Not collected in China, Argentina, Brazil, Chile, or Peru, for PBMC.
d This is an optional biopsy, post-second dosing of combination therapy (if possible 2 weeks post-C2D1 or 1 week 
pre-C3D1).
e Sample collection upon disease progression is optional, but highly recommended.
9.8.1
Additional Research Collection
This protocol will include both sample collection and residual sample storage for additional 
research (AR).
For All US sites:
Additional research is mandatory for all study participants.
•
If the IRB/ethics committees and site agree to the mandatory additional research retention 
and/or collection, then the study participant must agree to the mandatory additional 
research as a requirement for inclusion in the study.
For non-US Sites
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
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understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc. 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
Residual samples of tumor tissue (baseline and on-treatment,) whole blood, serum samples, and 
PBMC samples will be retained from selected time points for additional research purposes (see 
Table 9.8.1-1).
Samples kept for future research will be stored at 
 
 an independent, BMS-approved storage vendor.
•
The manager of these samples will ensure they are properly used throughout their usable life 
and will destroy the samples at the end of the scheduled storage period, no longer than fifteen 
(15) years after the end of the study or the maximum allowed by applicable law.
•
Transfers of samples by research sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Table 9.8.1-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Time Points for which residual samples will be retained
Tumor Biopsy
Pre-treatment, C2D15 (optional), upon progression (optional)
Whole blood sample (SNP)
C1D1
Whole blood sample (Gene 
Expression)
C1D1, C4D1, C6D1, C10D1, upon progression (optional)
Serum sample
C1D1, C2D1, C4D1, C5D1, C6D1, C8D1, C10D1, FU visits 1 and 2, upon 
progression (optional)
PBMC
C1D1, C4D1, C6D1, C8D1, and C10D1, upon progression (optional)
9.8.2
Immunogenicity Assessments 
Blood samples for immunogenicity analysis will be collected according to the schedule given in 
Table 9.5-1. Samples collected from prospective participants will be evaluated for development of 
Anti-Drug Antibody (ADA) by a validated electrochemiluminescent (ECL) immunoassay.
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Samples may also be analyzed for neutralizing antibodies and PK samples may be used for ADA 
analysis in the event of insufficient volume, to complete immunogenicity assessment, or to follow 
up on suspected immunogenicity-related AEs.
Further details of sample collection, processing, and shipment will be provided in the laboratory 
procedures manual.
9.8.3
Tumor Tissue Specimens
Pre-treatment tumor tissue specimens in the form of a paraffin-embedded block or a minimum of 
15 unstained slides will be submitted to central lab for PD-L1 IHC assessment prior to 
randomization. Participants must provide a fresh tumor biopsy from the primary disease site. If 
fresh tissue cannot be provided, a tissue block (or at least 15 FFPE slides) from the latest surgical 
resection (eg, radical cystectomy) can be accepted if collected within 2 years prior to enrollment 
period, and the participant did not receive systemic anticancer agents or radiotherapy since 
collection of sample. The PD-L1 stained tissue sections will be assessed by a pathologist and 
membranous PD-L1 expression scored in tumor cells if a minimum of a hundred (100) evaluable 
tumor cells are present. Participants with tumor samples containing less than a hundred tumor cells 
per tissue section will not be randomized, but participants with positive, negative or indeterminate 
(membrane staining is obscured by high cytoplasmic staining) PD-L1 expression will be stratified 
based on their expression. Participants with “indeterminate” PD-L1 expression, will be included 
as PD-L1 negative. In addition, this pre-treatment tumor sample may be used to assess other 
putative predictive biomarkers of nivolumab/ipilimumab efficacy and/or to better characterize the 
tumor-immune microenvironment within the resected tissue. Various molecular markers with 
potential predictive value for the treatment of bladder cancer with nivolumab/ipilimumab and other 
immunotherapies are currently under investigation and may be assessed in this study. These tumor 
tissue biomarkers include, but are not limited to PD-1, PD-L2, TILs or subpopulations of TILs and 
a Th1 immune mRNA expression signature. In addition, other methods of measuring tumor PD-L1 
expression may also be assessed. These pre-treatment tumor samples may also be used to further 
characterize the tumor-immune microenvironment through assessment of markers that may be 
associated with the efficacy of nivolumab/Ipilimumab combination treatment, including but not 
limited to other T-cell checkpoint receptors and ligands (eg, Lag-3, Tim-3), intratumoral immune 
cell subsets, including macrophages, natural killer (NK) cells and B cells. It is highly 
recommended to collect an on-treatment biopsy sample in metastatic sites (e.g. lymph nodes) one 
week prior to the third combination dosing. Tumor tissue collection at relapse is also highly 
recommended. Although these on-treatment and relapse biopsies are optional, they are absolutely 
needed to understand the reasons of disease relapse, the mechanism of action of 
nivolumab/ipilimumab and how to benefit patients with optimal treatment strategies. They may be 
used for the assessment of markers implicated in resistance to immunotherapeutic agents, 
including but not limited to other T cell checkpoint receptors and ligands (eg, Lag-3, Tim-3) and 
intratumoral immune cell subsets, including but not limited to, T regulatory cells and myeloid 
derived suppressor cells. These samples may also be used to investigate the effect of 
nivolumab/ipilimumab on the expression of potentially relevant predictive and/or prognostic 
bladder cancer biomarkers. Both the pre- and on-treatment tumor samples and the sample collected 
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upon recurrence may be retrospectively profiled for gene expression/mutation status, as well as for 
the expression of other immune or bladder cancer related genes, RNAs, miRNA and proteins, or 
for the presence of immune cell populations using a variety of methodologies inclusive of, but not 
limited to IHC, qRT-PCR, genetic mutation detection and fluorescent in-situ hybridization (FISH).
9.8.4
Peripheral Blood Markers
A variety of factors that may impact the immunomodulatory properties and efficacy of 
nivolumab/ipilimumab will be investigated in peripheral blood specimens taken from all 
participants prior to or during treatment. Data from these investigations will be evaluated for 
associations with response, survival, and/or safety (adverse event) data. Several analyses will be 
completed and are described briefly below.
9.8.5
Single Nucleotide Polymorphisms (SNPs)
Whole blood will be collected from all participants prior to treatment to generate genomic DNA 
for Single Nucleotide Polymorphism (SNP) analyses. These analyses will focus on SNPs within 
genes associated with PD1 and other immunoregulatory signaling pathways to determine if natural 
variation within those genes is associated with response to nivolumab/ipilimumab and/or with 
adverse events during treatment.
9.8.6
Serum-Soluble Factors
Blood samples for exploratory serum biomarker analyses will be drawn at specified time points. 
Additionally, serum samples will be collected when clinically safe and feasible, upon occurrence 
of a Grade 3 drug-related AE and/or any lab abnormality regarded as a drug-related SAEs. Serum 
samples may be assessed by ELISA, seromics, microRNA profiling, circulating tumor DNA 
measurements, metabolomics and/or other relevant multiplex-based protein assay methods for 
immune-related factors that will predict for nivolumab/ipilimumab benefit or correlate with 
treatment-related adverse events. Numerous potential serum/plasma-based biomarkers are 
currently under investigation for their potential to predict or correlate with safety or efficacy to 
nivolumab/ipilimumab combination or other immunotherapies, including but not limited to levels 
of soluble PD-L1, anti-tumor antibodies, cytokines, chemokines, inflammatory factors, NKG2D 
ligands (eg, soluble MICA), circulating tumor DNA, and microRNAs (such as, but not limited to, 
miR-513 and miR19b. Myeloid Derived Suppressor Cells (MDSC) Myeloid derived suppressor 
cells are an immune cell population capable of suppressing T cell activation and proliferation. Low 
pre-treatment MDSC levels in peripheral blood may be associated with better overall survival in 
bladder cancer participants treated with the combination nivolumab/ipilimumab. MDSCs will be 
measured at baseline and on-treatment to assess pharmacodynamic changes or associations with 
outcome.
9.8.7
Peripheral Blood Mononuclear Cells (PBMCs)
Peripheral blood samples will be taken prior to initiation of study therapy and at designated time
points on-treatment for PBMC preparation. Samples must be shipped within 48 hours to a BMS-
designated central laboratory for processing.
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These PBMC samples may be used for immunophenotyping or characterization of the immune 
cell subsets in the periphery, including, but not limited to, T cells, B cells, NK cells, or 
subpopulations of the aforementioned immune cell types. These samples may also be used to 
assess immune cell function or antigen specific T cell proliferation or activation pending emerging 
information from other nivolumab/ipilimumab studies.
9.8.8
Plasma
The presence of cell-free DNA in circulating blood is a well-documented phenomenon. Fragments 
of DNA are shed into the blood stream from dividing cells during cell proliferation or cell death. 
In participants with cancer, a fraction of this DNA is tumor-derived and is termed circulating tumor 
DNA (ctDNA). Albeit small, fragments of DNA average between 180 to 200 base pairs and 
specific genomic regions can be amplified with PCR. Moreover, several studies have detected 
mutations in ctDNA that exactly correspond to mutations from the parent tumor. Using tissue and 
plasma, BEAMing or similar technology will be utilized to measure cell-free DNA and the 
presence/frequency of eventual mutations in circulation.
9.8.9
Whole Blood Gene Expression
The expression level of genes related to response to nivolumab/ipilimumab therapy will be 
quantified using molecular methods such as Affymetrix by microarray and/or quantitative reverse 
transcription polymerase chain reaction (RT-PCR) analysis in whole blood samples. Analysis may 
include, but not necessarily be limited to, genes associated with immune-related pathways, such 
as T cell activation and antigen processing and presentation.
9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
Details on accrual assumptions are in Section 5.2.
Primary Study:
The sample size of the primary study accounts for 2 primary comparisons of the primary endpoint 
(OS): in cisplatin-ineligible participants and in PD-L1 positive (≥1%) participants with previously 
untreated unresectable or metastatic UC.
The overall alpha for the primary study is 0.05, which is split with 0.02 to evaluate OS in cisplatin-
ineligible participants and 0.03 to evaluate OS in PD-L1 positive (≥1%) participants, accounting 
for one formal interim analysis in each primary population. 
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Substudy:
The sample size of the substudy accounts for the dual-primary efficacy endpoints: PFS based on 
BICR assessments and OS, evaluated in cisplatin-eligible participants with previously untreated 
unresectable or metastatic UC.
The overall alpha for the substudy is 0.05, which is split with 0.01(two-sided) to evaluate PFS and 
0.04(two-sided) to evaluate OS. No interim analysis of PFS is planned. One formal OS interim 
analysis at 75% information fraction and one final analysis are planned to assess efficacy.
Primary Study and Substudy:
For the primary study and substudy, simulation models incorporating aspects of immunotherapy-
like delayed separation (observed as late separation of survival curves between the experimental 
and SOC arms), long term survival benefits (observed as a long-lasting plateau towards the tail of 
the survival curve) and potential access to immunotherapy as second line therapy among 
participants randomized into the SOC chemotherapy arm post first-line progression were 
developed for sample size estimation. Sample size calculations for this study design were done 
using EAST 6 (v. 6.3.1) and R.
Overall approximately 445 cisplatin-ineligible participants (per eligibility criteria see Section 6.1) 
and 845 cisplatin-eligible participants will be randomized. Of the 845 cisplatin-eligible 
participants, approximately 245 will be randomized in the primary study and 600 will be 
randomized in the substudy.
