A Phase 3 Randomized, Double-Blind Study of Nivolumab Monotherapy or Nivolumab Combined With Ipilimumab vs Placebo in Participants With Localized Renal Cell Carcinoma Who Underwent Radical or Partial Nephrectomy and Who Are at High Risk of Relapse
Phase: PHASE3
Conditions: Carcinoma, Renal Cell
Sponsor: Bristol-Myers Squibb

 
 
Official Title of Study: 
A Phase 3 Randomized, Double-Blind Study of Nivolumab Monotherapy or Nivolumab  
Combined with Ipilimumab vs Placebo in Participants with Localized Renal Cell Carcinoma  
Who Underwent Radical or Partial Nephrectomy and Who Are at High Risk of Relapse 
CheckMate 914: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 914 
 
Protocol: CA209-914 
 
NCT Number: NCT03138512 
 
Document Date (Date in which document was last revised): 08-Dec-2022 

Page:
1
Protocol Number:
CA209914
IND Number:
122,840
EUDRACT Number
2016-004502-34
Date
14-Feb-2017
Revised Date
08-Dec-2022
CLINICAL PROTOCOL CA209914
A Phase 3 Randomized, Double-Blind Study of Nivolumab Monotherapy or Nivolumab 
Combined with Ipilimumab vs Placebo in Participants with Localized Renal Cell Carcinoma 
Who Underwent Radical or Partial Nephrectomy and Who Are at High Risk of Relapse
CheckMate 914: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 914
Protocol Amendment 06
Medical Monitoring Contact Information
Senior Clinical Trial Physician
Bristol Myers Squibb Company
100 Binney Street Cambridge, MA 02142
Phone: 
email: 
Senior Clinical Scientist
Bristol Myers Squibb Company
86 Morris Avenue Summit, NJ 07901
Phone 
email: 
Clinical Scientist
Bristol Myers Squibb Company
3401 Princeton Pike, Lawrenceville,
NJ 08648
Phone 
email: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
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BMS-936558
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Protocol Amendment No.: 06
Date: 08-Dec-2022
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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). 
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Protocol Amendment No.: 06
Date: 08-Dec-2022
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Changes
Protocol 
Amendment 06
08-Dec-2022
The purpose of Protocol Amendment 06 is to address the timing of interim 
and final disease-free survival (DFS) analyses in Part B, which were 
initially planned to occur at least 8 months of each other. However, the 
earlier versions of the protocol did not capture the scenario to proceed 
directly to the final DFS analysis in Part B in the event that the interim 
analysis and final analysis are projected in a shorter time interval 
(approximately within 6 months). With this amendment, the scenario with 
DFS final analysis only is explicitly stated. Also, the redundant OS interim 
analysis scenario in Part B is now omitted.
Protocol 
Amendment 05
13-Feb-2022
The purpose of Protocol Amendment 05 is to address the timing of interim 
and final disease-free survival (DFS) analyses in Part A, which were 
initially planned to occur within 6 months of each other. However, the 
earlier versions of the protocol did not capture the scenario to proceed 
directly to the final DFS analysis in Part A in the event that Part B 
enrollment is ongoing when the required number of events needed for 
interim analysis of DFS in Part A is achieved. With this amendment, the
scenario with DFS final analysis only is pre-specified.
Administrative 
Letter 10
19-Feb-2021
Corrected language in Section 9.2.5, Pregnancy to ensure proper 
alignment throughout all sections of the protocol.
Administrative 
Letter 09
04-Jan-2021
• Updated Study Personnel
• Clarifications to Synopsis and to Section 5.1, Overall Design
• Corrected typographical errors in Section 10.3.4, Interim Analyses and 
Hierarchical Testing
Revised Protocol 
04
27-Oct-2020
The purpose of Revised Protocol 04 is to remove Interim Analysis 1 for 
disease-free survival (DFS), from both Part A and Part B, to delay Interim 
Analysis 2 for DFS in Part A, and for both Part A and Part B Overall 
Survival (OS) to be hierarchically analyzed at the same time as the interim 
or final analysis for DFS in the same group of subjects. This revision also 
incorporates several changes to provide additional information and/or 
clarification to sections indicated. Some updates include clarifications and 
updates to contraception requirements, the clarification of timing for 
follow up visits and patient-reported outcomes collection, the addition of 
SARS-CoV-2 serology collection with a corresponding exploratory 
objective and endpoint, the addition of Appendix 9 regarding TNM 
staging and Fuhrman grading correlations, the incorporation of additional 
biomarker sample collections to better align with tumor assessments,
collection of tumor necrosis status which will allow for SSIGN score 
assessments, and an extension of the required length of time to collect 
adverse events (AEs) (serious adverse events [SAEs] or non-serious AEs)
considered related to the study therapy. This revision also incorporates 
Administrative Letter 08.
Administrative 
Letter 08
05-Feb-2020
Advises sites of inadvertent omission to Revised Protocol 03 of changes 
made to protocol in Administrative Letters 05 and 07. Although changes 
were omitted, they were still effective.
Revised Protocol 
03
01-Nov-2019
The purpose of Revised Protocol 3 is to add Part B to the study for 
evaluation of nivolumab monotherapy. 
Also incorporates Administrative Letter 06
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Protocol Amendment No.: 06
Date: 08-Dec-2022
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Administrative 
Letter 07
05-Feb-2019
Update Appendix 4
Administrative 
Letter 06
16-Nov-2018
Study Personnel Updates
Administrative 
Letter 05
01-Aug-2018
Correct typographical errors in Sections 6.1 and 7.2, and corresponding 
sections of the synopsis.
Revised Protocol 
02
06-Apr-2018
The purpose of this revised protocol is to reduce frequency of patient 
questionnaires, update exclusion criterion for serum creatinine, remove 
42-day screening window, provide more flexibility in scheduling scans, 
update background data, and provide additional information and/or 
clarification to sections indicated.
Administrative 
Letter 03
28-Mar-2018
The main purpose of this letter is to update the information related to a 
change in the Medical Monitor for this study.
Administrative 
Letter 02
16-Nov-2017
The main purpose of this letter is to update the information related to a 
change in the Medical Monitor for this study.
Administrative 
Letter 01
28-Jun-2017
The main purpose of this letter is to correct a typographical error in 
Exclusion Criteria 2b and 4a in Revised Protocol 01, dated 22-Mar-2017.
Revised Protocol 
01
22-Mar-2017
Incorporates Amendment 01
Amendment 01
22-Mar-2017
•
Consider the placebo products as investigational products
•
Remove the bioequivalence language
Original Protocol
14-Feb-2017
Not Applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 06:
The purpose of Protocol Amendment 06 is to address the timing of interim and final disease-free 
survival (DFS) analyses in Part B, which were initially planned to occur at least 8 months apart 
from each other. However, the earlier versions of the protocol did not capture the scenario where 
the interim and final analyses of DFS in Part B are projected to occur in a shorter time interval 
(approximately within 6 months).
Therefore, this amendment for Part B is being issued to allow the possibility of conducting only 
the final DFS analysis without the interim DFS analysis in the event these two analyses in Part B 
would occur within 6 months of each other. Table 10.1.22provides details on the alpha, critical 
hazard ratio, and target number of events for this scenario. A 6-month period was determined as 
the  threshold  based  on  the  operational  considerations  of  this  3-arm  study  part.  Overall,  this 
amendment for Part B is similar to Protocol Amendment 05, which added a similar scenario for 
Part A.
Additionally, wording clarifications have been made for the interim overall survival (OS) analyses 
in  Part  B. If  the  first  interim  OS  analysis  were  to  reach  the  statistical  significance  with 
approximately  102  events,  
then  the  study  would stop  for  early  superiority  for  
the  formal  OS 
comparison,  and  second  interim  OS  analysis  with  approximately  127  events  would  not  be 
performed. Due to this reason, the scenario with 127 OS events is redundant, and it is now omitted 
from the protocol to simplify the interim OS analyses plan in Part B. With this update, it is now 
clearly stated that the  
interim OS analyses  
in Part B are to be based on 102 and 146 events, as 
initially planned.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & Title 
Description of Change
Brief Rationale
Section 10.1.1Part A: Combination 
Comparison of DFS
Typographical  error  has  been 
updated within the section to align 
with  values  presented  in Table 
10.1.1-1.
Typographical  error  has  been 
corrected.
Section  
10.1.2:  
Part  
B: 
Monotherapy Comparison of DFS
Table 10.1.2-2: Part B Summary of 
Sample  Size  Parameters  and 
Schedule of Monotherapy (without 
an Interim Analysis)
Section  10.3.4:  Interim  Analyses 
and Hierarchical Testing
Parameters and schedule of analysis 
for final DFS analysis alone in Part 
B were  added.  Also,  summary 
Table 10.1.2-2 was added.
In the event that the target number of 
events needed for the final analysis is 
projected  in  a  shorter  time  interval 
(approximately within 6 months), the 
interim  analysis  of  DFS  will  not  be 
performed and only one final analysis 
of DFS will be conducted in Part B.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & Title
Description of Change
Brief Rationale
Section 10.3.4: Interim Analyses 
and Hierarchical Testing
Language of the Part B OS interim
analyses is clarified and one of the 
scenarios for the second interim OS 
analysis in Part B is omitted.
The Part B OS interim analyses 
language is updated to clearly state the 
plan for the pre-specified interim 
analyses. Also, OS interim analysis 
with approximately 127 events is a
redundant scenario, and it is now 
omitted.
Section 10.3.1: Efficacy Analyses
Stratum(s) with small number of 
participants.
In the event that there are fewer 
subjects randomized to a stratum, the 
participants in the stratum will be 
combined into another stratum.
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Date: 08-Dec-2022
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 06: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 Research Hypothesis ................................................................................ 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Indication Background ............................................................................. 
 
3.2.1.1 Nivolumab Monotherapy in RCC ................................................... 
 
3.2.1.2 Ipilimumab in Renal Cell Carcinoma ............................................. 
 
3.2.1.3 Nivolumab Plus Ipilimumab in RCC............................................... 
 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
 
3.2.3 Ipilimumab Mechanism of Action ............................................................ 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
 
5.1.1.1 Data Monitoring Committee ........................................................... 
 
5.1.1.2 Blinded Independent Central Review .............................................. 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.4.1 Rationale for Selection of Participants at Moderate to High Risk of 
Relapse ........................................................................................................ 
 
5.4.2 Rationale for 6 Month Treatment Duration ............................................. 
 
5.4.3 Rationale for 30 min Infusion Duration for Nivolumab and Ipilimumab 
 
5.4.4 Rationale for Nivolumab Monotherapy ................................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 Justification for Dosage in Combination Treatment of Nivolumab and 
Ipilimumab .................................................................................................. 
 
5.5.2 Justification for Dose of Nivolumab Monotherapy Treatment in Part B. 
 
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 .................................................................................. 
 
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CA209914
nivolumab
Protocol Amendment No.: 06
Date: 08-Dec-2022
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7.1.1 Administration ......................................................................................... 
 
7.1.1.1 Nivolumab ....................................................................................... 
 
7.1.1.2 Ipilimumab ...................................................................................... 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.3.1 Unblinding at the Time of Disease Recurrence ....................................... 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Dose Delay Criteria for Study Treatment ................................................ 
 
7.4.2 Criteria to Resume Treatment .................................................................. 
 
7.4.3 Treatment of Study Treatment-related Infusion Reactions ...................... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.3 Permitted Therapy ................................................................................... 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Study Treatment Discontinuation Criteria ............................................... 
 
8.1.2 Post Study Treatment Study Follow-up.................................................... 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Definitions of Recurrence ........................................................................ 
 
9.1.2 Methods of Measurements ....................................................................... 
 
9.1.3 Imaging and Clinical Assessment ............................................................ 
 
9.1.3.1 Assessment of Baseline Disease-free Status ................................... 
 
9.1.3.2 Investigator Assessment of Recurrence .......................................... 
 
9.1.3.3 BICR Assessment of Recurrence ..................................................... 
 
9.1.3.4 Date of Recurrence ......................................................................... 
 
9.1.4 Imaging Restriction and Precautions ...................................................... 
 
9.1.5 Outcomes Research Assessments ............................................................. 
 
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 .................................................................... 
 
9.2.9 Management Algorithms .......................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
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CA209914
nivolumab
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9.4 Safety ................................................................................................................ 
 
9.4.1 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.2 Imaging Safety Assessment ...................................................................... 
 
9.5 Pharmacokinetics .............................................................................................. 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Additional Research Collection ............................................................... 
 