The primary analysis in the primary study is based on the number of OS events observed in each 
primary population (cisplatin-ineligible participants and PD-L1 positive (≥1%) participants by 
IHC). Once at least 445 cisplatin-ineligible participants and at least 235 PD-L1 positive 
participants are randomized into Arms A and B of the primary study, the primary study will cease 
enrollment (Arms A and B). (This is regardless of the number of cisplatin-eligible participants 
randomized in the primary study.) Subsequent cisplatin-eligible participants will only be 
randomized to the substudy.
10.1.1
Sample Size Justification for the Primary Overall Survival Endpoints in
the Primary Study
The primary study accounts for two primary comparisons of the primary endpoint (OS): in 
cisplatin-ineligible participants and in PD-L1 positive (≥1%) participants with previously 
untreated unresectable or metastatic UC.
The overall alpha for this primary study is 0.05, which is split with 0.02 to evaluate OS in cisplatin-
ineligible participants and 0.03 to evaluate OS in PD-L1 positive (≥1%) participants, accounting 
for one formal interim analysis in each primary population.
10.1.1.1
Overall Survival in Cisplatin-ineligible Participants
One of the primary objectives of the primary study is to compare OS of nivolumab combined with 
ipilimumab to SOC chemotherapy in cisplatin-ineligible participants with previously untreated, 
unresectable or metastatic UC. The number of events and power of this comparison were 
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calculated assuming a non-proportional hazard model with a 3-month delayed treatment effect and 
a 0.23 cure fraction in the nivolumab combined with ipilimumab arm (weighted average of 
estimated OS cure rate of 20% in PD-L1 negative (<1%) participants and 30% in PD-L1 positive 
(≥1%) participants) and a 0.10 cure fraction in the SOC chemotherapy arm.
Approximately 348 events (i.e., deaths), observed among the 445 randomized cisplatin-ineligible 
participants, provides 80% power to detect an average HR of 0.71 with an overall type 1 error of 
0.02 (two-sided). The average HR of 0.71 corresponds to a 40.8% increase in the median OS, 
assuming a median OS of 13.0 months17in the SOC chemotherapy arm (median estimate assuming 
a median OS of 11 months in cisplatin-ineligible participants increased by 2 months for use of 
PD-1/PD-L1 in the refractory setting) and 18.3 months in the experimental treatment arm, taking 
into account 3-month delayed treatment effect and cure rates in each arm as specified above.
One formal interim analysis of OS in cisplatin-ineligible participants is planned in this primary 
study. This interim analysis is planned after 278 observed events (i.e., deaths) corresponding to
80% of the targeted OS events for final analysis and it is expected to happen 41 months from the 
randomization of the first participant. The alpha allocation for the interim and final analyses is 
based on the Lan-DeMets alpha spending function approach using an O’Brien Fleming stopping 
boundary controlling for a two-sided overall type 1 error of 2%. The stopping boundary will 
depend on the actual number of deaths at the time of the interim analysis and the final analysis.
Under the assumptions for accrual and OS distribution stated above, it will take approximately 
55 months from the randomization of the first participant to observe the required number of OS 
events for the final OS analysis (28 months for accrual and 27 months for minimum follow-up). It 
is projected that an observed hazard ratio of 0.77 or less would results in a statistically significant 
improvement of nivolumab combined with ipilimumab at the final analysis of OS in cisplatin-
ineligible participants.
10.1.1.2
Overall Survival in PD-L1 Positive (≥ 1%) Participants
One of the primary objectives of the primary study is to compare OS of nivolumab combined with 
ipilimumab to SOC chemotherapy in PD-L1 positive (≥ 1%) participants by IHC with previously 
untreated, unresectable or metastatic UC. The number of events and power of this comparison
were calculated assuming a non-proportional hazard model with a 3-month delayed treatment 
effect, a 0.30 cure fraction in the nivolumab combined with ipilimumab arm and a 0.13 cure 
fraction in the SOC chemotherapy arm (weighted average of estimated OS cure rate of 10% in 
cisplatin-ineligible participants and 20% in cisplatin-eligible participants), accounting for use of 
second-line immunotherapy.
Approximately 163 events (i.e., deaths), observed among the 235 randomized PD-L1 positive 
(≥1%) participants by IHC, provides 84% power to detect an average HR of 0.61 with an overall 
type 1 error of 0.03 (two-sided). The average HR of 0.61 corresponds to a 70.2% increase in the 
median OS, assuming a median OS of 14.1 months (weighted average of estimated median OS of 
13 months in cisplatin-ineligible participants and 16 months in cisplatin-eligible participants, both 
being increased by 2 months for use of PD-1/PD-L1 in the refractory setting) in the SOC 
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chemotherapy arm and 24.0 months in the experimental treatment arm, taking into account 
3-month delayed treatment effect and cure rates in each arm as specified above.
One formal interim analysis of OS in PD-L1 positive (≥ 1%) participants is planned in this primary 
study. This interim analysis is planned after 130 observed events (i.e., deaths) corresponding to 
80% of the targeted OS events for final analysis and it is expected to happen 41 months from the 
randomization of the first participant. The alpha allocation for the interim and final analyses is 
based on the Lan-DeMets alpha spending function approach using an O’Brien Fleming stopping 
boundary controlling for a two-sided overall type 1 error of 3%. The stopping boundary will 
depend on the actual number of deaths at the time of the interim analysis and the final analysis.
Under the assumptions for accrual and OS distribution stated above, it will take approximately 
52 months from the randomization of the first participant to observe the required number of OS 
events for the final OS analysis (28 months for accrual and 24 months for minimum follow-up). It 
is projected that an observed hazard ratio of 0.70 or less would results in a statistically significant 
improvement of nivolumab combined with ipilimumab at the final analysis of OS in PD-L1 
positive (≥ 1%) participants by IHC.
10.1.2
Sample Size Justification for the Secondary Overall Survival Endpoint 
in All Randomized Participants in the Primary Study
Under the accrual projection detailed in the Section 5.2, Number of Participants, it is estimated 
that approximately 690 participants will be randomized in the primary study, with an estimated 
445 cisplatin-ineligible participants and 245 cisplatin-eligible participants.
One of the secondary objectives of the primary study is to compare OS of nivolumab combined 
with ipilimumab to SOC chemotherapy in all randomized participants with previously untreated, 
unresectable or metastatic UC. The HR in the all randomized participants is expected to be in a 
range. The number of events and power of this comparison were calculated assuming a non-
proportional hazard model with a 3-month delayed treatment effect, a 0.23 cure fraction (per 
weighted average) in the nivolumab combined with ipilimumab arm and a 0.13 cure fraction (per 
weighted average) in the SOC chemotherapy arm.
One formal interim is planned in the all randomized participants. The interim and final analyses 
are planned at the corresponding time of the interim and final analysis of the primary comparisons.
Assuming an average HR of 0.75, at the final OS analysis of the primary comparisons 
(approximately 55 months from the randomization of the first participant), it is expected to observe 
approximately 518 events (i.e., deaths) among the 690 randomized participants in the two 
respective treatment arms. This would lead to a 90% power for the all randomized comparison
with an overall type 1 error of 0.05 (two-sided). The average HR of 0.75 corresponds to a 33% 
increase in the median OS, assuming a median OS of 13.9 months in the SOC chemotherapy 
arm11,17 (increased by 2 months for use of PD-1/PD-L1 in the refractory setting) and 18.5 months 
in the experimental treatment arm.
At the interim analysis, it is expected to observe 414 events (80.0% of the targeted OS events for 
final analysis). 
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The alpha allocation for the interim and final analyses is based on the Lan-DeMets alpha spending 
function approach using an O’Brien Fleming stopping boundary controlling for a two-sided overall 
type 1 error passed from the primary comparisons. The stopping boundary will depend on the 
actual number of deaths at the time of the interim analysis and the final analysis.
10.1.3
Sample Size Justification for the Dual Primary Endpoints of 
Progression Free Survival and Overall Survival in Cisplatin-eligible 
Randomized Participants in the Substudy
The substudy accounts for dual primary endpoints: PFS as per BICR and OS. Overall alpha is set 
at 0.05, which is split with 0.01 to evaluate PFS and 0.04 to evaluate OS.
10.1.3.1
Progression Free Survival
One of the primary objectives of the substudy is to compare PFS (based on BICR assessments) of 
nivolumab combined with SOC chemotherapy to SOC chemotherapy in cisplatin-eligible 
participants with previously untreated, unresectable or metastatic UC. The number of events and 
power were calculated assuming a non-proportional hazards model with a 3-month delayed 
treatment effect, a 0.20 cure fraction in Arm C and a 0.15 cure fraction in the Arm D.
For the comparison of PFS endpoint using log rank test, 460 PFS events among the 
600 randomized cisplatin-eligible participants will show a statistically significant difference
between the treatment arms with 70% power under a two-sided experiment-wise alpha = 0.01
when the average HR of the experimental arm to SOC arm is 0.7. This HR of 0.7 is equivalent to 
demonstrating a 42% improvement in median PFS, assuming a median PFS of 7.7 months11 in the 
SOC chemotherapy arm and a median PFS of 10.9 months in the experimental treatment arm. No
interim analysis of PFS is planned for this substudy. 
If OS superiority is demonstrated in interim analysis for the substudy, formal testing of PFS will 
be performed. The significance level of the PFS will depends on the number of PFS events occur 
at time of the interim analysis. The hierarchical testing procedure under the group sequential 
testing setting will be employed to control the overall type 1 error. It is projected that 
approximately 368 PFS events may occur (80% of total events) at the time of OS interim analysis.
Under the assumptions for accrual and PFS distribution stated above, it will take approximately 
45 and 54 months from the randomization of the first participant in the substudy to observe the 
required number of PFS events for the interim (if performed) and final PFS analysis (44 months 
for accrual and 10 months for minimum follow up), respectively.). It is projected that an observed 
HR of 0.786 or less would result in a statistically significant improvement in the final analysis of 
PFS. However, the PFS final analysis will be performed at the time of final OS analysis which 
may be earlier than the planned number of PFS events.
Table 10.1.3.1-1 summarizes the power of PFS corresponding to different potential numbers of 
PFS events observed at the time of OS final analysis if no PFS interim analysis is performed, for 
a two-sided total alpha level of 0.01 (without alpha recycling) and 0.05 (with alpha recycling).
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Table 10.1.3.1-1:
PFS per BICR Power for Different Potential Number of PFS Events 
at OS Final Analysis (Cis-eligible Randomized Participants)
Potential number of PFS events 
at OS final analysis
Total alpha
PFS power
405
0.01
59%
0.05
80%
410
0.01
61%
0.05
82%
415
0.01
62%
0.05
83%
10.1.3.2
Overall Survival
One of the primary objectives of the substudy is to compare the OS of nivolumab combined with 
SOC chemotherapy to SOC chemotherapy in cisplatin-eligible participants with previously 
untreated, unresectable or metastatic UC. The number of events and power were calculated 
assuming a non-proportional hazards model with a 3-month delayed treatment effect, a 0.234 cure 
fraction in Arm C and a 0.20 cure fraction in the Arm D.