9.8.2 Tissue Specimens ..................................................................................... 
 
9.8.3 Exploratory Serum Biomarkers ............................................................... 
 
9.8.4 Peripheral Blood RNA ............................................................................. 
 
9.8.5 Myeloid-Derived Suppressor Cells .......................................................... 
 
9.8.6 Peripheral Blood DNA Mutation Research ............................................. 
 
9.8.7 Whole Blood for Genotyping ................................................................... 
 
9.8.8 Immunogenicity Assessments ................................................................... 
 
9.8.9 Other Assessments ................................................................................... 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.1.1 Part A: Combination Comparison of DFS ............................................ 
 
10.1.2 Part B: Monotherapy Comparison of DFS ............................................ 
 
10.1.3 Contribution of Components Analysis of DFS: ..................................... 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.3 Other Analyses ....................................................................................... 
 
10.3.3.1 Pharmacokinetic Analyses ............................................................ 
 
10.3.3.2 Biomarker Analyses ...................................................................... 
 
10.3.3.3 Outcomes Research Analyses ....................................................... 
 
10.3.4 Interim Analyses and Hierarchical Testing ........................................... 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERANCE CONSIDERATIONS .................................... 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 6 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 4.0 ......................................................................................................... 
 
APPENDIX 7 COUNTRY-SPECIFIC REQUIREMENTS ......................................... 
 
APPENDIX 8 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
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Clinical Protocol
BMS-936558
CA209914
nivolumab
Protocol Amendment No.: 06
Date: 08-Dec-2022
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APPENDIX 9 CORRELATIONS OF CLASSIFICATIONS IN CANCER STAGING 
SYSTEMS............................................................................................................... 
 
 
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1
SYNOPSIS
Protocol Title: A Phase 3 Randomized, Double-Blind Study of Nivolumab Monotherapy or 
Nivolumab Combined with Ipilimumab vs Placebo in Participants with Localized Renal Cell 
Carcinoma Who Underwent Radical or Partial Nephrectomy and Who Are at High Risk of 
Relapse 
Short Title: CheckMate 914: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 
914
Study Phase: 3
Rationale:
The current standard treatment for early stage (I-III) renal cell cancer (RCC) is surgery. While the 
prognosis of stage I tumors is excellent, stage II and particularly stage III have a high risk of relapse 
and represent a high unmet medical need.
The clinical activity of nivolumab and nivolumab plus ipilimumab observed to date in advanced 
RCC include 1 positive Phase 3 study demonstrating prolonged survival with nivolumab 
monotherapy compared to everolimus in metastatic RCC and significant improvement in OS with 
nivolumab plus ipilimumab compared with sunitinib in the Checkmate 214 study. Based on the 
Checkmate 214 study results, the combination of nivolumab and ipilimumab is approved by the 
US Food and Drug Administration (FDA) for the treatment of intermediate- and poor-risk, 
previously untreated patients with advanced RCC, and it is incorporated into the European 
Association of Urology guidelines. These results suggests the potential for improved clinical 
outcomes also in the adjuvant setting. In 2015, nivolumab was approved in the United States for 
the treatment of metastatic RCC in patients who previously received anti-angiogenic therapy. 
The study CA209914 aims to explore the role of the nivolumab and ipilimumab combination 
compared to placebo and the role of nivolumab monotherapy compared to placebo post-surgery in 
added efficacy and safety in preventing disease recurrence and the impact on survival.
If the safety profile is acceptable and nivolumab monotherapy or nivolumab combined with 
ipilimumab is shown to improve DFS, this study would support the approval of nivolumab or 
nivolumab combined with ipilimumab in treatment-naive advanced RCC patients post-surgery. 
Study Population:
Participants with predominately clear cell RCC who have had a nephrectomy will be included. 
Key Inclusion Criteria:
a) Kidney tumor has been completely resected with negative surgical margins obtained. The 
randomization must occur greater than 4 weeks and less than (or equal to) 12 weeks from 
the date of nephrectomy. Partial nephrectomy is allowed provided all inclusion criteria are 
met.
b) Post-nephrectomy tumor shows RCC with a predominately clear cell histology, including 
participants with sarcomatoid features. 
Protocol Amendment No.: 06
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c) Pathological TNM staging per AJCC staging version 2010 (refer to Appendix 9 for 
correlations of classifications in cancer staging systems): 
•
pT2a, G3 or G4, N0M0
•
pT2b, G any, N0M0
•
pT3 (a, b, c), G any, N0M0
•
pT4, G any, N0M0
•
pT any, G any, N1M0
d) Participants must have no clinical or radiological evidence of macroscopic residual disease 
or distant metastases (M0) after nephrectomy
i)
Baseline tumor assessment, performed 4 to approximately 12 weeks after nephrectomy, 
shows no metastasis or residual tumor lesions per local review and as confirmed by 
Blinded Independent Central Review (BICR). Results of BICR of the baseline tumor 
assessment confirming absence of metastasis or residual tumor lesions must be received 
before randomization. 
Note: participants with one or more regional lymph nodes identified with short axis 
≥15 mm on the baseline (post-operative) tumor assessments are considered to have 
gross residual disease and are therefore ineligible.
e) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 (Appendix 5).
f)
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue 
sections, obtained within 3 months prior to enrollment, preferably from nephrectomy, with 
an associated pathology report, must be submitted to the central laboratory prior to 
randomization. FFPE block or 20 unstained slides is ideal, but a minimum of 10 unstained 
slides will be acceptable if tumor tissue is limited. Biopsy should be excisional, incisional, 
or core needle. Fine needle aspiration is unacceptable for submission.
Key Exclusion Criteria
a) Any severe or serious, acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study drug 
administration including ongoing or active infection requiring parental antibiotics
b) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days prior to the first dose of study drug. Topical, ocular, intra-articular, intranasal, 
inhaled steroids, and adrenal replacement steroid doses > 10 mg daily prednisone or the 
equivalent are permitted in the absence of active immune disease. 
c) Uncontrolled adrenal insufficiency
d) Participants with an active known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. 
Protocol Amendment No.: 06
Date: 08-Dec-2022
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CA209914
BMS-936558
nivolumab
Objectives and Endpoints:
Objective
Endpoint
Primary
•
Part A: To compare disease-free survival (DFS) 
per Blinded Independent Central Review 
(BICR) of nivolumab combined with 
ipilimumab versus placebo infusions in 
participants with localized RCC, with a 
predominantly clear cell histology who have 
undergone a nephrectomy. 
•
Part B: To compare disease-free survival (DFS) 
per Blinded Independent Central Review 
(BICR) of nivolumab versus placebo infusions 
in participants with localized renal cell 
carcinoma, with a predominantly clear cell 
histology who have undergone nephrectomy.
The primary endpoint is DFS. The primary endpoint of 
DFS will be programmatically determined based on the 
disease recurrence date provided by the BICR. DFS is 
defined as the time from randomization to development 
of local disease recurrence (ie, recurrence of primary 
tumor in situ or occurrence of a secondary RCC 
primary cancer), distance metastasis, or death, 
whichever came first.
Secondary
•
Part A: To compare OS, including the 5-year 
OS rates, of nivolumab combined with 
ipilimumab versus placebo infusions in 
participants with localized RCC with a 
predominantly clear cell histology who have 
undergone a nephrectomy.
•
Part B: To compare overall survival (OS), 
including the 5-year OS rates, of nivolumab 
versus placebo infusions in participants with 
localized renal cell carcinoma with a 
predominantly clear cell histology who have 
undergone a nephrectomy.
•
Part B: To evaluate differences in disease-free 
survival (DFS) per Blinded Independent Central 
Review (BICR) and overall survival (OS) of 
contemporaneously randomized nivolumab 
combined with ipilimumab participants versus 
nivolumab participants with localized renal cell 
carcinoma, with a predominantly clear cell 
histology, who have undergone a nephrectomy.
•
OS, defined as the time between the date of 
randomization and the date of death. For participants 
without documentation of death, OS will be censored 
on the last date the participants was known to be 
alive. 
•
DFS and OS in contemporaneously randomized 
combination and monotherapy participants.
•
To describe the safety and tolerability of 
nivolumab combined with ipilimumab
and 
nivolumab monotherapy up to 30 and 100 days 
of last dose of study therapy.
•
Safety and tolerability endpoint: type, incidence, 
severity (graded by the National Cancer Institute 
[NCI] Common Terminology Criteria for Adverse 
Events [CTCAE, Version 4.0], timing, seriousness, 
and relatedness, and laboratory abnormalities up to 
30 and 100 days of last dose of study therapy in all 
treated participants
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
Overall Design:
The original study design (Part A) is a double-blind, randomized trial of the nivolumab and 
ipilimumab combination therapy versus placebo infusions in participants with early stage localized 
RCC with a predominantly clear cell histology who underwent radical or partial nephrectomy. 
Approximately 1000 participants will be screened, and approximately 800 participants will be 
randomized. 
At the implementation of Revised Protocol 03, Part A of the study remains identical to the original 
protocol design. The addition of Part B to the protocol includes a monotherapy nivolumab arm. A 
target of approximately 800 participants are planned to be randomized between 3 arms in a 
1:1:2 ratio in Part B, with the primary endpoint of DFS and secondary endpoints of OS, and safety 
and tolerability.  
Approximately 1600 participants in total are expected to be randomized in this study. 
TNM staging will be stratified according to the following characteristics:
•
pT2a, G3 or G4, N0, M0 and pT2b, G any, N0, M0
•
pT3, G any, N0, M0
•
pT4, G any, N0, M0 and pT any, G any, N1, M0
Randomization must occur greater than 4 weeks and less than (or equal to) 12 weeks from the date 
of nephrectomy.
Tumor tissue obtained within 3 months prior to enrollment, preferably at the time of the 
nephrectomy, must be provided for biomarker analyses. 
Screening/baseline imaging should be performed at least 4 weeks post-nephrectomy- and 
submitted to the radiology vendor for BICR confirmation of disease-free status. Pre-nephrectomy 
images are also requested, if available. Participant eligibility must be confirmed by BICR prior to 
randomization and will be based only on the review of the baseline scans (and pre-nephrectomy 
scans if available). As a result, pre-nephrectomy scans, if available, and baseline scans are 
encouraged to be submitted to BICR within 8 weeks of the nephrectomy to allow for timely return 
of the decision from the BICR. 
The Treatment Phase begins when the randomization call is made into the Interactive Response 
Technology (IRT). 
For Part A of the study:
•
Arm A: nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every 
third nivolumab dose if dosing is delayed) 
•
Arm B: Placebo infusions at the same frequency of nivolumab and ipilimumab infusions
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
For Part B:
•
Arm A: nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every 
third nivolumab dose if dosing is delayed) 
•
Arm B: Placebo infusions at the same frequency of nivolumab and ipilimumab infusions
•
Arm C: Nivolumab 240 mg every 2 weeks and ipilimumab placebo every 6 weeks (or every 
third nivolumab dose if dosing is delayed) 
Treatment must be completed within 36 weeks after the first dose; any cycles not received within 
36 weeks after the first dose will be omitted, and the participant will enter the Follow-up Phase. 
Tumor assessments will occur in accordance with the Schedule of Activities or until recurrence 
has been identified by the investigator and is confirmed by BICR. Sites should submit all scans to 
the third-party vendor on a rolling basis, preferably within 7 business days of scan acquisition, and 
submit any pertinent cytology/pathology report for central review. PK and immunogenicity 
samples, biomarker assessments, and NCCN Functional Assessment of Cancer Therapy - Kidney 
Symptom Index (FKSI-19) and EuroQoL’s EQ-5D-3L will be collected according to the Schedule 
of Activities. Adverse event (AE) assessments should be documented at each clinic visit. 
The Follow-up Phase begins at the completion of 12 cycles, when the decision to discontinue a 
participant from study therapy is made (no further treatment with study therapy), or at Week 36, 
whichever comes first. Participants will have 2 follow-up visits (Follow-up 1 and Follow-up 2) for 
safety within 30 (± 7 days) and 100 days (± 7 days), respectively, from the last dose of study 
therapy. If the date of discontinuation is greater than 30 days after last dose, the Follow-up visit 1
can coincide with the date of discontinuation (± 7 days). Any ongoing treatment related- AEs will 
be followed until the toxicities resolve, return to baseline, or are deemed irreversible. After the 
Follow-up 2 Visit, all participants will be followed for overall survival status every 12 weeks 
(± 1 week) until death, withdrawal of consent, lost to follow-up, or end of study.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
Figure 1:
CA209914 Study Design Schematic for Part A 
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
Figure 2:
CA209914 Part B Study Design Schematic
Number of Participants: 
Approximately 1600 participants will be randomized in this study, 800 participants in Part A and 
800 participants in Part B. 
Treatment Arms and Duration:
For Part A of the study:
•
Arm A: Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or 
every third nivolumab dose if dosing is delayed) 
•
Arm B: Placebo infusions at the same frequency of nivolumab and ipilimumab infusions
For Part B of the study:
•
Arm A: Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or 
every third nivolumab dose if dosing is delayed) 
•
Arm B: Placebo infusions at the same frequency of nivolumab and ipilimumab infusions
•
Arm C: Nivolumab 240 mg every 2 weeks and ipilimumab Placebo every 6 weeks (or every 
third nivolumab dose if dosing is delayed) 
Each cycle will be 2 weeks (14 days). Participants will receive study drug until the end of 12 cycles 
(12 nivolumab doses and 4 ipilimumab doses), recurrence, unacceptable toxicity, 36 weeks after 
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
first dose, or withdrawal of consent, whichever occurs first. The first cycle will be a combination 
dose.
Study Treatment: 
Study Drug for CA209914
Medication
Potency
IP/Non-IP
Nivolumab Solution for Injection
100 mg (10 mg/mL) or 
40 mg (10 mg/mL)
IP
Ipilimumab
200 mg (5 mg/mL)
IP
0.9% Sodium Chloride for Injection
NA
IP
5% Dextrose for Injection
NA
IP
Data Monitoring Committee:
A Data Monitoring Committee (DMC) will be established to provide oversight of safety and 
efficacy considerations in protocol CA209914. Additionally, the DMC will provide advice to the 
sponsor regarding actions the committee deems necessary for the continuing protection of 
participants. The DMC will be charged with assessing such actions in light of an acceptable 
benefit/risk profile for nivolumab and ipilimumab. The DMC will act in an advisory capacity to 
BMS and will monitor participant safety and evaluate the available efficacy data for the study. The 
oncology therapeutic area of BMS has primary responsibility for design and conduct of the study.
Blinded Independent Review Committee:
The BICR will review tumor images and pertinent clinical data (cytology/pathology report) in all 
randomized participants to determine eligibility and response for the DFS analyses. Details of the 
BICR responsibilities, procedures, composition, and process will be specified in the BICR charter.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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v

Clinical Protocol
CA209914
BMS-936558
nivolumab
|
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA209914) All Participants
Procedure
Screening Visita
Notes
Eligibility Assessments
Informed Consent
X
Register in Interactive Response Technology (IRT) system to obtain participant number.
Inclusion/Exclusion Criteria
X
Must be confirmed prior to randomization.
Medical History
X
All medical history relevant to the disease under study.
Safety Assessments
Full Physical Examination, 
Measurements, Vital Signs, and 
Performance Status
X
Includes height, weight, ECOG Performance Status (Appendix 5), BP, HR, and 
temperature within 14 days prior to randomization. 
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization.
Review of Concomitant Medications
X
Within 14 days prior to randomization. Document vaccine use within 30 days prior to first 
dose of study treatment. See Section 6.2 and Section 7.7 for additional details.
Serious Adverse Events (SAE)
Assessment
X (see Notes)
Collect Serious Adverse Events from time of consent.
In addition, collect all AEs (SAEs and non-serious AEs) associated with suspected or 
confirmed SARS-CoV-2 infection from time of consent.
Laboratory Tests
Laboratory Test
X
Must be performed within 14 days prior to randomization:
•
CBC w/differential
•
Chemistry panel including: AST, ALT, ALP, T.Bili, BUN or serum urea level, 
creatinine, phosphate, Ca, Na, Mg, K, Cl, LDH, glucose, and albumin
•
Thyroid panel including TSH, Free T4, Free T3
•
Hep B/C (HBVsAg, HCV antibody or HCV RNA) 
•
(sites in countries or locals where HIV testing is required, see Appendix 7)
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
|
Table 2-1:
Screening Procedural Outline (CA209914) All Participants
Procedure
Screening Visita
Notes
Pregnancy Test 
X
WOCBP only. 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 prior to first dose of study 
therapy. 
Efficacy Assessments
Baseline Tumor Assessments
X
CT/MRI of the chest, abdomen, and pelvis. See Section 9.1.3.1. Baseline assessments should 
be taken no less than 4 weeks after the nephrectomy, and sites are strongly encouraged to 
submit scans to the Blinded Independent Central Review (BICR) preferably within 8 weeks 
after the nephrectomy to allow for return of the results from the BICR. Pre-nephrectomy 
images are also requested, if available, and should be submitted to the BICR within 8 weeks 
post-nephrectomy. BICR confirmation of disease-free status is required prior to 
randomization.
Tumor Tissue Samples
X
Submission of sufficient tumor tissue, preferably obtained from the nephrectomy, with 
associated pathology report will be required. Formalin-fixed, paraffin-embedded (FFPE) 
block or 20 unstained slides, a minimum of 10 slides will be acceptable if tumor tissue is 
limited (see Section 9.8.2).
AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BICR, Blinded Independent Central Review; BP, 
blood pressure; BUN, blood urea nitrogen; Ca, calcium; CBC, complete blood count; Cl, chloride; ECOG, Eastern Cooperative Oncology Group; FFPE, formalin-
fixed paraffin-embedded; HBVsAg, hepatitis B surface antigen; HCG, human chorionic gonadotropin; HCV, hepatitis C virus; HIV, human immunodeficiency 
virus; HR, heart rate; IRT, Interactive Response Technology; LDH, lactate dehydrogenase; K, potassium; Mg, magnesium, NA, sodium; SAE, serious adverse 
event; T.Bili, total bilirubin; WOCBP, women of childbearing potential. 
a 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.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
Table 2-2:
On-treatment Procedural Outline (CA209914) Part A and Part B
Procedure
Cycle 1 Day 1
(Nivolumab + 
Ipilimumab )
Cycles 2, 3, 5, 6, 8, 
9, 11, & 12
Day 1a,b
Each Cycle = 
2 weeks
(Nivolumab 
alone)
Cycles 4, 7, & 
10
Day 1,
(Nivolumab + 
Ipilimumab)
Notes
Safety Assessments
Targeted Physical 
Examination, Vital Signs, 
and Performance Status
X
X
X
Weight, BP, HR, temperature, and ECOG Performance Status 
(Appendix 5) to be performed within 72 hours prior to dosing
Assessment of Signs and 
Symptoms
X
X
X
Adverse Event
(AE)Assessment and 
Serious Adverse Event 
(SAE) Assessment
Continuously (see Notes)
Participants will be followed for drug-related toxicities until these 
toxicities resolve, return to baseline, or are deemed irreversible. All 
adverse events (SAEs and non-serious AEs), including those 
associated with suspected or confirmed SARS-CoV-2 infection, will 
be collected continuously during the treatment period and 
documented for a minimum of 100 days after last dose (Appendix 3).
Review of Concomitant 
Medications
X
X
X
Record at each visit.
Laboratory Tests
X
X
X
Laboratory tests do not need to be repeated at C1D1 if performed 
within 14 days prior to first dose. 
After C1D1, within 72 hours prior to dosing and results should be 
reviewed prior to administration of each dose of study drug:
•
CBC w/differential.
•
Chemistry panel including AST, ALT, ALP, T. Bili, BUN or 
serum urea level, creatinine, phosphate, Ca, Mg, Na, K, Cl, LDH, 
glucose, and albumin.
•
TSH (with reflexive Free T4 and Free T3).
Protocol Amendment No.: 06
Date: 08-Dec-2022
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v

Clinical Protocol
CA209914
BMS-936558
nivolumab
Table 2-2:
On-treatment Procedural Outline (CA209914) Part A and Part B
Procedure
Cycle 1 Day 1
(Nivolumab + 
Ipilimumab )
Cycles 2, 3, 5, 6, 8, 
9, 11, & 12
Day 1a,b
Each Cycle = 
2 weeks
(Nivolumab 
alone)
Cycles 4, 7, & 
10
Day 1,
(Nivolumab + 
Ipilimumab)
Notes
Pregnancy Test
X
X
X
Within 24 hours prior to the initial administration of study drug, then
every 4 weeks, regardless of dose delay. Serum or Urine. WOCBP 
only.
Pharmacokinetic 
Samples
PK Samples
X
X
See Table 9.5-1. At Cycles 1, 2, 5, 8, & 11.
Immunogenicity blood 
sample 
X
X
See Table 9.5-1. At Cycles 1, 2, 5, 8, & 11. 
Exploratory Biomarker 
Assessments
Whole Blood (DNA)
X
Only at baseline. 
Serum
X
X
Prior to dosing.
At Cycle 1, 4, and 7, and upon occurrence of ≥ Grade 3 non-laboratory 
drug-related AE and/or lab abnormalities regarded as a drug-related
SAE, to be collected when clinically safe and feasible.
ctDNA
X
X (C2D1, C5D1, 
C9D1 only)
Samples should be collected prior to dosing. Subsequent sample 
collections will be aligned with tumor assessments performed on 
Weeks 23, 36, and 52 (± 1 week window). If a tumor assessment is 
not performed, ctDNA sampling is not required.
Peripheral Blood RNA
X
Prior to dosing at Cycle 1 and upon ≥ Grade 3 non-laboratory 
drug-related AE and/or laboratory abnormalities regarded as a
drug-related SAE, to be collected when clinically safe and feasible.
Myeloid Derived 
Suppressor Cells 
X
X
Cytochex Tube. Prior to dosing.
At Cycle 1 and 7.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
Table 2-2:
On-treatment Procedural Outline (CA209914) Part A and Part B
Procedure
Cycle 1 Day 1
(Nivolumab + 
Ipilimumab )
Cycles 2, 3, 5, 6, 8, 
9, 11, & 12
Day 1a,b
Each Cycle = 
2 weeks
(Nivolumab 
alone)
Cycles 4, 7, & 
10
Day 1,
(Nivolumab + 
Ipilimumab)
Notes
SARS-CoV-2 Serology
X
X (C12D1 only)
Samples should be collected prior to dosing. Serum will be collected 
at C1D1 and C12D1 for all participants, and approximately 4 weeks 
after a suspected or confirmed SARS-CoV-2 infection to be used for
potential future measurements of anti-SARS-CoV-2 serology (anti-
SARS-CoV-2 total or immunoglobulin G (IgG) [see Section 9.8.9]). If 
a suspected or confirmed SARS-CoV-2 infection occurs within 4 
weeks of the C1D1 or C12D1 time point, a single serum sample will 
be collected to satisfy the requirements for both the C1D1 or C12D1
and approximately 4 week after infection time points.
Efficacy Assessments
Tumor Assessments 
See Notes. 
CT/MRI of the chest, abdomen, and pelvis. Assessment should be 
performed at Weeks 23, 36, and 52 (± 1 week) regardless of any dose 
delays. Use same imaging method as was used at screening/baseline. 
See Section 9.1.3 for additional details. 
Patient-Reported 
Outcomes
EQ-5D-3L
X
Cycles 3, 6, 9, and 
12
Completed on Day 1 of Cycles 1, 3, 6, 9, and 12 prior to any 
study-related procedures.
FKSI-19
Xc
Cycles 3, 6, 9 and 
12
Completed on Day 1 of Cycles 1, 3, 6, 9, and 12 prior to any 
study-related procedures.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
Table 2-2:
On-treatment Procedural Outline (CA209914) Part A and Part B
Procedure
Cycle 1 Day 1
(Nivolumab + 
Ipilimumab )
Cycles 2, 3, 5, 6, 8, 
9, 11, & 12
Day 1a,b
Each Cycle = 
2 weeks
(Nivolumab 
alone)
Cycles 4, 7, & 
10
Day 1,
(Nivolumab + 
Ipilimumab)
Notes
Drug Administration
Randomize
X
Begins with call to Interactive Response Technology.
Administer nivolumab or 
placebo
X
X
X
Participants must begin study treatment within 3 calendar days of 
randomization. 
Administer ipilimumab or 
placebo
X
X
Participants must begin study treatment within 3 calendar days of 
randomization.
AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; BUN, blood urea nitrogen; 
C1D1, Cycle 1 Day 1; Ca, calcium; CBC, complete blood count; Cl, chloride; ECOG, Eastern Cooperative Oncology Group; FKSI-19, Functional Assessment of 
Cancer Therapy - Kidney Symptom Index; HR, heart rate; LDH, lactate dehydrogenase; K, potassium; Mg, magnesium, NA, sodium; SAE, serious adverse event; 
SARS CoV-2, severe acute respiratory syndrome coronavirus 2; T.Bili, total bilirubin; TSH, thyroid stimulating hormone; WOCBP, women of childbearing 
potential. 
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
b If all cycles are not given within 36 weeks after the first dose, the participant will discontinue treatment and move to Post-treatment Follow-up.
c Note: at baseline visit (C1D1) only, Question GP5 on FKSI-19 can be left blank as participant has not yet received treatment.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
Table 2-3:
Post-treatment Follow-up (CA209914) Part A and Part B
Procedure
Follow-Up 
Visit 1 and 2a
Survival Follow-Upb
Notes
Safety Assessments
Targeted Physical 
Examination, Vital 
Signs, and Performance 
Status
X
Weight, BP, HR, temperature, and ECOG Performance Status
(Appendix 5). 
Assessment of Signs 
and Symptoms
X
Adverse Event (AE)
Assessment and Serious 
Adverse Event (SAE)
Assessment
X
See Notes
Participants will be followed for drug-related toxicities until these 
toxicities resolve, return to baseline, or are deemed irreversible. All 
AEs will be documented for a minimum of 100 days after last dose 
(Appendix 3).
Participants will be followed for all SAEs, non-serious AEs of special 
interest (as defined in Section 9.2), and all AEs (SAEs and 
non-serious AEs) associated with suspected or confirmed 
SARS-CoV-2 infection and study treatment-related AEs (SAEs and 
non-serious AEs) until resolution, the condition stabilizes, the event is 
otherwise explained, the event is deemed irreversible, the participant 
is lost to follow-up (as defined in Section 8.3), or for suspected cases 
of SARS-CoV-2, until SARS-CoV-2 infection is ruled out.
Also, all non-serious AEs considered related to the study treatment
should be collected through survival follow-up visits until 
approximately 1 year following discontinuation of study treatment
(see Section 9.2.1 and Section 9.2.3 for additional details). 
Review of Concomitant 
Medications
X
X
During survival follow-up any new anti-tumor therapy initiated for 
either disease recurrence or a secondary malignancy at any time 
during this period will be captured in the CRF
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
Table 2-3:
Post-treatment Follow-up (CA209914) Part A and Part B
Procedure
Follow-Up 
Visit 1 and 2a
Survival Follow-Upb
Notes
Laboratory Tests
X
CBC w/differential, AST, ALT, ALP, T. Bili, BUN or serum urea
level, creatinine, phosphate, Ca, Mg, Na, K, Cl, LDH, glucose, and 
TSH (with reflexive Free T4 and Free T3).
Pregnancy Test
X
Serum or Urine. WOCBP only.
Pharmacokinetic 
Samples
PK Samples
X
Immunogenicity blood 
sample
X
Exploratory 
Biomarker 
Assessments
Serum
See Notes
Upon disease recurrence or occurrence of  ≥ Grade 3 non-laboratory 
drug-related AE and/or lab abnormalities regarded as a drug-related
SAE, to be collected when clinically safe and feasible
Peripheral Blood RNA
See Notes
Upon disease recurrence or occurrence of ≥ Grade 3 non-laboratory
drug-related AE and/or lab abnormalities regarded as a drug-related
SAE, to be collected when clinically safe and feasible.
ctDNA
See Notes
Sample collection is aligned with the tumor assessments on
Weeks 23, 36, and 52 (± 1 week window). If a tumor assessment is 
not performed, ctDNA sampling is not required.
SARS-CoV-2 Serology
See Notes
Serum will be collected at Follow-up visit 2 only for all participants, 
and approximately 4 weeks after a suspected or confirmed 
SARS-CoV-2 infection to be used for potential future measurements 
of anti-SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgG [see 
Section 9.8.9]). If a suspected or confirmed SARS-CoV-2 infection 
occurs within 4 weeks of the follow-up visit 2 time point, a single 
serum sample will be collected to satisfy the requirements for both the 
follow-up visit 2 and approximately 4 week after infection time points.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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v