For the comparison of OS endpoint using log rank test, at least 356 OS events among the 
600 randomized cisplatin-eligible participants are required to show a statistically significant 
difference in OS between the treatment arms with 85% power under a 2-sided experiment-wise 
alpha = 0.04 when the average HR of the experimental arm to SOC arm is 0.7. The HR of 0.7 is 
equivalent to demonstrating a 47% improvement in median OS, assuming a median OS of 
16 months11 in the SOC chemotherapy arm and a median OS of 23.5 months in the experimental 
treatment arm.
One interim analysis of OS is planned for the substudy when 267 OS events (75% information 
fraction) have occurred. The alpha allocation for the interim and final analyses is based on the Lan-
DeMets alpha spending function approach using an O’Brien Fleming stopping boundary 
controlling for a 2-sided overall type 1 error of 4%. The stopping boundary will depend on the 
actual number of OS events at the time of the interim analyses and the final analysis.
Under the assumptions for accrual and OS distribution stated above, it will take approximately 45
and 54 months from the randomization of the first participant in the substudy to observe the 
required number of OS events for the interim and final OS analyses, respectively. It is projected 
that an observed HR of 0.74 and 0.8 or less would result in a statistically significant improvement 
in the interim and final analysis of OS, respectively.
10.1.4
Analysis Timing Projections
As stated above, approximately 1290 participants with previously untreated, unresectable or 
metastatic UC will be randomized (see Section 5.2). 
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It will take approximately 28 months to complete the randomization of the primary study and 
6 extra months to complete the randomization of the substudy.
Table 10.1.4-1 summarizes populations and the projected timing of primary comparisons and 
secondary endpoints analyses planned in the primary study and of primary endpoint analysis in the 
substudy.
It is expected that final OS analysis in each primary population of the primary study will occur at 
3 months interval and will have their interim OS analysis at the same time. However, because the 
OS event rate pattern may be different between cisplatin-ineligible participants and PD-L1 positive 
participants, the interim OS analyses of the primary study will occur at the same time if the targeted 
OS events are projected to happen with less than 5 months interval. The same rule will apply for 
the final OS analyses of the primary study.
The substudy final analysis will be OS driven and will be conducted when the OS final analysis 
events (at least 356) are reached. The substudy PFS final analysis will be conducted at the same 
time as the OS final analysis. 
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Table 10.1.4-1:
Populations and Projected Timing for Analysis of Primary 
Endpoints: Primary Study and Secondary Study
Endpoint
Population
Criteria
Projected 
timing
Type 1 error
Primary study
Primary OS in PD-L1 
positive
(Interim Analysis)
All PD-L1 positive
randomized 
participants in 
primary study
At least 130 events
41 monthsa
O’Brien Fleming 3% 
two-sided
Primary OS in PD-L1 
positive
(Final Analysis)
All PD-L1 positive
randomized 
participants in 
primary study
At least 163 events
52 monthsa
O’Brien Fleming 3% 
two-sided
Primary OS in 
cisplatin-ineligible 
(Interim Analysis)
All cisplatin-
ineligible randomized 
participants in 
primary study
At least 278 deaths
41 monthsa
O’Brien Fleming 2%
(or 5%) two-sided (for 
details, see Section
10.3.1.1)
Primary OS in 
cisplatin-ineligible 
(Final Analysis)
All cisplatin-
ineligible randomized 
participants in 
primary study
At least 348 events
55 monthsa
O’Brien Fleming 2% 
(or 5%) two-sided (for 
details, see Section
10.3.1.1)
Secondary OS in all 
randomized 
(Interim Analysis)b
All randomized 
participants in 
primary study
At time of interim OS 
final analysis, in a 
hierarchical fashion 
(for details, see 
Section 10.3.1.2)
~ 414 deaths
41 monthsa
O’Brien Fleming 2% 
(or 5%)
two-sided (for details, 
see Section 10.3.1.2)
Secondary OS in all 
randomized 
(Final Analysis)b
All randomized 
participants in 
primary study
At time of interim OS 
final analysis, in a 
hierarchical fashion 
(for details, see 
Section 10.3.1.2)
~ 518 deaths
55 monthsa
O’Brien Fleming 2% 
(or 5%)
two-sided (for details, 
see Section 10.3.1.2)
Substudy
Substudy OS (Interim 
Analysis)
All cisplatin-eligible 
randomized 
participants in the 
substudy
At time of cisplatin-
ineligible OS final
analysis of primary 
study
~ 267 OS (75% 
information fraction) 
events
55 months
(ie, 45
monthc)
O’Brien Fleming 4% 
two-sided
Substudy OS and PFS
(Final Analysis)
All cisplatin-eligible 
randomized 
participants in the 
substudy
At least 356 OS
events
64 months
(ie, 54
monthsc)
O’Brien Fleming 1%
(PFS), 4 % (OS) two-
sided
a Projected timing from first participant’s randomization date in primary study.
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b Under hierarchical testing procedure (See Section 10.3.1 for further details).
c Projected timing from first participant’s randomization date in substudy.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All enrolled participants
All participants who signed an informed consent form and were registered into 
the IRT.
All randomized participants
All randomized participants overall.
Cisplatin-ineligible 
randomized participants
All randomized participants meeting cisplatin-ineligibility criteria (See Section
6.1) at the time of randomization. This is one of the primary populations for the 
primary study. Analysis of demography, protocol deviations, baseline 
characteristics and primary efficacy analysis will be performed for this 
population.
All randomized participants 
with PD-L1 at ≥1% 
expression by 
immunohistochemistry (IHC) 
in the primary study
All randomized participants with PD-L1 expressing tumor (≥1%) who were 
randomized in the primary study. This is one of the primary populations for the 
primary study. Analysis of demography, protocol deviations, baseline 
characteristics and primary efficacy analysis will be performed for this 
population
All randomized participants 
in the primary study
All randomized participants in the primary study. This population is considered 
as the secondary efficacy analysis population for the primary study. Analysis of 
demography, protocol deviations, baseline characteristics, secondary efficacy 
analysis and outcome research analysis will be performed for this population. 
Cisplatin-eligible randomized 
participants in the primary 
study
All randomized participants meeting cisplatin-eligibility criteria (See 
Section 6.1) at the time of randomization in the primary study. This population is 
considered as the exploratory efficacy analysis population for the primary study. 
Analysis of demography, protocol deviations, baseline characteristics, 
exploratory efficacy analysis and outcome research analysis will be performed 
for this population.
Cisplatin-eligible randomized 
participants in the substudy
All randomized participants meeting cisplatin-eligibility criteria (See 
Section 6.1) at the time of randomization in the substudy. This is the primary 
efficacy analysis population of the sub-study. Analysis of demography, protocol 
deviations, baseline characteristics and primary efficacy analysis will be 
performed for this population.
All treated participants
All participants who received any dose of study therapy. This is the primary 
dataset for drug exposure and safety analysis.
PK participants
All participants with available serum time-concentration data from randomized 
participants dosed with nivolumab.
Immunogenicity participants
All participants with available data from randomized participants dosed with 
nivolumab.
Immunogenicity evaluable 
participants
All treated participants with baseline and at least one post baseline 
immunogenicity assessment.
Outcome research 
participants
All treated participants who have an assessment at baseline and at least one 
subsequent assessment.
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Population
Description
Biomarker participants
All randomized participants with available biomarker data (PD-L1 expression 
status and other assays).
All randomized participants 
with PD-L1 expression at 
≥1% expression by 
immunohistochemistry (IHC) 
in the substudy
All randomized participants with PD-L1 expressing tumor (≥1%) who were 
randomized in the substudy. This is the primary dataset for the secondary 
efficacy analysis in the PD-L1 expressing group in the substudy.
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 and unused data. Below is a summary of planned statistical analyses of the primary and 
secondary endpoints.
10.3.1
Efficacy Analyses
Primary Study:
The primary objective of the primary study is to compare OS (defined in Section 9.1.1 of 
nivolumab combined with ipilimumab to SOC chemotherapy in the cisplatin-ineligible and in the 
PD-L1 positive (≥1%) randomized participants. 
The first secondary objective of the primary study is to compare OS of nivolumab combined with 
ipilimumab to SOC chemotherapy in all randomized participants in the primary study. This will 
be measured by the same definition of OS, as specified in Section 10.3.1.1, in the all randomized 
population in the primary study.
For these 3 comparisons, multiplicity adjustment (as described in Section 10.3.1.1 and 10.3.1.2)
will be applied to ensure strong control of the Type I error rate at 0.05. 
The second secondary objective of this study is to evaluate PFS in nivolumab combined with 
ipilimumab versus SOC chemotherapy in the two primary populations and in all randomized 
participants in the primary study. This will be measured by PFS endpoint defined in Section 
10.3.1.2, in the two primary populations and in all randomized participants in the primary study.
The third secondary objective of this study is to evaluate changes from baseline in health-related 
QOL in nivolumab combined with ipilimumab versus SOC chemotherapy in all randomized 
participants in the primary study. This will be measured by QLQ-C30 Global Health Status score, 
as specified in Section 10.3.1.2, in the all randomized population in the primary study.
Substudy:
The primary objective of the substudy is to compare PFS (based on BICR assessments) and OS of 
nivolumab combined with SOC chemotherapy to SOC chemotherapy in the cisplatin-eligible 
randomized participants in the substudy. This will be measured by the PFS and OS endpoints
defined in Section 10.3.1.1, in the cisplatin-eligible randomized participants in the substudy.
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The secondary objectives of this study are:
•
To evaluate changes from baseline in health-related QOL in nivolumab combined with SOC
chemotherapy versus SOC chemotherapy in the cisplatin-eligible randomized participants in
the substudy. This will be measured by QLQ-C30 Global Health Status score, as specified in
Section 10.3.1.2, in the cisplatin-eligible randomized population in the substudy.
•
To evaluate whether PD-L1 expression is a predictive biomarker of efficacy (PFS and OS) of
nivolumab combined with SOC chemotherapy as first-line therapy in cisplatin-eligible
participants with previously untreated, unresectable or metastatic UC using Kaplan-Meier
survival plot between treatments by PD-L1 expression status (<1% or ≥1%).
10.3.1.1
Primary Endpoints
Primary Study:
Overall survival is the primary endpoint in the primary study.
The formal comparison of OS will be conducted in the two primary populations, using a two-sided 
0.03 stratified log-rank test (adjusted for interim analysis) in the PD-L1 positive (≥1%) 
participants by IHC and a two-sided 0.02 stratified log-rank test (adjusted for interim analysis) in 
the cisplatin-ineligible participants, each comparison with the randomization stratification factors 
as recorded in IRT as stratification factors. At either the interim or final analysis: in case OS in the 
PD-L1 positive (≥ 1%) participants is significant, its significance level of 0.03 will be passed on 
to the other primary comparison (ie OS in the cisplatin-ineligible participants will be tested at a 
local significance level of 0.05 [adjusted for interim analysis]). 
Median OS will be estimated via the Kaplan-Meier product limit method. Median survival time 
along with two-sided 95% CI will be constructed based on a log-log transformed CI for the survival 
function. Kaplan-Meier plots of OS will be presented. Hazard ratios (HR) and corresponding two-
sided (1 - adjusted alpha)% confidence intervals (CI) will be estimated using a Cox proportional 
hazards model, with treatment arm as a single covariate, stratified by the stratification factors, 
corresponding to the comparison of OS.
Rates at landmark time will be derived from the KM estimate and corresponding CI will be derived 
based on Greenwood formula for variance derivation and on log-log transformation applied on the 
survivor function.