Clinical Protocol
CA209914
BMS-936558
nivolumab
Table 2-3:
Post-treatment Follow-up (CA209914) Part A and Part B
Procedure
Follow-Up 
Visit 1 and 2a
Survival Follow-Upb
Notes
Tumor Biopsy
See Notes
Tumor biopsy collection at the time of recurrence is optional but 
highly encouraged.
Efficacy Assessments
Tumor Assessments 
See Notes
•
Timing for scans should be based on date of first treatment, which 
is considered Week 1. Weeks 23, 36, and 52 (± 1 week window at 
each time point).
•
After Week 52 (first year), tumor assessments should occur every 
6 months (± 2 week window) until Year 6. 
•
Annually for Year 6 to Year 10 (± 2 week window).
•
Additional imaging of potential disease sites should be performed 
whenever disease recurrence or occurrence of a secondary 
malignancy is suspected. 
•
Tumor assessments can be discontinued when recurrence has been 
confirmed by BICR.  
•
Brain CT or MRI with contrast or bone imaging (confirmatory 
imaging in addition to bone imaging may be required) if clinically 
indicated.
•
See Section 9.1.3 for additional details. 
Patient-Reported 
Outcomes
EQ-5D-3L
Xc (see Notes)
See Notesc
Perform at Follow-up 1 and 2, the first Survival Visit and at every 
other survival Follow-Up visit thereafter (Survival Follow-up visit 3, 
5, 7, etc).c
All patient-reported outcomes should be completed prior to 
study-related procedures, if possible.
FKSI-19
Xc (see Notes)
See Notesc
AE, Adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; BUN, blood urea nitrogen; 
Ca, calcium; CBC, complete blood count; Cl, chloride; ctDNA, circulating tumor DNA; ECOG, Eastern Cooperative Oncology Group; FKSI-19, Functional 
Assessment of Cancer Therapy - Kidney Symptom Index; HR, heart rate; LDH, lactate dehydrogenase; K, potassium; Mg, magnesium, NA, sodium; SAE, serious 
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nivolumab
adverse event; SARS CoV-2, severe acute respiratory syndrome coronavirus 2; T.Bili, total bilirubin; TSH, thyroid stimulating hormone; WOCBP, women of 
childbearing potential. 
a Participants must be followed for at least 100 days after last dose of study treatment. Follow-up visit 1 (Follow-up 1) = 30 days from the last dose ± 7 days or 
coincide with the date of discontinuation (± 7 days) if date of discontinuation is greater than 30 days after last dose.  Follow-up visit 2 (Follow-up 2) = 100 days 
(± 7 days) from the last dose of study medication.
b From Follow-up 2, all participants will be followed for overall survival status every 12 weeks (± 7 days) until the time for the final analysis. Survival status can 
be ascertained by telephone contact if the participant is unable to return to the site. If new anti-tumor therapy is initiated for either disease recurrence or a 
secondary malignancy at any time during this period, this and all other pertinent data obtained should be recorded on the appropriate Case Report Form (CRF).
c If participant is unable to perform the patient-reported outcome assessment in person, the EQ-5D-3L and FKSI-19 can be performed via telephone. The same 
window (± 7 days) applies for telephone contacts.
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3
INTRODUCTION
Renal cell carcinoma (RCC) is the eighth most common cancer in the world with an increasing 
incidence.1 In the United States, there were approximately 63,000 new cases in 2015 and almost 
14,000 deaths.2 There were approximately 84,000 cases of RCC and 35,000 deaths due to kidney 
cancer in 2012 in the European Union.3,4 Despite the earlier detection of smaller kidney tumors, 
the rate of RCC-related mortality has increased,5,6 suggesting that recurrence and advanced disease 
are responsible for mortality. In this context, optimizing the management of early-stage RCC, as 
well as advanced RCC, are key priorities in the oncological clinical practice. 
When RCC is localized early in the course of the disease, it is well established that radical surgical 
resection is curative for a proportion of patients however, it is estimated that 20-30% of patients 
will experience relapse.16 Most relapses occur within 3 years after surgery, with a median time of 
1-2 years however; recurrences have been reported through 30 years.16 Prognostic factors that 
have been associated with an increased risk of recurrence include anatomic extent of disease, 
histopathology, presence of tumor necrosis, and certain biomarkers.7 Effective adjuvant therapy, 
in addition to surgical management, may offer an alternative approach to the standard of care for 
patients with high risk of recurrence. Investigational research is currently ongoing regarding 
prognostic factors, time and risk of recurrence, and use of adjuvant therapy in the localized RCC 
setting.
Several trials have shown no benefit with adjuvant interferon- or interleukin-2-based therapies or 
a CA-IX antibody. This is in contrast to a number of clinically proven therapies for stage IV RCC. 
Additional trials are currently assessing the efficacy of the approved multi-targeted tyrosine kinase 
inhibitors, including sorafenib (SORCE) and axitinib (ATLAS) (Table 3-1), in the adjuvant setting.
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Table 3-1:
Clinical Trials Database Listed Large, Multicenter, Placebo-Controlled, Randomized, Double-
blind, Adjuvant Clinical Trials in RCC (Completed)
Acronym
Trial 
No.
Status
Intervention
Funding Body/
Sponsors
Design
Start Date/
Est 
Complete 
Date
Stratification
Estimated 
Enrollment
Outcome 
Measures
ARISER
NCT000
87022
Completed
Girentuximab
Industry; Wilex
MC, DB, 
R, PC
07/2004
10/2012
High-risk patients 
based on TN stage or 
Fuhrman grade, 
ECOG PS = 0 or 1
864
Primary 
endpoint DFS, 
not met
ASSURE
NCT032
6898
Completed
Sorafenib or 
Sunitinib
NIH; NCI, 
ECOG, SWOG, 
Cancer and 
Leukemia 
Group B, NCIC
MC, DB, 
R, PC
05/2006
04/2016
At least intermediate 
high-risk UISS, 
ECOG PS = 0 or 1, 
clear or non-clear cell 
RCC
1923
Primary 
endpoint DFS 
not met
ATLAS
NCT015
99754
Terminated
Axitinib
Industry; SF J 
Pharma., Pfizer
MC, DB, 
R, PC
04/2012
05/2019
High-risk UISS, 
ECOG PS = 0 or 1, 
predominate clear 
cell histology
592
OS, DFS, 
toxicity
PROTECT
NCT012
35962
Completed
Pazopanib
Industry; GSK
MC, DB, 
R, PC
11/2010
04/2017
Modified UISS, 
Karnofsky 
performance scale of 
at least 80, clear cell 
or predominate clear 
cell histology
1500
Primary 
endpoint DFS 
not met
SORCE
NCT004
92258
Completed
Sorafenib
Medical 
Research 
Council UK
MC, DB, 
R, PC
05/2007
2013
Intermediate- and 
high-risk SSIGN, 
ECOG PS = 0 or 1, 
clear or non-clear cell 
RCC
1656
OS, DFS, 
toxicity, QoL
SWOG-
S0931
NCT011
20249
Active, not 
recruiting
Everolimus
NIH, SWOG, 
NCI
MC, DB, 
R, PC
04/2011
Pathological high or 
very high risk, no 
further details 
available, ECOG PS 
= 0 or 1
1218
RFS, OS
toxicity
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Table 3-1:
Clinical Trials Database Listed Large, Multicenter, Placebo-Controlled, Randomized, Double-
blind, Adjuvant Clinical Trials in RCC (Completed)
Acronym
Trial 
No.
Status
Intervention
Funding Body/
Sponsors
Design
Start Date/
Est 
Complete 
Date
Stratification
Estimated 
Enrollment
Outcome 
Measures
S-TRAC
NCT003
75674
Completed
Sunitinib
Industry, Pfizer
PC, DB, 
R, DB
07/2007
06/2017
High-risk UISS, 
ECOG PS = 0-2, 
predominate clear 
cell histology
720
Primary 
endpoint DFS 
met per IRC not 
met per 
investigator. OS 
(immature)
ARISER, Adjuvant Rencarex Immunotherapy Phase III trial to Study Efficacy in non-metastatic RCC8; ASSURE, Adjuvant Sorafenib or Sunitinib for Unfavorable 
Renal Carcinoma; ATLAS, Adjuvant Axitinib9 Treatment of Renal Cancer: A Randomized Double-blind Phase 3 Study of Adjuvant Axitinib v Placebo in Subjects 
at High Risk of Recurrent RCC; PROTECT, a Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy and Safety of Pazopanib as 
Adjuvant Therapy for Subjects with Localized or Locally Advanced RCC Following Nephrectomy; SORCE, a Phase III Randomized, Double-blind Study 
Comparing Sorafenib with Placebo in Patients with Resected Primary Renal Cell Carcinoma at High or Intermediate Risk of Recurrence; S-TRAC, Sunitinib 
Treatment of Renal Adjuvant Cancer: A Randomized Double-blind Phase 3 Study of Adjuvant Suntinib v Placebo in Subjects at High Risk of Recurrent RCC10; 
SWOG-S0931, EVEREST, EVErolimus for Renal Cancer Ensuring Surgical Therapy, a Phase III Study.
DB, Double-blind; ECOG, Eastern Cooperative Group; DFS, Disease-free survival; PS, performance score; MC, multicenter; NCI, National Cancer Institute; NIH, 
National Institute of Health; OL, open-label; OS, overall survival; PC, placebo-controlled; QoL, quality of life; SWOG, Southwest Oncology Group; R, randomized; 
TN, tumor, node; UISS, UCLA Integrated Staging System
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The first trial to report results, ECOG 2805 (ASSURE), revealed no benefit in disease-free survival 
(DFS) after 1 year of adjuvant sunitinib or sorafenib versus placebo.11 Median DFS was 5.8 years 
(IQR, 1.6−8.2) for sunitinib (hazard ratio [HR] 1.02, 97.5% CI 0.85–1.23, P = 0.8038), 6.1 years 
(IQR, 1.7–not estimable [NE]) for sorafenib (HR 0.97, 97.5% CI 0.80–1.17, P=0.7184), and 
6.6 years (IQR, 1.5–NE) for placebo. The most common Grade 3 or worse AEs were hypertension 
(105 [17%] participants on sunitinib and 102 [16%] participants on sorafenib), hand-foot syndrome 
(94 [15%] participants on sunitinib and 208 [33%] participants on sorafenib), rash (15 [2%] 
participants on sunitinib and 95 [15%] participants on sorafenib), and fatigue (110 [18%] 
participants on sunitinib and 44 [7%] participants on sorafenib). Reduced doses of sunitinib still 
resulted in high toxicity.
In the Phase III PROTECT trial, 1538 participants with completely resected RCC were randomly 
assigned to pazopanib or placebo for 1 year. The starting dose of pazopanib was reduced from 800 
to 600 mg daily, after enrollment of 403 participants, due to high rates of treatment 
discontinuations due to excess risk of hepatotoxicity. After median follow-up of approximately 
60 months, DFS for those treated with 600 mg/day dosing was not statistically different between 
pazopanib and placebo (67 versus 64 percent three-year DFS, HR 0.94, 95% CI 0.77-1.14). 
However, DFS was improved for those assigned to 800 mg/day dosing (66 versus 56 percent, HR 
0.66, 95% CI 0.49-0.90). Overall survival, a secondary endpoint, was immature.12
In a Phase III randomized, double-blind, placebo-controlled trial (ATLAS) conducted in 
724 participants with localized RCC status postnephrectomy, axitinib 5 mg oral twice daily, failed 
to demonstrate a DFS advantage in the total study population. There was no significant difference 
in DFS per independent review committee assessment in the intention-to-treat population (HR 
0.870, 95% CI 0.660–1.147; p 0.3211) or per investigator assessment (HR 0.776, 95% CI 0.599–
1.005; P = 0.0536).Overall survival data were not mature. Grade 3 or greater toxicities were more 
frequent in the axitinib arm (61 versus 30 percent).13
Another large Phase III trial, ARISER, a double-blind, placebo-controlled study, evaluated 
girentuximab (an antibody targeting carbonic anhydrase IX). Co-primary endpoints were DFS and 
OS assessed by independent radiologic review. No statistically significant DFS (HR = 0.97; 95% 
CI 0.79–1.18) or OS (HR = 0.99; 95% CI 0.74–1.32) benefit was observed. 14
In SORCE, a Phase III study comparing sorafenib 400 mg twice daily for 3 years, sorafenib 400 mg 
twice daily for 1 year followed by placebo for 2 years, and placebo for 3 years. Participants were
randomized in a 3:3:2 fashion. This study targeted intermediate- or high-risk disease by Leibovich 
score and allows both clear cell and non-clear cell histologies. The initial sorafenib dose was 
400 mg twice per day orally, amended during trial recruitment to a reduced starting dose of 400 mg 
daily. The primary outcome was investigator-reported DFS. There were no differences in DFS or 
OS for all randomized participants, high-risk participants only, and participants with only clear 
cell RCC. Median DFS was not reached for three years of sorafenib or for placebo (HR= 1.01, 
95% CI 0.82 -1.23, P = 0.946). The mean DFS was 6.81 years for three years of sorafenib and 6.82 
years for placebo, a difference of 0.01 (95% CI 0.49 – 0.48, P = 0.99).15
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Recently, the S-TRAC study was reported to have met its primary endpoint of improved DFS by 
blinded independent central review (BICR) for sunitinib vs placebo. The population targeted in 
the study was predominantly clear cell and had a diagnosis of locoregional RCC (tumor stage 3 or 
higher, regional lymph-node metastasis or both) on the basis of modified UISS criteria. The 
median DFS was 6.8 years (95% CI, 5.8 to NR) vs 5.6 years (95% CI, 3.8 to 6.6), (HR = 0.76, 