Substudy:
Progression-free survival (PFS) and overall survival (OS) are the dual primary endpoints in the 
substudy.
The formal comparison of PFS will be conducted using a two-sided 0.01 stratified log-rank test, 
with the randomization stratification factors as recorded in IRT as stratification factors among 
cisplatin-eligible randomized participants in the substudy. 
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The formal comparison of OS will be conducted using a two-sided 0.04 stratified log-rank test, 
with the randomization stratification factors as recorded in IRT as stratification factors among 
cisplatin-eligible randomized participants in the substudy.
Median PFS and OSwill be estimated via the Kaplan-Meier product limit method. Median survival 
time along with two-sided 95% CI will be constructed based on a log-log transformed CI for the 
survival function. Kaplan-Meier plots of PFS and OS will be presented. HR and corresponding 
two-sided (1-adjusted alpha) % CI will be estimated using a Cox proportional hazards model, with 
treatment arm as a single covariate, stratified by the stratification factors, corresponding to the 
comparison of PFS and OS.
In case OS is significant at either the interim analysis or final analysis, its significance level of 
0.04 will be passed on to the PFS primary comparison (ie PFS will be tested at a local significance 
level of 0.05). If OS superiority is demonstrated in interim analysis, a formal testing of PFS will 
be performed at the time of the OS interim analysis (hierarchical testing). The significance level 
of the PFS will depends on the number of PFS events occur at time of the interim analysis. The 
Lan-DeMets alpha spending function with O’Brien and Fleming type of boundary under the group 
sequential testing setting will be used to ensure the control of type 1 error. Detailed hierarchical 
testing procedure can be found in Section 7.5.10 of the SAP with both graphical presentation and 
the exact significance level if the analysis is conducted at the planned number of events. Similarly, 
if PFS is tested significant at final analysis, its significance level of 0.01 will be passed on to the 
OS final analysis (ie OS will be tested at a local significance level of 0.05 at final analysis under 
group sequential testing procedure and adjusts for the OS interim analysis).
Rates at landmark time will be derived from the KM estimate and corresponding CI will be derived 
based on Greenwood formula for variance derivation and on log-log transformation applied on the 
survivor function.
10.3.1.2
Secondary Endpoints
Primary Study:
Overall Survival
If OS superiority is demonstrated in cisplatin-ineligible participants, formal testing of OS among 
all randomized participants in the primary study will be performed. (If, at a given timepoint, OS 
in the PD-L1 positive (≥ 1%) population is significant, but not OS in the cisplatin-ineligible
population then OS in the all randomized participants will not be tested.) Local significance level 
will be 0.02 if no significance level was passed from the PD-L1 positive (≥ 1%) population to the 
cisplatin-ineligible population; 0.05 otherwise. For OS in all randomized participants, one interim 
analysis is planned; thus the local significance level (0.02 or 0.05) will be adjusted based on the 
Lan-DeMets alpha spending function approach using an O’Brien Fleming stopping boundary. The 
stopping boundary will depend on the actual number of deaths at the time of the interim and the 
final analysis. Analyses of OS among all randomized participants in the primary study will be 
similar to those conducted towards the assessment of the primary OS objective.
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Progression-Free Survival
PFS will be evaluated among each primary population and among all randomized participants in 
the primary study.
Median PFS will be estimated via the Kaplan-Meier product limit method. Median survival time 
along with two-sided 95% CI will be constructed based on a log-log transformed CI for the survival 
function. Kaplan-Meier plots of PFS will be presented. HR and corresponding two-sided 95% CI
will be estimated using a Cox proportional hazards model, with treatment arm as a single covariate, 
stratified by the stratification factors, corresponding to the comparison of PFS.
Analysis for investigator-assessed PFS will be performed similarly.
Rates at landmark time will be derived from the KM estimate and corresponding CI will be derived 
based on Greenwood formula for variance derivation and on log-log transformation applied on the 
survivor function.
EORTC QLQ-C30 Global Health Score
The analysis of EORTC QLQ-C30 Global Health Status score will be performed for participants 
who have an assessment at baseline (Visit 1 assessment prior to administration of drug) and at least 
1 subsequent assessment.
For EORTC QLQ-C30 all scales and single items are scored on categorical scales and linearly 
transformed to 0-to-100 scales, with higher scores for the Global Health Status representing higher 
levels of Global Health Status. Data will be analyzed as change from baseline scores. 
Baseline and change from baseline in EORTC QLQ-C30 Global Health Status score data will be 
summarized at each of the assessment time points. 
Substudy:
EORTC QLQ-C30 Global Health Score
The analysis of EORTC QLQ-C30 Global Health Status score will be performed for participants 
who have an assessment at baseline (Visit 1 assessment prior to administration of drug) and at least 
1 subsequent assessment.
For EORTC QLQ-C30 all scales and single items are scored on categorical scales and linearly 
transformed to 0-to-100 scales, with higher scores for the Global Health Status representing higher 
levels of Global Health Status. Data will be analyzed as change from baseline scores. 
Baseline and change from baseline in EORTC QLQ-C30 Global Health Status score data will be 
summarized at each of the assessment time points. 
PD-L1 Expression
PD-L1 expression as a predictive biomarker of efficacy (PFS and OS) of nivolumab combined 
with SOC chemotherapy as first-line therapy in cisplatin-eligible participants with previously 
untreated, unresectable or metastatic UC will be evaluated by Kaplan-Meier survival plot between 
treatments by PD-L1 expression status (<1% or ≥ 1%).
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10.3.1.3
Exploratory Endpoints
Primary Study and Substudy:
Objective Response Rate
ORR (based on BICR assessments) will be summarized by binomial response rates and their 
corresponding two-sided 95% exact CIs using Clopper-Pearson method, by treatment group. 
Analysis for investigator-assessed ORR will be performed similarly.
The BICR-assessed objective response will be further characterized by the time to objective 
response (TTR) and duration of response (DOR). DOR and TTR will be evaluated for responders 
(confirmed CR or PR) only.
TTR is defined as the time from randomization to the date of the first confirmed response (CR or 
PR), as assessed by the BICR.
TTR will be summarized using descriptive statistics for the responders.
DOR is defined as the time between the date of first confirmed response (CR or PR) to the date of 
the first documented tumor progression as determined by the BICR (using the RECIST 1.1 criteria) 
or death due to any cause, whichever occurs first. Participants who start subsequent therapy 
without a prior reported progression will be censored at the last evaluable tumor assessment prior 
to initiation of the subsequent anticancer therapy. Participants who die without a reported prior 
progression will be considered to have progressed on the date of their death. Participants who 
neither progress nor die will be censored on the date of their last evaluable tumor assessment.
DOR will be summarized for the participants who achieved confirmed PR or CR using the Kaplan-
Meier (KM) product-limit method. Median values of DOR, along with two-sided 95% CI using 
Brook-Meyer and Crowley method, will also be calculated.
10.3.2
Safety Analyses
Safety and tolerability will be measured by the incidence of adverse events, serious adverse events, 
deaths and laboratory abnormalities. Adverse events incidence rate is defined as the proportion of 
participants with any grade adverse events among participants treated in each treatment arm. 
Events reported from the first dose up to and including 100 days following the last dose of study 
treatment could be included in estimating this incidence rate.
The safety analysis will be performed in all treated participants. Select safety analysis will also be 
performed in cisplatin-ineligible participants and in cisplatin-eligible participants. Additional 
details will be provided in statistical analysis plan. Descriptive statistics of safety will be presented 
using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 by treatment arm. All AEs, drug-related AEs, SAEs and drug-related SAEs 
will be tabulated using the worst grade per NCI CTCAE v4.0 criteria by organ class and preferred 
term. On-study lab parameters including hematology, coagulation, chemistry, liver function and 
renal function will be summarized using worst grade per NCI CCAE v4.0 criteria. 
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10.3.3
Other Analyses 
PK, immunogenicity, and biomarker exploratory analyses will be described in the statistical 
analysis plan finalized before database lock. The population pharmacokinetics analysis and 
pharmacodynamic analyses will be presented separately from the main clinical study report. 
10.3.3.1
Pharmacokinetic Analyses
The nivolumab and ipilimumab concentration data obtained in this study may be combined with 
data from other studies in the clinical development program to develop or refine a population PK 
model. This model may be used to evaluate the effects of intrinsic and extrinsic covariates on the 
PK of nivolumab and to determine measures of individual exposure (such as steady-state peak, 
trough, and time-averaged concentration). In addition, model determined exposures may be used 
for exposure-response analyses. Results of population PK and exposure response-analyses will be 
reported separately.
10.3.3.2
Immunogenicity Analyses
Immunogenicity may be reported for ADA positive status (such as persistent positive, only last 
sample positive, other positive, baseline positive) and ADA negative status, relative to baseline. 
In addition, presence of neutralizing antibodies may be reported, if applicable. Effect of 
immunogenicity on safety, efficacy, biomarkers and PK may be explored. Additional details will 
be described in the SAP.
10.3.3.3
Biomarker Analyses
Pharmacodynamic Analyses
To assess pharmacodynamic effects in serum, blood RNA, or peripheral cells obtained from 
participants on each treatment arm, summary statistics for biomarkers of immunoregulatory 
activity (eg, IFN-inducible proteins, miRNAs, gene expression, immune cells) and their 
corresponding changes (or percent changes) from baseline will be tabulated by planned study visit. 
In addition, the time course of biomarker outcomes will be investigated graphically. If there is 
indication of a meaningful pattern across time, further analysis may be completed to characterize 
the relationship. Possible associations between changes in biomarker measures of interest and 
exposure to study drug will be explored graphically.
Pharmacogenomics and Exploratory Analyses
Potential relationships between biomarker data and efficacy or safety endpoints will be 
investigated as part of an analysis plan aimed at identifying baseline biomarkers that may be used 
to prospectively identify participants likely (or not likely) to respond to nivolumab and to identify 
participants who may be predisposed to having adverse reactions to treatment. These exploratory 
predictive biomarker analyses will be completed with biomarkers measured in blood and in tumor 
samples and will focus primarily, as outlined in the exploratory objectives, on SNPs in select genes 
associated with immunity or on the expression of selected proteins in tumor specimens, such as 
PD-1, and PD-L2. Similar analyses will be completed with data regarding serum-soluble factors, 
blood RNA and/or immune cell types.
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Associations between biomarkers and efficacy measures will be analyzed on all participants 
treated with at least one dose of study medication and with corresponding efficacy and biomarker 
measurements. Efficacy measures will include response, PFS, and OS. Demographic and case-
history factors will be examined to determine whether stratification or adjustments should be made 
within the subsequent statistical analyses, and if necessary, the appropriate stratification or 
adjustment will be made.
Biomarkers will be summarized graphically as they relate to efficacy and safety endpoints, as 
applicable. Summary statistics will be tabulated. SNP allele frequencies will be summarized. The 
relationships between binary measures (eg, response) and candidate biomarkers will be 
investigated using logistic regression. Associations will be summarized in terms of point and 
interval estimates of hazard ratios, odds ratios, or other statistics, as appropriate for the analyses 
completed. Models to predict clinical activity based on combinations of biomarkers may also be 
investigated.
Additional post hoc statistical analyses not specified in the protocol, such as alternative modeling 
approaches may be completed. All analyses described in this section are based on the availability 
of the data.