95% CI, 0.59-0.98, P = 0.03). Of note, investigator-assessed DFS did not show any statistical 
difference between sunitinib and placebo. Overall survival (OS) data were not mature at the time 
of data cutoff. Dose reductions because of AEs were more frequent in the sunitinib group than in 
the placebo group (34.3% vs 2%), as were dose interruptions (46.4% vs 13.2%) and 
discontinuations (28.1% vs 5.6%). Grade 3 or 4 AEs were more frequent in the sunitinib group 
(48.4% for Grade 3 events and 12.1% for Grade 4 events) than in the placebo group (15.8% and 
3.6%, respectively). There was a similar incidence of serious adverse events (SAEs) in the 2 groups 
(21.9% for sunitinib vs 17.1% for placebo). No deaths were attributed to toxic effects. From a
quality of life prospective, participants in the sunitinib arm had lower scores (EQ-5D and 
QLC-C30) than the placebo group, reaching clinically significant differences for diarrhea and loss 
of appetite.10
Based on the above results, sunitinib (50 mg daily 4 weeks on, 2 weeks off, for 1 year) was 
approved in the United States as adjuvant therapy following nephrectomy for participants at high 
risk of relapse. Although improved DFS findings per BICR were noted in the S-TRAC study, there 
was an absence of DFS improvement based on investigator assessment, immature OS finding, a 
need for frequent dose adjustments, and interruptions to manage sunitinib-related toxicities, and 
an overall decrease in quality of life of participants on sunitinib. National Cancer Comprehensive 
Network (NCCN) guidelines have been updated and indicate for RCC clear cell histology and high 
risk; clinical trial (preferred) or surveillance or adjuvant sunitinib (category 2B).16
In conclusion, at this time, surgery for primary tumors remains the best chance to cure patients 
with localized RCC. However, survival rates in higher risk patients remain poor, and novel 
therapeutic approaches are needed to improve prognosis in these patients.
3.1
Study Rationale
Encouraging results have been observed in both treatment-experienced and treatment-naive 
advanced RCC participants who received either nivolumab monotherapy or nivolumab plus 
ipilimumab (Section 3.2.1). Therefore, it is rational to continue to evaluate these immunotherapies 
in the adjuvant setting versus the current RCC standard of care. 
With the implementation of this proposed amendment, Part A of the study remains identical to the 
original protocol design. The addition of Part B to the protocol includes a monotherapy nivolumab 
arm. A target of approximately 1600 participants are planned (n=800 Part A and n=800 Part B) to 
be randomized in study CA209914, with the primary endpoint of DFS and secondary endpoints of 
OS, and safety and tolerability. 
The study is designed to demonstrate superiority of the combination of nivolumab and ipilimumab 
over placebo, and to then demonstrate superiority of monotherapy nivolumab over placebo and to 
support registration of the combination and monotherapy in adjuvant RCC. The contribution of 
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components  of  
the  combination  
is  planned  
to  be  assessed  using  a  contemporaneously  enrolled 
combination and monotherapy subgroup within the CA209914 study. 
The original primary endpoint, DFS for the combination treatment compared to the placebo arm 
is largely unimpacted by Revised Protocol 03. The primary test for participants randomized 1:1 to 
receive nivolumab + ipilimumab versus placebo will occur as originally planned.
The  additional  monotherapy  arm  in  Part  B,  will  allow  the  efficacy  assessment  by  directly 
evaluating the difference between 200 participants, contemporaneously randomized to nivolumab 
+ ipilimumab versus 400 participants contemporaneously randomized to nivolumab monotherapy.
Evaluating both nivolumab monotherapy and the combination of nivolumab and ipilimumab will 
provide a risk-benefit assessment of both adjuvant combination therapy and monotherapy. 
3.1.1 
Research Hypothesis
Treatment  with  nivolumab  combined  with  ipilimumab  compared  withplacebo  infusions and 
treatment with  nivolumab  monotherapy compared with placebo  
infusions, will  
improve DFS  
in 
participants with localized RCC with a predominantly clear cell histology who underwent radical 
or partial nephrectomy.
3.2 
Background
A  detailed  description  of  
the  chemistry,  pharmacology,  efficacy,  and  safety  of  nivolumab  and 
ipilimumab in combination is provided in the Nivolumab Investigator’s Brochure (IB).
3.2.1 
Indication Background
3.2.1.1 
Nivolumab Monotherapy in RCC
Harnessing the immune system would be an attractive opportunity, 
togetherwitheortsto ﬁnd cell
surface markers that can be used to trace and target dormant renal-cell carcinoma cells. Nivolumab 
monotherapy  has  been  studied  in  participants  with  advanced  RCC in  several  BMS-sponsored 
studies (Phase 1 through 3): MDX1106-03, CA209009, CA209010, and CA209025. MDX1106-03
was a Phase I refractory solid tumor trial, which included 34 participants with previously-treated 
advanced RCC who received nivolumab at 1 mg/kg (n = 18) or 10 mg/kg (n = 16) given every 
2 weeks.17,18,19In  both  
the  1  mg/kg  and  10  mg/kg  cohorts,  approximately  30%  of participants
experienced an objective response with median duration of response of 12.9 months. Responses 
were generally rapid with a median time to response of 16 weeks. Notably, responses could occur 
after treatment  cessation  and  persist off  
treatment.  Median  progression-free  survival  
(PFS)  was 
7.3 months. Median overall survival (mOS) was 22.4 months. These results were promising given 
that  many  of  
the  participants were  heavily  pre-treated  with  71% having  had  2 or  more  
lines  of 
therapy. Treatment-related AEs of any grade were observed in 85% of RCC participants; the most 
common were fatigue (41%), rash (27%), diarrhea (18%), and pruritis (18%). Grade 3-4 treatment-
related AEs were observed in 18% of RCC participants. The spectrum, frequency, and severity of
treatment-related  AEs  were  similar  in  the RCC population  compared  to  the  overall  study 
population and were similar across dose levels. 
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In order to identify a potential dose-response relationship in RCC, a randomized Phase 2 study 
(CA209010) was conducted in 168 participants with advanced RCC previously treated with an 
antiangiogenic therapy who received nivolumab at 0.3 mg (n = 60), 2 mg/kg (n = 24) or 10 mg/kg 
(n=54) given every 3 weeks.18 No dose response relationship was found as measured by PFS, with 
median PFS of 2.7, 4.0, and 4.2 months for the 0.3, 2, and 10 mg/kg groups, respectively (P = 0.9). 
Objective response rate (ORR) was 20%, 22%, and 20% in the 0.3, 2, and 10 mg/kg groups, 
respectively. Median time to achievement of an objective response was 2.8-3.0 months. The 
median duration of response was 22.3 months (4.8, NR) in the 10 mg/kg arm and not yet reached 
in the 2 lower dose cohorts. Median OS was at 18.2 to 25.5 months, with a minimum of follow-up 
of 24 months. Fatigue was the most frequent toxicity (22-35%). No new toxicities were identified 
with 11% experiencing Grade 3-4 treatment-related AEs, none of which were due to pneumonitis. 
Treatment-related AEs led to discontinuation of study drug in 7% of participants. 
A parallel biomarker-focused trial, CA209009, using the same 3 nivolumab dose levels (0.3, 2, 
and 10 mg/kg every 3 weeks) was executed to explore predictors of response and identify 
mechanisms of resistance.20 This study included 67 participants with previously-treated, advanced 
RCC who were randomized to one of the 3 nivolumab dose groups and 24 participants with 
previously-untreated RCC who received nivolumab at 10 mg/kg every 3 weeks. The results 
mirrored the efficacy and toxicity profile of CA209010, with an ORR of 18% in previously-treated 
participants, and 13% in previously untreated participants and disease stabilization in another 32% 
of previously treated and untreated participants. At 24 weeks, 36% of participants were free from 
progression. Of 56 participants with evaluable pretreatment tumor samples, 18 (32%) had ≥5% 
PD-L1 tumor expression. ORR was 22% among those with ≥5% PD-L1 tumor expression versus 
8% among those with < 5% PD-L1 tumor expression. 
Based on the clinical activity of nivolumab observed in these Phase 1 and 2 studies, a large Phase 3 
trial (CA209025) was conducted in 821 participants with advanced RCC previously treated with 
1 or 2 antiangiogenic therapies who were randomized to receive nivolumab 3 mg/kg every 2 weeks 
or everolimus 10 mg daily. A planned interim analysis, after a minimum of follow-up of 
14 months, demonstrated a statistically significant and clinically meaningful improvement in OS 
of nivolumab monotherapy vs everolimus (median OS, 25.0 months vs 19.6 months, respectively; 
HR 0.73 [98.5% CI, 0.57 to 0.93] P = 0.002). ORR was 25% for nivolumab vs 5% for everolimus. 
Additional efficacy results are presented in Table 3.2.1.1-1. Among 756 participants with 
quantifiable PD-L1 tumor expression in pretreatment samples, 24% had ≥1% PD-L1 expression. 
Among participants with ≥1% PD-L1 expression, median OS was 21.8 months in the nivolumab 
group and 18.8 months in the everolimus group (HR, 0.79; 95% CI, 0.53 to 1.17). Among 
participants with < 1% PD-L1 expression, the median OS was 27.4 months in the nivolumab group 
and 21.2 months in the everolimus group (HR, 0.77; 95% CI 0.60 to 0.97). No new safety concerns 
were identified, and nivolumab monotherapy showed a favorable safety profile as compared to 
everolimus, evidenced by the lower rates of drug-related AEs (all grades, 79% vs 88%; Grade 3-
4, 19% vs 37%, respectively) and drug-related AEs leading to discontinuation (all grades, 8% vs 
13%, respectively) in the nivolumab group. These results were the basis for regulatory approval of 
nivolumab monotherapy in advanced RCC.
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Single agent activity and tolerability of anti-PD1 in the first line metastatic setting further supports 
the evaluation of  nivolumab monotherapy in the adjuvant setting. In the phase 2, nonrandomized, 
noncomparative, KEYNOTE-42721 study, pembrolizumab was studied as monotherapy in 110 
participants with advanced clear cell RCC who had not received prior systemic therapy, including 
41 IMDC favorable-risk participants. The interim data showed single-agent activity with an overall 
response rate of 38.2% including a CR rate of 2.7%. Responses lasting for 6 months or more were 
observed in 74.8% of participants. The median PFS was 8.7 months (95% CI: 6.7-12.2 months) 
and the 6 month PFS rate was 60.2%. In an analysis based on PD-L1 status, participants whose 
tumors expressed PD-L1 (combined positive score [CPS] ≥1) (n = 46) had an ORR of 50.0% (95% 
CI: 34.9–65.1), with a CR rate of 6.5%. In participants whose tumors did not express PD-L1 (CPS
< 1) (n = 53), ORR was 26.4% (95% CI: 15.3–40.3) (all responses were PRs).
TITAN-RCC provided support to the added value of ipilimumab in combination with nivolumab 
in advanced renal cell carcinoma. In the phase 2 TITAN-RCC22 study (0216-ASG), open-label 
nivolumab was initiated as monotherapy and an “immunotherapeutic boost” of nivolumab plus 
ipilimumab was given only to nonresponders. The study enrolled 207 previously untreated and 
pretreated (2nd line), advanced or metastatic renal cell carcinoma (mRCC) subjects with 
intermediate and high risk disease according to IMDC.
Participants were treated first-line (n = 108) or second-line (after a TKI, n = 99) with nivolumab 
240 mg given every 2 weeks as induction therapy. Those with early significant progressive disease 
by week 8 or either stable or progressive disease at week 16 received 2 to 4 boost cycles of 
nivolumab plus ipilimumab. Those who did not respond to the boosts were considered 
immunotherapy resistant. Partial (PR) and complete responders (CR) to nivolumab monotherapy 
continued with nivolumab maintenance therapy, with combination therapy added only if they 
began to progress.
Confirmed ORR with first-line nivolumab monotherapy at 16 weeks was 28.7% (95% confidence 
interval 20–38). Boosting improved ORR to 37% (95% confidence interval 28–47). In the 
second-line setting it was 18.2%. Boosting improved ORR to 28.3% (95% confidence interval 
20-8). 
In the first-line setting, improvement in BOR with the addition of boost therapy was 29.8%. In the 
second-line setting it was 38.6%. 
Discontinuation due grade 3 or 4 adverse events was 14% in the first-line and 20% in the second-
line setting.
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Table 3.2.1.1-1:
Summary of Efficacy Results - All Randomized Subjects -
CA209025
Efficacy Parameters
Nivolumab (N = 410)
Everolimus (N = 411)
Primary Endpoint
Overall Survival
Events, n (%)
183/410 (44.6)
215/411 (52.3)
Stratified log-rank test P valuea,b
0.0018
HR (98.52% CI)c
0.73 (0.57, 0.93)
Median OS (95% CI), monthsd
25.00 (21.75, NR)
19.55 (17.64, 23.06)
OS Rate at 6 months (95% CI), %d
89.2 (85.7, 91.8)
81.2 (77.0, 84.7)
OS Rate at 12 months (95% CI), %d
76.0 (71.5, 79.9)
66.7 (61.8, 71.0)
Secondary Endpoints
Objective Response Rate per 
Investigator (CR + PR)e
N (%)
103 (25.1)
22 (5.4)
95% CIf
(21.0, 29.6)
(3.4, 8.0)
Odds ratio estimate (95% CI)g,h
5.98 (3.68, 9.72)
P Valuei
< 0.0001
Duration of responsee
Ongoing responders, n/N (%)
49/103 (47.6)
10/22 (45.5)
Median (95% CI), monthsd
11.99 (7.85, 23.03)
11.99 (6.44, NR)
Min, Maxj
0.0, 27.6+
0.0+, 22.2+
Progression-free survival
Events, n (%)
318 (77.6)
322 (78.3)
Stratified log-rank test p valuea
0.1135
HR (95% CI)c
0.88 (0.75, 1.03)
Median 95% CI)
4.60 (3.71, 5.39)
4.44 (3.71, 5.52)
a Log-rank test stratified by the MSKCC risk group (poor vs intermediate vs favorable), the number of prior 
antiangiogenic therapies in the advanced/metastatic setting (1 vs 2), and the region (W. Europe, US/Canada vs Rest 
of the World) as entered into the IVRS.
b Based on the 398 observed deaths and O’Brien-Fleming alpha spending function, the boundary for statistical 
significance requires the P value to be less than 0.0148.
c Stratified Cox proportional hazard model. Hazard ratio is nivolumab over everolimus. 
d Based on Kaplan-Meier Estimates. 
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e The confirmed ORR was 88/410 (21.5%) in the nivolumab group and 16/411 (3.9%) in the everolimus group 
(stratified CMH test P value < 0.0001), with a median DOR of 23.03 months in the nivolumab group and 
13.73 months in the everolimus group.
f CR+PR, confidence interval based on the Clopper and Pearson method.
g Cochran-Mantel-Haenzel test stratified by the MSKCC risk group (poor vs intermediate vs favorable), the number 
of prior anti-angiogenic therapies in the advanced/metastatic setting (X vs 2) and the region (Western Europe vs 
US/Canada vs Rest of the World) as entered into the IVRS.
h Ratio of nivolumab over everolimus
i Two-sided p value from CMH test for the comparison of the odds ratio of nivolumab over everolimus.
j Symbol + indicated a censored value. 
3.2.1.2
Ipilimumab in Renal Cell Carcinoma
Ipilimumab monotherapy for the treatment of mRCC was studied in the Phase 2 clinical trial 
MDX010-11.23 Two sequential cohorts were studied, each with a loading dose of 3 mg/kg 
followed by 3 doses of either 1 mg/kg (group 3-1; n = 21) or 3 mg/kg (group 3-3; n = 40). 
Participants with stable disease or partial or complete response were allowed additional treatment. 
In Group 3-1 (n = 21), 1 participant (5%) had a PR.24 In Group 3-3 (n = 40), 5 participants (12.5%) 
had a PR. Among 14 treatment-naive participants in Group 3-3, 3 (21%) had a PR.
In the ipilimumab monotherapy Phase 2 clinical trial MDX010-11, the major toxicities were colitis 
(all Grade 3/4; 14% in Group 3-1, 33% in Group 3-3) and hypophysitis (1 Grade 3/4, 1 Grade 1/2 
in Group 3-3; none in Group 3-1). Most reported AEs were Grade 1/2 (57% in Group 3-1, 35% in 
Group 3-3) or Grade 3 (38% in Group 3-1, 48 % in Group 3-3).25 The most common 
treatment-related AEs in Group 3-1 (total 81%) and Group 3-3 (total 93%) were diarrhea (38% and 
40%, respectively) and fatigue (33% and 38%, respectively). Most AEs were manageable with 
appropriate treatment, including high-dose corticosteroids and hormone replacement. 
3.2.1.3
Nivolumab Plus Ipilimumab in RCC
Promising safety and efficacy results were also observed with the combination of nivolumab and 
ipilimumab in the advanced RCC population in study CA209016,26 a Phase 1 dose-escalation 
study of nivolumab in combination with VEGFR-TKIs or ipilimumab in participants with 
metastatic RCC. Treatment-experienced and -naive participants with metastatic RCC 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. In Arm N1+I3, 25 out of 47 participants (53%) were 
treatment-naive. Approximately 62% were characterized as Intermediate Risk by the Memorial 
Sloan Kettering Cancer Center (MSKCC) categories, and 4.3% were categorized as Poor Risk. In 
Arm N3 + I3, 21 of 47 participants (45%) were treatment-naive. Sixty-six percent (66.0%) were 
classified as Intermediate Risk, and 6.4% were categorized as Poor Risk. The primary objective 
was to assess safety/tolerability; the secondary objective was to assess antitumor activity. 
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After a minimum of 22 months, the level of clinical activity, as measured by confirmed ORR, for 
the combination of nivolumab and ipilimumab in CA209016 was substantially greater than that 
observed in studies of either nivolumab (Section 3.2.1.1) or ipilimumab monotherapy 
(Section 3.2.1.2) in metastatic RCC, including in the treatment-naive subpopulation (see Table 
3.2.1.3-1). The dosing regimen including nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg 
(N3 + I1) was chosen for further clinical evaluation because it exhibited similar clinical activity to 
nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg (N1 + I3) but had a more favorable safety 
profile.
Table 3.2.1.3-1:
Antitumor Activity in All Participants (CA209016)
N3 + I1 (n = 22)
Previously Treated
N3 + I1 (n = 25)
Treatment-Naive
N1 + I3 (n = 26)
Previously Treated
N1 + I 3 (n = 21)
Treatment-naive
Confirmed ORR, 
n (%) (95% CI)
10 ( 45.5)
9 (36.0)
(18.0, 57.5)
10 ( 38.5)
9 (42.9) 
(21.8, 66.0)
Median duration 
of response, 
weeks (range)
60.1 (9.29, NA)
88.7 (30.00, 
105.00)
74.4 (12.29, 108.29)
NR (23.57, NA)
Ongoing 
responses, 
% (n/N)
4 ( 40.0)
4 ( 44.4)
2 ( 20.0)
5 ( 55.6)
Best objective 
response, n (%)
Complete 
response
3 ( 13.6)
2 (8.0)
0
0
Partial response
7 ( 31.8)
7 (28.0)
10 ( 38.5)
9 (42.9)
Stable disease
6 ( 27.3)
13 (52.0)
11 ( 42.3)
6 (28.8)
Progressive 
disease
6 ( 27.3)
6 (27.3)
3 ( 11.5)
5 (23.8)
Unable to 
determine
0
0
2 (  7.7)
1 (4.8)
PFS
Median months 
(CI)
6.6 ( 1.41, 16.39)
8.3 ( 3.55, 19.29)
10.1 ( 5.42, 20.76)
8.5 ( 2.00, NA)
6-month PFS
Median months 
(CI)
54.5 ( 32.1,  72.4)
8.3 ( 3.55, 19.29)
65.4 ( 44.0,  80.3)
61.9 ( 38.1,  78.8)
Median OS
NR ( 10.02, NA)
NR (26.68, NA)
30.9 ( 25.99, NA)
NR ( 17.45, NA)
NA, not applicable; N,R not reached.
Among the 91 participants treated with the nivolumab + ipilimumab combination in CA209016 
who provided evaluable baseline tumor samples, 37.4% had ≥1% PD-L1 tumor expression, and 
16.5% had ≥5% PD-L1 tumor expression. ORR was 47.1% among participants with ≥1% PD-L1 
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expression and 36.8% among participants with < 1% PD-L1 expression. Among participants with 
≥5% PD-L1 expression, ORR was 40.0%. 
Among all treated participants in the Arms N3 + I1 and N1 + I3, AEs were seen in 43/47 (91.5%)
participants in the N3 + I1 arm and 45/47 (95.7%) participants in the N1 + I3 arm. In the N3 + 
I1 arm, the most frequently reported drug-related AEs were fatigue (51.1%); rash, and pruritus 
(each 31.9%); nausea (27.7%); arthralgia (25.5%).28 In the N1 + I3 arm, the most frequently 
reported drug-related AEs were fatigue (68.1%); diarrhea, and nausea (each 44.7%); pruritus 
(36.2%); lipase increased (34%); AST increased (31.9%); ALT increased, and decreased appetite 
(29.8%); hypothyroidism (27.7%); and rash (25.5%).28
In the N3 + I1 arm, the most frequently reported, Grade 3-4 drug-related AE was lipase increased 
(14.9%). In the N1 + I3 arm, the  most frequently reported Grade 3-4 drug related AEs were lipase 
increased (27.7%); ALT increased (21.3%); diarrhea, and colitis (14.9%); AST increased 
(12.8%).28
Treatment-related AEs (including Grade 3-4), treatment-related AEs leading to discontinuation, 
and treatment-related SAEs all occurred more commonly in participants in the N1 + I3 arm than 
in the N3 + I1 arm (Table 3.2.1.3-2).
Table 3.2.1.3-2:
Summary of Safety Results in Study CA209016 - All Treated 
Subjects
Arm I-1
IPI1 + NIV3
N = 47
Arm I-3
IP13 + NIV1
N = 47
Death, n (%)
16 ( 34.0)
18 ( 38.3)
Within 30 Days of Last Dose
0
1 (  2.1)
Within 100 Days of Last Dose
3 (  6.4)
4 (  8.5)
Due to Study Drug Toxicity 
0
0
Any Grade
Grade 3-4
Any Grade
Grade 3-4
All-causality SAEs, n (%)
29 ( 61.7)
20 ( 42.6)
30 ( 63.8)
24 ( 51.0)
Drug-related SAEs, n (%)
11 ( 23.4)
9 ( 19.1)
16 ( 34.0)
16 ( 34.0)
All-causality AEs Leading to 
Discontinuation, n (%)
5 ( 10.6)
3 (  6.4)
15 (31.9)
11 ( 23.4)
Drug-related AEs Leading to 
Discontinuation, n (%)
5 ( 10.6)
3 (  6.4)
13 ( 27.7)
9 ( 19.1)
All-causality AEs, n (%)
47 (100.0)
33 ( 70.2)
47 (100.0)
34 ( 72.3)
Drug-related AEs, n (%)
43 ( 91.5)
18 ( 38.3)
45 ( 95.7)
29 ( 61.7)
All-causality Select AEs, within 30 
Days of Last Dose, by Category, n 
(%)
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Endocrine
14 ( 29.8)
3 ( 6.4)
19 (40.4)
0
Gastrointestinal
16 ( 34.0)
3 ( 6.4)
25 (53.2)
12 ( 25.5)
Hepatic
11 ( 23.4)
3 ( 6.4)
15 (31.9)
8 ( 17.0)
Pulmonary
3 (  6.4)
0
5 (10.6)
0
Renal
11 ( 23.4)
2 (  4.3)
10 (21.3)
2 (  4.3)
Skin
29 ( 61.7)
1 (  2.1)
33 ( 70.2)
1 (  2.1)
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Table 3.2.1.3-2:
Summary of Safety Results in Study CA209016 - All Treated 
Subjects
Arm I-1
IPI1 + NIV3
N = 47
Arm I-3
IP13 + NIV1
N = 47
Hypersensitivity/Infusion Reactions
5 ( 10.6)
0
3 (  6.4)
0
Drug-related Select AEs, within 30 
Days of Last Dose, by Category, n 
(%)
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Endocrine
13 ( 27.7)
2 ( 4.3)
19  (40.4)
0
Gastrointestinal
12 ( 25.5)
2 ( 4.3)
21 ( 44.7)
11 ( 23.4)
Hepatic
9 ( 19.1)
3 ( 6.4)
13 ( 27.7)
8 ( 17.0)
Pulmonary
3 ( 6.4)
0
5 ( 10.6)
0
Renal
9 ( 19.1)
2 ( 4.3)
6 ( 12.8)
1 ( 2.1)
Skin
23 ( 48.9)
0
28 ( 59.6)
1 ( 2.1)
Hypersensitivity/Infusion Reactions
5 ( 10.6)
0
3 (  6.4)
0
All-causality Immune-mediated AEs, 
by Category
Immune-mediated AEs Treated with 
Immune-modulating medication
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Diarrhea/Colitis
3 ( 6.4)
2 ( 4.3)
12 ( 25.5)
10 ( 21.3)
Hepatitis
5 ( 10.6)
2 ( 4.3)
11 ( 23.4)
8 ( 17.0)
Pneumonitis
1 ( 2.1)
0
5 ( 10.6)
0
Nephritis and Renal Dysfunction
2 ( 4.3)
1 ( 2.1)
1 ( 2.1)
0
Rash
8 ( 17.0)
1 ( 2.1)
9 ( 19.1)
1 ( 2.1)
Hypersensitivity
0
0
0
0
Immune-Mediated Endocrine AEs 
Treated with or without Immune-
Modulating Medications
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Adrenal Insufficiency
3 ( 6.4)
1 ( 2.1)
6 ( 12.8)
0
Hypophysitis
1 ( 2.1)
1 ( 2.1)
2 ( 4.3)
0
Hypothyroidism/Thyroiditis
10 ( 21.3)
0
14 ( 29.8)
0
Hyperthyroidism
4 ( 8.5)
1 ( 2.1)
8 ( 17.0)
0
Diabetes Mellitus
0
0
0
0
MedDRA version 18.1; CTC version 4.0. All events are within 100 days of the last dose of study drug, unless otherwise 
indicated. 
Sources: Table S.6.2A (deaths), Table S.6.3A (all-causality SAEs), Table S.6.3B (drug-related SAEs), Table S.6.4B 
(all-causality AEs leading to discontinuation), Table S.6.4D (drug-related AEs leading to discontinuation), Table S.6.2 
(all-causality AEs), Table S.6.3.1 (drug-related AEs), Table S.6.101 (all-causality select AEs), Table S.6.105 (all-
causality endocrine select AEs), Table S.6.103 (drug-related select AEs), Table S.6.107 (drug-related endocrine select 
AEs), Table S.6.202 (all-causality IMAEs with exception of endocrine), and Table S.6.204 (all-causality endocrine 
IMAEs).
Based on the results from CA209016, a large Phase 3 trial was initiated comparing nivolumab 
3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses followed by 
nivolumab 3 mg/kg IV every 2 weeks vs sunitinib 50 mg orally daily for 4 weeks on, 2 weeks off, 
in participants with previously untreated advanced or metastatic RCC (CA209214). The co-
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primary endpoints were ORR, PFS, and OS in International Metastatic Renal Cell Carcinoma 
Database Consortium (IMDC) intermediate and poor-risk participants. Overall, alpha of 0.05 was 
split among the co-primary endpoints (0.001 for ORR, 0.009 for PFS, and 0.04 for OS). ORR, 
PFS, and OS in all randomized participants (including all IMDC risk groups) were secondary 
endpoints.
There were 550 participants randomized to nivolumab + ipilimumab (including 425 participants 
with intermediate/poor risk) and 546 participants randomized to sunitinib (including 422 
participants with intermediate/poor risk). The study was stopped early based on the independent 
data monitoring committee recommendation after reviewing the results of the planned interim 
analysis of OS (at a median follow-up of 25.2 months), which demonstrated a 37% reduction in 
the risk of death for intermediate/poor risk participants in the nivolumab + ipilimumab group 
compared to those in the sunitinib group. The combination of nivolumab with ipilimumab also met 