10.3.3.4
Outcome Research Analyses
EORTC QLQ-C30 Functional Scales and Symptom Scales
The analysis of EORTC QLQ-C30 functional scales and symptom scales will be performed for 
participants who have an assessment at baseline (Visit 1 assessment prior to administration of 
drug) and at least 1 subsequent assessment.
For EORTC QLQ-C30 all scales and single items are scored on categorical scales and linearly 
transformed to 0-to-100 scales with higher scores for a functional scale representing higher levels 
of functioning and higher scores for a symptom scale representing higher level of symptoms. Data 
will be analyzed as change from baseline scores. 
Baseline and change from baseline in the EORTC QLQ-C30 functional scales and symptom scales 
will be summarized at each of the assessment time points. 
In addition:
•
The percentage of participants demonstrating a clinically meaningful deterioration (defined as 
a 10 point change from baseline) will be presented for each scale at each assessment time point. 
Percentages will be based on number of participants assessed at assessment time point.
•
Participant compliance will be described per time point by the proportion of participants who 
filled out the EORTC QLQ-C30 assessments over the numbers of participant known to be alive 
and eligible for assessment at these time points. 
EuroQol EQ-5D-5L
The analysis of EQ-5D-5L will be performed for participants who have an assessment at baseline 
(Visit 1 assessment prior to administration of drug) and at least 1 subsequent assessment.
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The EQ-5D-5L comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety) and a VAS. The EQ-5D-5L descriptive system will be converted into a single summary 
index score which provides a simple measure of health on a scale of 0 to 1 (0 = death and 
1 = perfect health). EQ-5D-5L data will be described in the following three ways:
Participant’s overall health state on a visual analog scale (EQ-VAS) and a summary index 
(EQ-5D-5L index) at each assessment time point will be summarized using descriptive statistics. 
(N, mean, standard deviation, median, first and third quartiles, minimum, maximum).
•
Proportion of participants reporting problems for the 5 EQ-5D-5L dimensions at each 
assessment time point will be summarized by level of problem. Percentages will be based on 
number participants assessed at assessment time point.
•
A by-participant listing of EQ-5D-5L with the problem levels for each of the 5 dimensions 
(mobility, self-care, usual activities, pain / discomfort and anxiety/depression), health state 
(5 dimensions digits combined in a 5-digit number), EQ-5D-5L index, and EQ-VAS will be 
provided.
In addition, participant compliance will be described per time point by the proportion of 
participants who filled out the EQ-5D-5L assessments over the numbers of participant known to 
be alive and eligible for assessment at these time points.
10.3.4
Interim Analyses 
Primary Study:
One interim analysis of OS is planned in each primary population.
It is scheduled after approximately 130 deaths among the PD-L1 positive (≥1%) participants and 
278 deaths among the cisplatin-ineligible participants (approximately 80% of the targeted OS 
events in each primary population) have been observed based on above accrual rate and the non-
proportional hazards model. These formal comparisons of OS will allow for early stopping for 
superiority, and the boundaries for declaring superiority will be derived based on the actual number 
of deaths using Lan-DeMets alpha spending function with O’Brien and Fleming type of boundary 
in EAST 6 (v 6.3.1). The boundary for declaring superiority in terms of statistical significance for 
the final analysis after 163 deaths among the PD-L1 positive (≥1%) participants would be 0.70. 
The boundary for declaring superiority in terms of statistical significance for the final analysis 
after 348 deaths among the cisplatin-ineligible participants would be 0.77.
Interim analysis is also planned for OS in the all randomized population (secondary endpoint). It 
is projected that the interim analysis will happen with approximately 414 deaths in the all 
randomized population (approximately 80% of the 518 projected to occur at the final analysis). 
The boundaries for declaring superiority will be derived based on the actual number of deaths 
using Lan-DeMets alpha spending function with O’Brien and Fleming type of boundary in EAST 6 
(v 6.3.1).
Note that all deaths available at the time of the database-lock will be used for the primary and 
secondary analyses (even if it is more than pre-specified). 
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Substudy:
One interim analysis of OS is planned and is scheduled at the time of the cisplatin-ineligible final 
OS analysis in the primary study and it is expected after approximately 267 OS events
(approximately 75% of the targeted OS events in the substudy) have been observed among 
cisplatin-eligible randomized participants in the substudy based on above accrual rate and the non-
proportional hazards model.
This formal comparison of OS will allow for early stopping for superiority, and the boundaries for 
declaring superiority will be derived based on the actual number of OS events using Lan-DeMets 
alpha spending function with O’Brien and Fleming type of boundary in EAST 6 (v 6.3.1). The 
boundary for declaring superiority in terms of statistical significance for the interim analysis after 
267 events would be 0.74.
The Statistical Analysis Plan will further describe the planned interim analyses. An independent 
statistician external to BMS will perform interim analyses.
In addition to the formal planned interim analyses, the DMC will have access to periodic un-
blinded interim reports of efficacy and safety to allow a risk/benefit assessment. Details will be 
included in the DMC charter.
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11
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restraints on anti-tumor immunity for patients with melanoma. Cancer 2012;18:153-159.
46 Clinical Study Report: Study No. CA209004. A Phase 1b, Open- Label, Multicenter, 
Multidose, Dose-Escalation Study of MDX-1106 (BMS-936558) in Combination with 
Ipilimumab (BMS-734016) in Participants with Unresectable Stage III or Stage IV Malignant 
Melanoma. Bristol-Myers Squibb Company; 2014. Document Control No. 930082868.
47 Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma 
tumors. PNAS 2010; 107: 4275-80.
48 Wolchok J, Kluger H, Callahan MK, et al. Safety and clinical activity of nivolumab (anti-PD-
1, BMS-936558, ONO-4538) in combination with ipilimumab in participants (pts) with 
advanced melanoma (MEL). J Clin Oncol 2013; suppl; abstr 9012.
49 Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, et al. Combined Nivolumab and Ipilimumab 
or Monotherapy in Untreated Melanoma. N Engl J Med 2015 Jul 2;373(1):23-34. doi: 
10.1056/NEJMoa1504030. Epub 2015 May 31.
50 CA209016, Data on file.
51 Nivolumab Investigator Brochure Version 15; June 2016. 
52 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20.
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53 BMS Clinical Study Report CA209004, December 2014. 
54 Postow MA1, Chesney J, Pavlick AC, Robert C et al.Nivolumab and ipilimumab versus 
ipilimumab in untreated melanoma. N Engl J Med 2015 May 21;372(21):2006-17. doi: 
10.1056/NEJMoa1414428. Epub 2015 Apr 20
55 Hammers HJ, Plimack ER, Infante JR, et al. Expanded cohort results from CheckMate 016: A 
phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma 
(mRCC). J Clin Oncol 33, 2015 (suppl; abstr 4516)
56 Hellmann MD, Gettinger SN, Goldman JW et al. CheckMate 012: Safety and efficacy of first-
line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol 
34, 2016 (suppl; abstr 3001)
57 Antonia SJ, Bendell JC, Taylor MH, et al. Phase 1/2 study of nivolumab with or without 
ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. J Clin Oncol 
33, 2015 (suppl; abstr 7503)
58 Janjigian YY, Bendell JC, Calvo E, et al. CheckMate-032: Phase 1/2, open-label study of safety 
and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic 
(A/M) gastric cancer (GC). J Clin Oncol 34, 2016 (suppl; abstr 4010)
59 Ipilimumab Investigator Brochure Version 19; March 2016.
60 Brahmer J, Reckamo KL, Bass P, et al. Nivolumab versus docetaxel in advanced squamous-
cell non-small-cell lung cancer. N Engl J Med 2015;373(2):123-35.
61 Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-
cell carcinoma. N. Engl. J. Med. doi:10.1056/NEJMoa1510665 
62 Schadendorf D. et al. 2016 Annual Meeting of the European Association of Dermato-
Oncology; August 31-September 3, 2016; Vienna, Austria.
63 Schadendorf D, Hodi SF, Robert C, et al. Pooled analysis of long-term survival data from phase 
II and phase III Trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 
33:1889-1894.
64  Sharma P et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Metastatic Urothelial 
Carcinoma: First Results From the Phase I/II CheckMate 032 Study. SITC, DC, 2016.
65 The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & 
Co; 1994:253-256.
66 Momtaz P, Park V, Panageas KS, et al. Safety of Infusing Ipilimumab Over 30 Minutes. J Clin 
Oncol 2015;33(30):3454-3458.
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67 BMS-936558: A Phase 2, Randomized, Double Blinded Study of Nivolumab (BM-936558) in 
Combination with Ipilimumab vs Ipilimumab Alone in Participants with Previously Untreated, 
Unresectable or metastatic Melanoma). Bristol-Myers Squibb Company; 2013. Document 
Control No. 930084565.
68 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AT
aminotransaminases
BCG
Bacillus Calmette-Guerin
BICR
Blinded Independent Central Review Committee
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
ccRCC
Clear-cell renal cell carcinoma
CFR
Code of Federal Regulations 
CI
confidence interval
CLcr
creatinine clearance
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
minimum observed concentration
CNS
Central nervous system
CRF
Case Report Form, paper or electronic
CR
Complete response
DMC
Data monitoring committee
DOR
Duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
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Term
Definition
EEG
electroencephalogram
eg
exempli gratia (for example)
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire- Core 30 
EQ-5D
European Quality of Life 5 Dimension
FDA
Food and Drug Administration
FFPE
Formalin-fixed Paraffin Embedded
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
HRQoL
Health Related Quality of Life
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IMAE
Immune-mediated adverse event
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
I-O
Immuno-oncology 
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
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Term
Definition
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K+
potassium
kg
kilogram
KPS
Karnofsky Performance Status
L
liter
LAM
Lactation amenorrhea method
LC
liquid chromatography
LFT
Liver function test
LDH
lactate dehydrogenase
MDSC
Myeloid derived suppressor cells
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR
medical research
mRCC
Metastatic Renal Cell Carcinoma
MSKCC
Memorial Sloan Kettering Cancer Center
MTD
maximum tolerated dose
mWHO
Modified World Health Organization
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Objective response rate 
PBMC
Peripheral blood mononuclear cells
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Term
Definition
PD
Progressive diseases 
PFS
Progression-free survival
PK
pharmacokinetics
PR
Partial response 
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
UC
Urothelial carcinoma
ULN
Upper limit of normal
VEGF
Vascular epithelial growth factor
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 2
PERFORMANCE STATUS SCORES
SCALES
STATUS
KARNOFSKY
ZUBROD-ECOG-WHO
STATUS
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 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
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.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose, as a verbatim term (as reported by the 
investigator), should not be reported as an AE/SAE unless it is an intentional overdose taken 
with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae and should specify "intentional overdose" as the verbatim term.
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
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DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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 
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hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.)
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies.
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study 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 treatment, and pregnancies must be 
reported to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the 
electronic data capture (EDC) system is unavailable/not functioning for 
transmission of the eCRF to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
RECIST 1.1 GUIDELINES (WITH BMS MODIFICATIONS)
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:
10 mm by CT/MRI scan (CT scan slice thickness no greater than 5 mm), or ൒2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT 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, sagittal or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
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’).
2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
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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.
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(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.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
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individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (< 10mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 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).
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (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. Pleural effusions, pericardial effusions and ascites will not be 
followed as target or non-target lesions and will not contribute to response or progression. The 
designation of overall progression solely on the basis of change in non-target disease in the face 
of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
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 
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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.