the co-primary endpoint of ORR in intermediate/poor risk participants, yielding an ORR of 42% 
vs 27% in the sunitinib arm. A clinically meaningful improvement in PFS was also demonstrated 
with the nivolumab + ipilimumab combination vs sunitinib. Detailed information is presented in 
Table 3.2.1.3-3.
Table 3.2.1.3-3:
CA209-214 Overall Survival, Objective Response, Best Overall, and 
Duration of Response (Intermediate/Poor Risk)
Nivo + Ipi  (N = 425)
Sunitinib  (N = 422)
Overall survival (OS)
  Months (95% CI)
NR (28.2 -NE)
26.0 (22.1 -NE)
Hazard ratio (99.8% CI), 0.63 (0.44–0.89)  P < 0.0001
Confirmed objective response rate (ORR)a
  % (95% CI)
42 (37-47)
27 (22-31)
P <0.0001
Confirmed best overall response (BOR)a, %
Complete response
9
1
Partial response
32
25
Stable disease
31
45
Progressive disease
20
17
Unable to determine / not reported
8
12
Duration of response (DOR)
  Months (95% CI)
NR (21.8 -NE)
18.2 (14.8 - NE)
NE, not estimable; NR, not reached.
Source: ESMO Congress 2017
a Immune-related Response Criteria (irRC)-assessed ORR and BOR by RECIST v1.1
Among all treated participants, treatment-related AEs were seen in 93% (46% Grade 3/4) 
participants in the nivolumab + ipilimumab arm and 97% (63% Grade 3/4) participants in the 
sunitinib arm. In the nivolumab + ipilimumab arm, the most frequently reported treatment-
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related AEs were fatigue (37%), pruritus (28%), and diarrhea (27%). In the sunitinib arm, the 
most frequently reported treatment-related AEs were diarrhea (52%); fatigue (49%); 
hypertension (40%); hand-foot syndrome (43%); nausea (38%); and stomatitis and mucosal 
inflammation (each 28%).24,25
For all treated participants, treatment-related AEs leading to discontinuation occurred in 22% and 
12%, and treatment-related deaths occurred in 7 and 4 subjects for the nivolumab + ipilimumab 
combination and sunitinib arms, respectively. Detailed information is presented in Table 3.2.1.3-
4.
Table 3.2.1.3-4:
CA209-214 Treatment-Related Adverse Events: All Treated 
Participants
NIVO + IPI
N = 547
SUN
N = 535
Treatment-related event %
Any grade
Grade 3-4
Any grade
Grade 3-4a
AEs in ≥ 25% of participants
93
46
97
63
Fatigue
37
4
49
9
Pruritus
28
< 1
9
0
Diarrhea
27
4
52
5
Nausea
20
2
38
1
Hypothyroidism
16
< 1
25
< 1
Decreased appetite
14
1
25
1
Dysgeusia
6
0
33
< 1
Stomatitis
4
0
28
3
Hypertension
2
< 1
40
16
Mucosal inflammation
2
0
28
3
Hand-foot syndrome
1
0
43
9
AEs leading to discontinuation, %
22
12
Deaths
n = 7b
n =4c
Source: ESMO Congress 2017
a Two participants had grade 5 cardiac arrest.
b Pneumonitis, immune-mediated bronchitis, lower GI hemorrhage, hemophagocytic syndrome, sudden death, liver 
toxicity, lung infection.
c Cardiac arrest (n = 2), heart failure, multiple organ failure.
CA209214 demonstrated that the combination of nivolumab + ipilimumab yielded significant 
improvements in ORR and OS in intermediate/poor-risk treatment-naive advanced RCC compared 
to sunitinib. The safety profile of nivolumab + ipilimumab was manageable and consistent with 
previous studies, supporting the use of the combination as a new standard of care option in this 
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population.24,25,27 A recent publication also reports the finding of nivolumab plus ipilimumab 
leading to fewer symptoms and better HRQoL than sunitinib in participants at intermediate or poor 
risk with advanced renal cell carcinoma.
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.28,29,30
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).31 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.32 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 has 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.33 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 
of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a CMV 
restimulation 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).34
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 
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inhibitory and turn off T-cell-dependent immune responses.35 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.
3.3
Benefit/Risk Assessment
The current standard treatment for early stage (I-III) renal cell cancer (RCC) is surgery. While the 
prognosis of stage I tumors is excellent, stage II and stage III have a high risk of recurrence and 
represent a high unmet medical need.
The potential benefit of adjuvant nivolumab plus ipilimumab over standard-of-care (observation) 
after nephrectomy in early stage RCC is not yet known. 
Nivolumab in combination with ipilimumab in CA209214 study has demonstrated significant 
clinical benefits with reversible and manageable toxicities that are consistent with the known 
IMAE profile of anti-PD-1 immune therapies. The magnitude of OS benefit from the combination 
is unprecedented in studies of mRCC for intermediate- and poor-risk participants. Addition of 
ipilimumab to nivolumab as a combination regimen is expected to show an improvement of PFS 
over nivolumab monotherapy with a manageable increase in IMAEs. However, emerging data are 
providing evidence of clinical efficacy using single agent checkpoint therapy in 1L advanced clear 
cell RCC with the benefit of reduced frequency of IMAEs.36,37 These results suggests the potential 
for improved clinical outcomes also in the adjuvant setting.
The use of ipilimumab 1 mg/kg with a lower frequency of administration (ie, Q6W) in combination 
with nivolumab has been found to result in improved safety as well as efficacy compared to the 
N3 + I1 dosing schedule in a Phase 1 study in previously untreated advanced NSCLC (CA209012). 
Incorporating a dose of 1 mg/kg Q6W ipilimumab into the combination regimen in the RCC 
adjuvant setting is expected to optimize the safety profile of the combination, without impacting 
the overall efficacy of the combination. Further justification of the dose can be found in Section
5.5.
The safety profile of nivolumab and nivolumab plus ipilimumab is characterized by immune-
related toxicities, such as diarrhea, rash, pneumonitis, liver toxicity, and endocrinopathies.26 The 
frequencies and intensities of these events in the combination are variable and depend on the 
specific doses and schedule used (Section 3.2.1). Overall, the safety profile of nivolumab in 
combination with ipilimumab is manageable and generally consistent across completed and 
ongoing clinical trials. Most AEs are low-grade (Grade 1 to 2) with relatively few related high-
grade (Grade 3 to 4) AEs. A pattern of immune-related AEs has been defined, for which 
management algorithms have been developed; these are provided in Appendix 6. Most high-grade 
events are manageable with the use of corticosteroids or hormone replacement therapy 
(endocrinopathies) as instructed in these algorithms. More detailed information about the known 
and expected benefits and risks and reasonably anticipated AEs of nivolumab and ipilimumab may 
be found in the Nivolumab IB and will not be repeated herein.
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In Part B of the study, a nivolumab monotherapy arm of 240 mg Q2W will be included to evaluate 
its impact on DFS compared to placebo and the contribution of ipilimumab to efficacy and safety.
In the US, nivolumab is approved at 240 mg Q2W for several different tumor types including the 
treatment of participants with unresectable or metastatic melanoma, adjuvant treatment of 
melanoma, metastatic NSCLC, and advanced RCC. Incorporating a flat 240 mg dose of nivolumab 
into the monotherapy and combination regimens in the RCC adjuvant setting is expected to 
simplify treatment with nivolumab monotherapy without impacting the overall safety profile of 
the combination. The detailed rationale for the use of a flat 240 mg dose of nivolumab is provided 
in Section 5.5. 
Therefore this study will allow a direct evaluation of the benefits and risks of combined nivolumab 
with ipilimumab and nivolumab monotherapy. In addition, clinical and biological parameters 
(biomarkers) will be explored to assess whether the risks and benefits are altered within specific 
risk subgroups.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
Part A: To compare disease-free survival 
(DFS) per Blinded Independent Central 
Review (BICR) of nivolumab combined 
with ipilimumab versus placebo infusions 
in participants with localized RCC, with a 
predominantly clear cell histology who 
have undergone a nephrectomy. 
•
Part B: To compare disease-free survival 
(DFS) per Blinded Independent Central 
Review (BICR) of nivolumab versus 
placebo infusions in participants with 
localized renal cell carcinoma, with a 
predominantly clear cell histology who 
have undergone nephrectomy.
The primary endpoint is DFS. The primary endpoint of DFS will 
be programmatically determined based on the disease recurrence 
date provided by BICR. DFS is defined as the time from 
randomization to development of local disease recurrence (ie, 
recurrence of primary tumor in situ or occurrence of a secondary 
renal [RCC] primary cancer), distant metastasis, or death, 
whichever came first. See Table 10.3.1-1 for censoring rules.
Secondary
•
Part A: To compare OS, including the 5-
year OS rates, of nivolumab combined 
with ipilimumab versus placebo infusions 
in participants with localized RCC with a 
predominantly clear cell histology who 
have undergone a nephrectomy.
•
Part B: To compare overall survival (OS), 
including the 5-year OS rates, of 
nivolumab versus placebo infusions in 
participants with localized renal cell 
•
OS, defined as the time between the date of randomization 
and 
the date 
of 
death. 
For 
participants 
without 
documentation of death, OS will be censored on the last date 
the participants was known to be alive. 
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
carcinoma with a predominantly clear cell 
histology who have undergone a 
nephrectomy.
•
Part B: To evaluate differences in 
disease-free survival (DFS) per Blinded 
Independent Central Review (BICR) and 
overall survival (OS) of 
contemporaneously randomized
nivolumab combined with ipilimumab 
participants versus nivolumab participants 
with localized renal cell carcinoma, with 
a predominantly clear cell histology, who 
have undergone a nephrectomy. 
•
DFS and OS in contemporaneously randomized combination 
and monotherapy participants.
•
To describe the safety and tolerability of 
nivolumab combined with ipilimumab and 
nivolumab monotherapy up to 30 and
100 days of last dose of study therapy.
•
Safety and tolerability endpoint: type, incidence, severity 
(graded by the National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events [CTCAE, Version 
4.0], timing, seriousness, and relatedness, and laboratory 
abnormalities up to 30 and 100 days of last dose of study 
therapy in all treated participants.
Tertiary/Exploratory
•
To assess PFS2 (progression after 
recurrence) in participants with localized 
renal cell carcinoma with a predominantly 
clear cell histology who have undergone a 
nephrectomy.
•
To assess efficacy in the high and 
moderate risk subgroups.
•
To assess disease-related symptoms in 
each arm based on the National Cancer 
Comprehensive 
Network 
(NCCN)
Functional Assessment of Cancer Therapy 
- Kidney Symptom Index (FKSI-19).
•
PFS2.
•
DFS and OS by the high and moderate risk subgroups.
•
Change in FKSI-19 subscale and total scores relative to 
baseline.
•
To assess changes in global health status 
in each treatment arm based on EuroQoL’s 
EQ-5D-3L.
•
Change in scores from baseline in EQ-5D-3L in both the 
visual analog scale and the utility index.
•
To 
correlate 
the 
primary 
tumor’s 
expression of PD-L1 with efficacy 
outcome (DFS, OS).
•
DFS and OS as described above.
•
Assess association between PD-L1 status 
and DFS and OS.
•
Selected biomarkers.
•
To analyze biomarkers in tumor and 
peripheral blood to evaluate association 
with clinical efficacy or incidence of 
adverse events.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To assess the association between the gene 
signature recurrence score with efficacy 
outcomes (DFS, OS).
•
To characterize the pharmacokinetics of 
nivolumab and ipilimumab and explore 
exposure response relationships with
respect 
to 
safety 
and 
efficacy, 
if 
applicable.
•
Gene-signature based recurrence score and its relationship 
with efficacy endpoints.
•
•
Population PK parameters, exposure-response relationship 
between select PK measures of exposure and safety and 
efficacy endpoints, if applicable.
•
To characterize the immunogenicity of the 
combination of nivolumab and ipilimumab
and nivolumab monotherapy.
•
To assess the impact of SARS-CoV-2 
serologic status on participants receiving
the combination of nivolumab and 
ipilimumab or nivolumab monotherapy in 
the adjuvant setting for RCC 
 