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. 
•
A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. 
•
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are non-measurable) a useful test that can be applied when assessing participants 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 lymphangitic disease from localized to 
widespread, or may be described in protocols as ‘sufficient to require a change in therapy’. 
•
If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD 
at that point. 
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, ascites) will not be considered 
new lesions and will not contribute to response or progression. In the event a new fluid collection 
is seen on a post-baseline imaging exam, a comment may be made, but the appearance of a new 
fluid collection alone should not result in an assessment of Progressive Disease (PD).A lesion 
identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
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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.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
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.
2.3.2
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 2.3.2-
1 provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. When patients have non-measurable (therefore non-target) 
disease only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (+/- Non-Target) 
Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
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Table 2.3.2-1:
Time Point Response: Patients With Target (+/- Non-Target) 
Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from first treatment. 
The minimum time on study for determination of Best Response of SD will be based on the first 
scheduled follow-up imaging visit minus the permitted imaging time window. 
For example, if the first scheduled follow-up imaging visit is Week 9 (minus 7 days) for this 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
9 weeks (63 days) minus 7 days, for an absolute minimum time on-study of 56 days from the date 
of first dose (the date of first dose is considered Day 1 on study).  If the subject is not on-study for 
at least this amount of time, any tumor assessment indicating stable disease before this time period 
will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
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on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
28 days after the criteria for response are first met. For this study, the next scheduled tumor 
assessment can meet this requirement.
Verification of Progression: 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 5
MANAGEMENT ALGORITHIMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 6
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.*
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
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Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
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 
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
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Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
*Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 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.
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 7
NYHA FUNCTIONAL CLASSIFICATION
NYHA Class
Patients with Cardiac Disease (Description of HF Related 
Symptoms)
Class I (Mild)
Patients with cardiac disease but without resulting in limitation of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation (rapid or pounding heart beat), dyspnea 
(shortness of breath), or anginal pain (chest pain).
Class II (Mild)
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain
Class III (Moderate)
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV (Severe)
Patients with cardiac disease resulting in the inability to carry on 
any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased.
Reference: The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.
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APPENDIX 8
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the CRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following:  (1) the physical, safety or mental 
integrity of one or more subjects/participants; (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects/participants. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects/participants and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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The investigator is responsible for providing oversight of the conduct of the study at the site and
adherence to requirements of the following where applicable:
•
ICH guidelines
•
United States (US) Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
European Union (EU) Directive 2001/20/EC
•
European Regulation 536/2014 for clinical studies (if applicable)
•
European Medical Device Regulation 2017/745 for clinical device research (if applicable)
•
the IRB/IEC
•
all other applicable local regulations
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects/participants.
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects/participants currently enrolled in the study if they are affected by the amendment; and (3) 
the new form must be used to obtain consent from new subjects/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
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INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
•
Explain the nature of the study to the participant or his/her legally acceptable representative 
and answer all questions regarding the study.
•
Inform the participant that his/her participation is voluntary. The participant or his/her legally 
acceptable representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR Part 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC 
or study center.
•
Include a statement in the participant’s medical record that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
•
Re-consent the participant to the most current version of the ICF(s) during his/her participation.
•
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the 
investigator, should fully inform the participant or the participant's legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the participant's willingness to continue participation in the study. This 
communication should be documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
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subjects’/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
In situations where consent cannot be given by participants, their legally acceptable representatives 
(per country regulation) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
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.
Participants unable to give their written consent (eg, stroke or subjects/participants 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/participants are the most important 
considerations and should prevail over interests of science and society.
BMS COMMITMENT TO DIVERSITY IN CLINICAL TRIALS
The mission of BMS is to transform patients’ lives through science by discovering, developing, 
and delivering innovative medicines that help them prevail over serious diseases. 
BMS is committed to doing its part to ensure that patients have a fair and just opportunity to 
achieve optimal health outcomes.
BMS is working to improve the recruitment of a diverse participant population with the goal that 
the clinical trial becomes more reflective of the real-world population and the people impacted by 
the diseases studied.
DATA PROTECTION, DATA PRIVACY, AND DATA SECURITY
BMS collects and processes personal data of study participants, patients, health care providers, 
and researchers for biopharmaceutical research and development to advance innovative, high-
quality medicines that address the medical needs of patients. BMS ensures the privacy, protection, 
and confidentiality of such personal data to comply with applicable laws. To achieve these goals, 
BMS has internal policies that indicate measures and controls for processing personal data. BMS 
adheres to these standards to ensure that collection and processing of personal data are limited and 
proportionate to the purpose for which BMS collects such personal data. This purpose is clearly 
and unambiguously notified to the individual at the time of collection of personal data. In the true 
spirit of science, BMS is dedicated to sharing clinical trial information and data with participants, 
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medical/research communities, the media, policy makers, and the general public. This is done in a 
manner that safeguards participant privacy and informed consent while respecting the integrity of 
national regulatory systems. Clinical trial data, health-related research, and pharmacovigilance 
activities on key-coded health data transferred by BMS across national borders is done in 
compliance with the relevant data protection laws in the country and GCP requirements.
BMS protects Personal Information with adequate and appropriate security controls as indicated 
under the data protection laws. To align with the recommended security standards, BMS has 
adopted internal security standards and policies to protect personal data at every stage of 
its processing.
To supplement these standards, BMS enters into Clinical Trial Agreements (CTAgs) with 
confidentiality obligations to ensure proper handling and protection of personal data by third 
parties accessing and handling personal data.
BMS takes unauthorized access and disclosure of Personal Information very seriously. BMS has 
adopted the security standards that include National Institute of Standards and Technology 
Cybersecurity Framework for studies in the US. BMS aligns with these standards to continuously 
assess and improve its ability to protect, detect, and respond to cyberattacks and other unauthorized 
attempts to access personal data. These standards also aid in mitigating possible adverse effects. 
Furthermore, BMS Information Technology has defined 6 principles to protect our digital 
resources and information: 
1)
Responsibilities of IT Personnel
2) Securing the BMS Digital Infrastructure
3) Identity and Access Management
4) External Partner Connections
5) Cyber Threat Detection and Response
6) Internal Cyber Incident Investigation
SOURCE DOCUMENTS
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the electronic Case Report Form (eCRF) that are 
transcribed from source documents must be consistent with the source documents or the 
discrepancies must be explained. 
•
The investigator may need to request previous medical records or transfer records depending 
on the study. Also, current medical records must be available.
•
Definition of what constitutes source data and its origin can be found in the source data location 
list/map or equivalent document.
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The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, 
if applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form.
Sourced by site, and not supplied by 
BMS or its vendors (examples include IP 
The investigator or designee accepts responsibility 
for documenting traceability and study treatment
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If
Then
sourced 
from 
the 
sites 
stock or 
commercial supply, or a specialty 
pharmacy)
integrity in accordance with requirements applicable 
under law and the SOPs/standards of the sourcing 
pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does
not have an established system that meets these requirements.
CASE REPORT FORMS
The terms “participant” and “subject” refer to a person who has consented to participate in the 
clinical research study. Typically, the term “participant” is used in the protocol and the term 
“subject” is used in the Case Report Form (CRF).
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
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MONITORING
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of non-compliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
Records collected throughout the study will be stored in the BMS clinical data management system 
for a duration of the life of the product plus 25 years.
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. 
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Study treatments supplied by 
BMS (including its vendors)
Any unused study treatments supplied by BMS can only be 
destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study treatments containers 
must be immediately destroyed as required for safety, or to 
meet local regulations (eg, cytotoxics or biologics).
Partially used study interventions and/or empty containers may 
be destroyed after proper reconciliation and documentation. 
However, unused Investigational Medicinal Product must be 
reconciled by the site monitor/clinical research associate prior 
to destruction.
If study treatments will be returned, the return will be arranged 
by the responsible Study Monitor.
Study treatments sourced by 
site, not supplied by BMS (or 
its vendors) (examples include 
study treatments sourced from 
the sites stock or commercial 
supply, 
or 
a 
specialty 
pharmacy)
It is the investigator’s or designee’s responsibility to dispose of 
all containers according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the 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.
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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.
STUDY AND SITE CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to, the following:
For study termination:
•
Discontinuation of further study intervention development
For site termination:
•
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
•
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should ensure 
appropriate participant therapy and/or follow-up.
DISSEMINATION OF CLINICAL STUDY DATA
To benefit potential study participants, patients, health care providers, and researchers and to help 
BMS honor its commitments to study participants, BMS will make information about clinical 
research studies and a summary of their results available to the public per regulatory and BMS 
requirements. BMS will post study information on local, national, or regional databases in 
compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
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CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors.  No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
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Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 9
COUNTRY SPECIFIC REQUIREMENTS
Criteria for exclusion of HIV-positive subjects in Germany:
Country-specific language
Section 6.2 Exclusion
Criteria, Exclusion criterion 2k
“Known history of testing positive for human immunodeficiency virus (HIV)
or known acquired immunodeficiency syndrome (AIDS)”to be replaced with
“Positive test for HIV”.
Section 2 Flow Chart/Time and Events
Schedule, Table 2-1: Screening
Assessments- LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 9.4 SafetyAssessments
(baseline laboratoryassessments)
Add “HIV” test to Baseline local laboratory assessments to be done within 14
days prior to first dose.
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APPENDIX 10
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Revised Protocol 04, 20-Mar-2020
Overall Survival (OS) is the most unambiguous, unbiased and patient-relevant endpoint for 
oncology randomized trials. In particular, in the setting of newly diagnosed, metastatic urinary 
bladder cancer, there was recently a randomized phase III study reported, assessing the addition of 
a PD-L1 inhibitor to cytotoxic, platinum-based doublet chemotherapy (IMvigor 130). In the 
cisplatin-based treated cohort (n=273), the addition of the PD-L1 inhibitor to cisplatin/gemcitabine 
chemotherapy, led to a statistically significant PFS prolongation (HR = 0.73, 95% CI 0.55-0.97), 
corresponding to an absolute improvement of 2.4 months. In terms of OS, the experimental 
regimen resulted in a numerically higher mOS (HR = 0.66, 95% CI 0.47 – 0.94), with an absolute 
OS prolongation that reached 8.4 months. The afore-mentioned results indicate that OS is better 
fitted to capture the potential benefit of the addition of nivolumab, a PD-1 inhibitor, to cisplatin-
gemcitabine chemotherapy for patients with newly diagnosed, previously untreated metastatic 
bladder cancer. 
On the basis of these considerations, this revision incorporates the following changes in the 
CA209-901 protocol: 
•
OS elevation to become a primary endpoint, together with PFS 
•
Increase in the sample size of the CA209-901 sub-study by 300 cisplatin-eligible subjects, to 
ensure sufficient power for assessment of the primary endpoints OS and PFS
•
Removal of the interim PFS analysis, in accordance with scientific advice received previously 
by the regulatory authorities, and 
•
Addition of an interim analysis for OS
Summary of Key Changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis, Table 2
Changed substudy secondary objective and endpoint 
comparing OS of nivolumab combined with SOC 
chemotherapy versus SOC chemotherapy to substudy 
primary objectives and endpoints. 
See Overall Rationale
above.
Synopsis, Figure 1
Study schematic has been updated.
See Overall Rationale
above.
Synopsis, Substudy
Deleted text stating that the substudy will not stop enrolling 
participants before the primary study completes enrollment.
See Overall Rationale
above.
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Summary of Key Changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis, Number of 
Participants 
Increased number of participants enrolled from 1375 to 
1792. Increased number of participants randomized from 990 
to 1290.
Increased number of cisplatin-eligible participants in the 
substudy from 300 to 600.
Increased number of cisplatin-eligible participants to be 
randomized from 545 to 845.
Monthly participant accrual rate decreased from 21 to 18 
once enrollment in the primary study is closed.
See Overall Rationale 
above.
Section 4 Objectives and 
Endpoints, Table 4-2
Changed substudy secondary objective and endpoint 
comparing OS of nivolumab combined with SOC 
chemotherapy versus SOC chemotherapy to substudy 
primary objectives and endpoints. 
See Overall Rationale 
above.
Section 5.1, Overall 
Design, Figure 5.1-1
Study schematic has been updated.
Deleted text stating that the substudy will not stop enrolling 
participants before the primary study completes enrollment.
Edited figure note to reflect inclusion of OS as a primary 
objective in the substudy rather than a secondary endpoint.
See Overall Rationale 
above.
Section 5.2 Number of 
Participants
Increased number of participants enrolled from 1375 to 
1792. Increased number of participants randomized from 990 
to 1290.
Increased number of cisplatin-eligible participants in the 
substudy from 300 to 600.
Added text stating that randomization to the substudy is 
increased by 300 cisplatin eligible participants to ensure 
adequate power of primary endpoints OS and PFS.
Deleted text referencing changes in revised protocol version 
03.
Updated the number of months expected to randomize 600 
cisplatin-eligible participants in the substudy.
Deleted text stating that the substudy will not stop enrolling 
participants before the primary study completes enrollment.
Monthly participant accrual rate decreased from 21 to 18 
once enrollment in the primary study is closed.
See Overall Rationale 
above.
Section 7.4.4 
Management Algorithms 
for Immuno-Oncology 
Agents
Added myocarditis to list of management algorithms.
To meet current 
standards.
Section 9.8 biomarkers, 
Table 9.8-1
Corrected footnote c.
To accurately reflect 
countries for which 
PBMC sampling will 
occur.
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Summary of Key Changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.1 Sample 
Size Determination
Updated description of sample size and alpha level 
determination for the substudy to reflect inclusion of 2 
primary efficacy endpoints PFS and OS.
Updated description of sample size to reflect an increase to 
845 cisplatin-eligible participants, with 245 randomized in 
the primary study and 600 randomized in the substudy. 
Added text stating that cisplatin-eligible participants 
randomized following the end of enrollment into the primary 
study will be randomized into the substudy.
See Overall Rationale 
above.
Section 10.1.3 Sample 
Size Justification for the 
Dual Primary Endpoints 
of Progression Free 
Survival and Overall 
Survival in Cisplatin-
eligible Randomized 
Participants in the 
Substudy
Section heading updated.
Updated text to reflect inclusion of primary endpoints PFS 
and OS.
See Overall Rationale
above.
Section 10.1.3.1 
Progression Free 
Survival
Updated text describing justification for sample size in 
analysis of PFS.
Added text stating that if OS superiority is demonstrated in 
interim analysis for the substudy, formal testing of PFS will 
be performed.
Deleted text regarding inclusion of an interim analysis of 
PFS. 
Updated assumption underlying the time needed to observe 
the required number of PFS events for the interim analysis 
(if performed).
See Overall Rationale
above.
Section 10.1.3.2 Overall 
Survival
Added section describing sample size justification for OS as 
a primary endpoint for the substudy.
See Overall Rationale
above.
Section 10.1.4 Analysis 
Timing Projections
Table 10.1.4-1
Increased the number of participants with previously 
untreated, unresectable or metastatic UC to be randomized 
from 990 to 1290.
Updated table to reflect that the PFS interim analysis will 
only be performed if OS interim analysis is significant in the 
substudy, updated analysis criteria and projected timing.
See Overall Rationale
above.
Section 10.3.1 Efficacy 
Analyses
Updated description of the substudy analyses to reflect 
inclusion of OS and PFS as primary endpoints for primary 
objective. 
Deleted paragraph referencing OS as a secondary objective.
Added paragraph describing secondary objective of whether 
PD-L1 expression is a predictive biomarker of efficacy.
See Overall Rationale
above.
Section 10.3.1.1 Primary 
Endpoints
Updated description of the substudy analyses to reflect 
inclusion of OS and PFS as primary endpoints for primary 
objectives.
See Overall Rationale
above.
Protocol Amendment No.: 05
Date: 27-Apr-2023
184
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Summary of Key Changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Added paragraph describing details of the testing strategy 
between the PFS and OS endpoints for the substudy.
Section 10.3.1.2 
Secondary Endpoints
Deleted text describing analysis of OS as a secondary 
endpoints.
Added text describing PD-L1 expression as a predictive 
biomarker of efficacy.
See Overall Rationale
above.
Section 10.3.3.3 
Biomarker Analyses
Deleted PD-L1 from the list of exploratory biomarker 
analyses to be conducted in the substudy. 
See Overall Rationale
above.
Section 10.3.4 Interim 
Analyses
Revised text to reflect inclusion of an interim analysis of OS 
and hierarchical testing of interim analysis of PFS if OS 
interim analysis is significant.
See Overall Rationale
above.
Appendix 5 
Management Algorithms
Updated appendix. 
To meet current 
standards.
Appendix 8 Study 
Governance 
Considerations
Updated appendix.
To meet current 
standards.
Overall Rationale for the Revised Protocol 03, 09-Apr-2019
This revision removes PFS as a co-primary objective and endpoint and adds OS in PD-L1 positive 
(≥ 1%) as a primary population, adds 100 cisplatin-ineligible participants ineligible and a 
corresponding number of cisplatin-eligible  to the primary study, and revises the timing of the OS 
interim analysis for the primary study. The timing of the interim analysis for the substudy is revised 
as well.
This protocol is revised to react to the dynamic changes of cancer treatment options and rapidly 
emerging scientific evidence. Accumulated evidence indicates that PFS would not be clinically 
meaningful and is not comparable in immunotherapy with chemotherapy in cisplatin-ineligible 
participants, thus it is removed. Growing data point to the benefit of immunotherapy in PD-L1 
positive patients and, supported by regulatory approval for the application of pembrolizumab and 
atezolizumab in PD-L1 positive cisplatin-ineligible patients, adding OS in PD-L1 positive 
metastatic UC patients is reasonable. To ensure sufficient power for the two (amended) primary 
populations for the endpoint of OS in cisplatin ineligible and OS in PD-L1 positive metastatic UC, 
100 cisplatin-ineligible participants will be added to the primary study and the number of cisplatin 
eligible participants will be increased accordingly. After removing the co-primary endpoint PFS, 
the timing for the interim OS analysis was revised, similarly, the timing for the substudy interim 
analysis was revised to align with the primary study interim analysis.
Protocol Amendment No.: 05
Date: 27-Apr-2023
185
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Title page
Study director changed to Shengting Li
To update information
Synopsis, Key Inclusion/Exclusion, 
Inclusion
Corrected fourth bullet to allow for 
fresh biopsy within 2 years prior to 
enrollment period
To align with Section 
6.1 and Table 2-1
Synopsis, Key Inclusion/Exclusion, 
Exclusion
6.2 Exclusion Criteria (6 c, d)
Added exclusion for vaccine
Added exclusion for treatment with 
botanical preparations
For consistency with 
program standards
Synopsis, Table 1, Objectives and 
Endpoints: Primary Study
3.1.1.1 Research Hypothesis for Primary 
Study
3.1.4 Rationale for PD-L1 Subpopulation 
being Co-primary Analysis Population
Table 4-1 Objectives and Endpoints: Primary 
Study
5.4 Scientific Rationale for Study Design
10.1 Sample Size Determination
10.2 Population for Analyses
10.3.1.2 Secondary Endpoints
Removed PFS as co-primary objective 
and endpoint
Added comparison of OS in PD-L1 
positive (PD-L1 ≥ 1%) participants and 
OS endpoint as primary objective
Added new rationale subsection 3.1.4
Removed PFS in all randomized 
participants as secondary objective
In Secondary Objectives, changed PFS 
analysis to the cisplatin-ineligible and 
PD-L1 populations as well as all 
randomized participants
Removed PD-L1 as secondary objective
Removed PFS as exploratory objective
See Overall Rationale 
above
Synopsis Table 2  Objectives and Endpoints: 
Substudy
Table 4-2 Objectives and Endpoints: 
Substudy
Inserted “cisplatin-eligible” before 
participant
Changed ipilimumab to “SOC 
chemotherapy”
Changed PPK to PK parameters
To correct 
typographical errors
Synopsis, Figure 1 Study Design Schematic
Figure 5.1-1 Study Design Schematic
Updated Figure, Footnotes, and Notes
Changed stratification (ii) from 
“cisplatin-ineligibility” to “cisplatin-
eligibility” and removed Primary Study 
prior to substudy start
In the notes, the first sentence of the 
section was revised to clarify that “all 
participants” will be randomized 1:1 to 
Arms A or B during the primary study; 
the primary study secondary endpoint 
language was revised to clarify “all 
randomized participants;” and the 
substudy secondary endpoint language 
was revised to add reference to 
“hierarchical testing procedure”
For greater clarity and 
for consistency with 
changes made 
through-out protocol
Synopsis, Figure 1 Study Design Schematic
Table 2-2 On Treatment Procedural Outline 
for Arm A, Part 1: Ipilimumab/Nivolumab 
Combination Treatment
Added 1 week window for week 9 
assessments
For consistency
Protocol Amendment No.: 05
Date: 27-Apr-2023
186
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-3 On Treatment Procedural Outline 
for Arms A and C, Part 2 Nivolumab 
Monotherapy Treatment
Table 2-4 On Study Assessments Treatment 
Arm B and Arm D (Cisplatin-Eligible) 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-5 On Study Assessments Treatment 
Arm B (Cisplatin-Ineligible) Doublet 
Gemcitabine/Carboplatin Chemotherapy
Table 2-6 On Study Assessments Treatment 
Substudy: (Arm C, Part 1) Nivolumab + 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-7 Follow-Up Period
Figure 5.1-1 Study Design Schematic
Synopsis, Number of Participants
5.2 Number of Participants
10.1 Sample Size Determination
Revised screen failure rate, sample size 
numbers, added PD-L1 population, 
revised accrual enrollment numbers
Added 100 cisplatin-ineligible and 
adjusted  cisplatin eligible participants 
to primary study to ensure adequate 
power in both primary populations
See Overall Rationale 
above
Table 2-1 Screening Procedural Outline for 
All Participants
Table 2-2 On Treatment Procedural Outline 
for Arm A, Part 1: Ipilimumab/Nivolumab 
Combination Treatment
Table 2-3 On Treatment Procedural Outline 
for Arms A and C, Part 2 Nivolumab 
Monotherapy Treatment
Table 2-6 On Study Assessments Treatment 
Substudy: (Arm C, Part 1) Nivolumab + 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-7 Follow-Up Period
9.4 Safety
Specified that total T3 and T4 are 
acceptable if free T3 and T4 are not 
available
To allow for 
differences in lab 
testing globally
Table 2-1 Screening Procedural Outline for 
All Participants
6.1 Inclusion Criteria (2j)
Added details regarding palliative 
radiotherapy
For consistency with 
program standards
Table 2-1 Screening Procedural Outline for 
All Participants
Table 2-2 On Treatment Procedural Outline 
for Arm A, Part 1: Ipilimumab/Nivolumab 
Combination Treatment
Specified that CT with or without 
contrast is acceptable if MRI prohibited 
for medical reasons
Permit image 
submission of 
alternate modality
Protocol Amendment No.: 05
Date: 27-Apr-2023
187
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-3 On Treatment Procedural Outline 
for Arms A and C, Part 2 Nivolumab 
Monotherapy Treatment
Table 2-4 On Study Assessments Treatment 
Arm B and Arm D (Cisplatin-Eligible) 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-5 On Study Assessments Treatment 
Arm B (Cisplatin-Ineligible) Doublet 
Gemcitabine/Carboplatin Chemotherapy
Table 2-6 On Study Assessments Treatment 
Substudy: (Arm C, Part 1) Nivolumab + 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-7 Follow-Up Period
Table 2-2 On Treatment Procedural Outline 
for Arm A, Part 1: Ipilimumab/Nivolumab 
Combination Treatment
Table 2-3 On Treatment Procedural Outline 
for Arms A and C, Part 2 Nivolumab 
Monotherapy Treatment
Table 2-4 On Study Assessments Treatment 
Arm B and Arm D (Cisplatin-Eligible) 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-5 On Study Assessments Treatment 
Arm B (Cisplatin-Ineligible) Doublet 
Gemcitabine/Carboplatin Chemotherapy
Table 2-6 On Study Assessments Treatment 
Substudy: (Arm C, Part 1) Nivolumab + 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
For PRO assessments, removed 
reference to phone administration
Assessment will be 
done at time of visit
Table 2-2 On Treatment Procedural Outline 
for Arm A, Part 1: Ipilimumab/Nivolumab 
Combination Treatment Table 2-3 On 
Treatment Procedural Outline for Arms A 
and C, Part 2 Nivolumab Monotherapy 
Treatment
Table 2-3 On Treatment Procedural Outline 
for Arms A and C, Part 2 Nivolumab 
Monotherapy Treatment
Table 2-4 On Study Assessments Treatment 
Arm B and Arm D (Cisplatin-Eligible) 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-5 On Study Assessments Treatment 
Arm B (Cisplatin-Ineligible) Doublet 
Gemcitabine/Carboplatin Chemotherapy
In 2-2, clarified tumor tissue collection 
upon disease progression “and” at 
C2D15 in Procedure column
Changed “or” to “and” after 
progression in Notes column
In Table 2-6 inserted the individual 
biomarkers assessments
To collect biopsy at 
both times
Table 2-6 was revised 
to align with Table 
9.8-1
Protocol Amendment No.: 05
Date: 27-Apr-2023
188
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-6 On Study Assessments Treatment 
Substudy: (Arm C, Part 1) Nivolumab + 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-2 On Treatment Procedural Outline 
for Arm A, Part 1: Ipilimumab/Nivolumab 
Combination Treatment Table 2-3 On 
Treatment Procedural Outline for Arms A 
and C, Part 2 Nivolumab Monotherapy 
Treatment
Table 2-7 Follow-Up Period
Added Table 9.5-2 to 
PK/Immunogenicity Assessments
For completeness
Table 2-3 On Treatment Procedural Outline 
for Arms A and C, Part 2 Nivolumab 
Monotherapy Treatment
Footnote a - revised text to distinguish 
different delay periods for Arms A and 
C
In 2-3, Drug Supply, removed
“± 2 days” for  nivolumab
For greater clarity
For consistency with 
7.1.1.2
Table 2-4 On Study Assessments Treatment 
Arm B and Arm D (Cisplatin-Eligible) 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-5 On Study Assessments Treatment 
Arm B (Cisplatin-Ineligible) Doublet 
Gemcitabine/Carboplatin Chemotherapy
Table 2-6 On Study Assessments Treatment 
Substudy: (Arm C, Part 1) Nivolumab + 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Removed Performance Status at D8
Mid-cycle 
performance status 
assessment not 
required
Table 2-4 On Study Assessments Treatment 
Arm B and Arm D (Cisplatin-Eligible) 
Doublet Gemcitabine-Cisplatin 
Chemotherapy
Table 2-5 On Study Assessments Treatment 
Arm B (Cisplatin-Ineligible) Doublet 
Gemcitabine/Carboplatin Chemotherapy
For PRO, added timing in the event of 
additional cycles as per local guidelines
For consistent data 
collection across 
various local 
guidelines
Table 2-7 Follow-Up Period
Added detail to the physical examine
Clarified that serum collection should 
occur at both Follow-Up Visit 1 and 
Follow Up Visit 2
For clarity
To align with Table 
9.8-1
3 Introduction
6.1 Inclusion Criteria (2c)
Revised description of eligible prior 
treatment
For greater clarity
5.1 Study Design
Revised text on number of cycles for 
Arm B and D
For compliance with 
local guidelines
6.4.1 Retesting During Screening or Lead-in 
Period
Clarified definition of pre-treatment 
failure
For consistency with 
program standards
Protocol Amendment No.: 05
Date: 27-Apr-2023
189
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Table 7-1 Study Treatment for CA209901
Added row for China sourcing of a 
study treatment
For completeness
Table 7.1-1 Treatment Administration
7.1.2 Study Drug Preparation and Infusion
7.1.4 Arm C: Nivolumab plus Platinum-
Doublet Chemotherapy
7.1.5 Arm D: Platinum-Doublet 
Chemotherapy (Cisplatin-Eligible)
7.5 
Preparation/Handling/Storage/Accountability
Added footnote that information only 
applies to chemotherapy and that 
infusion durations and premedications 
may follow local guidelines
For compliance with 
local guidelines
7.1.1.1 Arm A: Part 1 Study Drug 
Administration - Nivolumab and Ipilimumab 
Combination Therapy (Cycles 1-4)
Added text regarding participants who 
experience AEs on combination dose 
therapy proceeding to nivolumab 
monotherapy without completing all 4 
combination doses
For consistency with 
program standards
7.1.2 Study Drug Preparation and Infusion
Deleted some study drug description 
and referred instead to pharmacy 
manual or IB
Removed forward slash in first sentence 
of the last paragraph of the section to 
read, “Doses of nivolumab and/or 
ipilimumab”
For consistency with 
program standards
7.1.3.1 Gemcitabine/Cisplatin
Added that additional cycles may be 
permitted
For completeness
7.4.2.1 Nivolumab or Ipilimumab Dose 
Delay Criteria
Deleted text that during Part 1, 
nivolumab and ipilimumab should be 
discontinued together
For consistency with 
program standards
7.4.5  Treatment Beyond Progression
Removed approval by Medical Monitor
Revised radiographic assessment timing 
language so that it accords with Section 
2
For consistency with 
program standards
For clinical and 
operational ease
7.7.1. Prohibited and/or Restricted 
Treatments (4 d,e)
Added prohibitions for live/attenuated 
vaccines and for botanical preparations
For consistency with 
program standards
7.7.3.1. Imaging Restriction and Precautions
Added text should brain MRI not be 
available
Permit image 
submission of 
alternate modality
8.1.1.1 Discontinuation of Nivolumab or
Ipilimumab
Added text specifying that 
discontinuation assessment should be 
made separately for each drug
Added myocarditis to Grade 3 section
For consistency with 
program standards
8.1.2.2 Criteria to Resume Treatment with 
Platinum Doublet Chemotherapy
In the first bullet, ≥symbol for ANC 
was corrected to > symbol
To correct 
typographical error
Protocol Amendment No.: 05
Date: 27-Apr-2023
190
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
9.1.1. Overall Survival
Reordered study evaluations
For consistency with 
changes to protocol
9.1.4.1  BICR Assessment of Progression
Changed “performed” to “expedited” 
regarding timing of BICR assessment
Corrected to align with 
the imaging manual
9.4 Safety
Corrected arms for on-treatment 
monitoring of amylase and lipase
To correct 
misstatement
9.8 Biomarkers
Revised arm descriptions
To clarify treatment 
arms
9.8-1 Biomarker Sampling Schedule (All 
Participants)
Added 2 footnotes with country-
specific collection information for 
MDSCs and Whole Blood (Gene 
Expression)
For operational ease
10.1 Sample Size Determination
Removed accrual assumptions and 
referred to Section 5.2
Revised alpha for the primary study
Changed from 2 to 1 formal interim 
analysis for substudy
See Overall Rationale 
above
10.1.1 Sample Size Justification for the 
Primary OS in the Primary Study
10.1.1.1 Overall Survival in Cisplatin-
ineligible participants
10.1.1.2  Overall Survival in PD-L1 positive 
(≥ 1%) participants
Revised titles
Add new subsection on PD-LI 
population
Moved cisplastin-ineligible participants 
subsection up and revised event, power, 
cure fraction, HR calculations, and 
interim analysis details
See Overall Rationale 
above
10.1.2 Sample Size Justification for the 
Secondary OS Endpoint in All Randomized 
Participants in the Primary Study
10.3.4 Interim Analyses
Removed PFS section
Revised numbers and event, power, 
cure fraction, HR calculations, and 
interim analysis details for OS in all 
randomized participants
See Overall Rationale 
above
10.1.3.1 Progression Free Survival
10.3.4 Interim Analyses
Revised event, power, and accrual 
assumptions
Changed from 2 to 1 formal interim 
analysis and revised details
See Overall Rationale 
above
10.1.4 Analysis Timing Projections
10.1.4-1 Populations and Projected Timing 
for Analysis of Primary Endpoints: Primary 
Study and Substudy
Revised text, removed 4 bullets, and 
revised table
Added paragraph with rule for timing of 
interim analysis
See Overall Rationale 
above
Protocol Amendment No.: 05
Date: 27-Apr-2023
191
6.0
Approved
930107916
6.0
v
Approved
3.0
v

Clinical Protocol
CA209901
BMS-936558
Nivolumab
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
10.2 Population for Analyses
Added row on PD-LI positive patients
Revised text in row on PD-LI from 
“primary study” to “substudy”
Deleted paragraph regarding ITT under 
the table
For consistency with 
changes to the 
protocol
Any participant 
randomized will be 
included in the 
efficacy analysis and 
ITT is not a defined 
study population
10.3.1 Efficacy Analyses
10.3.1.1 Primary Endpoints
10.3.1.2 Secondary Endpoints
Revised text for primary study, 
including revisions for testing to control 
for Type 1 error, and substudy
Added details on significance levels
For consistency with 
changes through-out 
the protocol
To outline technical 
changes
Appendix 2 Performance Status Scores
Updated with revisions in Status 
Column
For clarity
Appendix 3 AE and SAE Definitions and 
Procedures for Recording, Evaluating, 
Follow-up, and Reporting
Updated
For consistency with 
program standards
Appendix 5 Management Algorithms
Updated to 2018 version
For consistency with 
program standards
Appendix 6 WOCBP Definitions and 
Methods of Contraception
Removed hormonal methods of 
contraception from User Independent 
Section
For consistency with 
program standards
Protocol Amendment No.: 05
Date: 27-Apr-2023
192
6.0
Approved
930107916
6.0
v
Approved
3.0
v