•
To describe the safety of nivolumab 
combined with ipilimumab and nivolumab 
monotherapy beyond 100 days and up to 
1 year of last dose of study therapy.
•
Incidence of anti-nivolumab and anti-ipilimumab antibodies
and their potential relationship with safety and efficacy 
endpoints.
•
Exploratory measurements of SARS-CoV-2 serology 
(anti-SARS-CoV-2 total or IgG), from serum samples 
collected at C1D1, C12D1, follow-up visit 2 and upon 
occurrence of SARS-CoV-2 infection-related events and the 
potential association between these measurements and 
selected endpoints related to safety, efficacy, and/or 
biomarkers.
•
Safety endpoint: type, incidence, severity (graded by the NCI 
CTCAE, Version 4.0), timing, seriousness, and relatedness
beyond 100 days and up to 1 year of last dose of study 
therapy in all treated participants.
5
STUDY DESIGN
5.1
Overall Design
The original study design (Part A) is a double-blind, randomized trial of the nivolumab and 
ipilimumab combination therapy versus placebo infusions in participants with early stage localized 
RCC with a predominantly clear cell histology who underwent radical or partial nephrectomy. 
Approximately 1000 participants will be screened, and approximately 800 participants will be 
randomized.
At the implementation of Revised Protocol 03, Part A of the study remains identical to the original 
protocol design. The addition of Part B to the protocol includes a monotherapy nivolumab arm. A 
target of approximately 800 participants are planned to be randomized between 3 arms in a 
1:1:2 ratio in Part B, with the primary endpoint of DFS and secondary endpoints of OS, and safety 
and tolerability. 
Approximately 1600 participants in total are expected to be randomized in this study. 
Participants will be stratified by pathology according to TNM staging per AJCC staging version 
2010 and Fuhrman nuclear grading categories (described below) and by type of nephrectomy 
procedure (partial versus radical). 
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TNM staging will be stratified according to the following characteristics:
•
pT2a, G3 or G4, N0, M0 and pT2b, G any, N0, M0 
•
pT3, G any, N0, M0 
•
pT4, G any, N0, M0 and pT any, G any, N1, M0
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
CA209914 Part A Study Design Schematic
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Figure 5.1-2:
CA209914 Part B Study Design Schematic
Screening Phase
Screening begins by establishing the participant’s initial eligibility and signing of the informed 
consent form (ICF). Randomization must occur greater than 4 weeks and less than (or equal to) 
12 weeks from the date of nephrectomy. 
Tumor tissue obtained within 3 months prior to enrollment, preferably at the time of the 
nephrectomy, must be provided for biomarker analyses. Formal
infixed, paraffin-
embedded- (FFPE) tumor blocks or unstained slides are required for study assessment. Local 
histopathology review and confirmation of eligibility is required for randomization. 
Screening/baseline imaging should be performed at least 4 weeks post-nephrectomy- and 
submitted to the radiology vendor for BICR confirmation of disease-free status. Pre-nephrectomy 
images are also requested, if available. Participant eligibility must be confirmed by BICR prior to 
randomization and will be based only on the review of the baseline scans (and pre-nephrectomy 
scans if available). As a result, pre-nephrectomy scans, if available, and baseline scans are 
encouraged to be submitted to BICR within 8 weeks of the nephrectomy to allow for timely return 
of the decision from the BICR. 
During the Screening Phase, laboratory and other tests may be repeated as needed. The most 
current result prior to randomization is the value by which study inclusion will be assessed (see 
Section 6.4.1).
The Screening Phase ends with either confirmation of full eligibility and randomization for the 
participant or with the confirmation that the participant is a screen failure. 
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Treatment Phase (Part A)
The Treatment Phase begins when the randomization call is made into the IRT. The participant is 
randomly assigned to 1 of the 2 treatment arms:
•
Arm A: Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every 
third nivolumab dose if dosing is delayed)
•
Arm B: Placebo infusions at the same frequency of nivolumab and ipilimumab infusions
Note: Study treatment must begin within 3 calendar days of randomization.
Treatment Phase (Part B): 
The Treatment Phase begins when the randomization call is made into the IRT. The participant is 
randomly assigned to 1 of the 3 treatment arms: 
•
Arm A: Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every 
third nivolumab dose if dosing is delayed) 
•
Arm B: Placebo infusions at the same frequency of nivolumab and ipilimumab infusions
•
Arm C: Nivolumab 240 mg every 2 weeks and ipilimumab Placebo every 6 weeks (or every 
third nivolumab dose if dosing is delayed) 
•
Note: Study treatment must begin within 3 calendar days of randomization.
Randomization can occur once IRT has received confirmation of eligibility from BICR. Each cycle 
will be 2 weeks (14 days). Participants will receive study drug until the end of 12 cycles 
(12 nivolumab doses and 4 ipilimumab doses), recurrence, unacceptable toxicity, 36 weeks from 
first dose, or withdrawal of consent, whichever occurs first. The first cycle will be a combination 
dose. See Table 7.1.1-2 for the dosing schedule. Study drug may be delayed for toxicity (see 
Section 7.4.1). Treatment must be completed within 36 weeks after the first dose; any cycles not 
received within 36 weeks after the first dose will be omitted, and the participant will enter the 
Follow-up Phase.
A negative pregnancy test should be documented within 24 hours prior to the start of the first dose 
of the investigational product and every 4 weeks thereafter regardless of dosing. On-study 
laboratory assessments should be drawn within 72 hours prior to dosing and will be assessed at the 
local laboratory. Results should be reviewed prior to administration of each dose of study drug.
Tumor assessments will occur in accordance with Table 2-2 until recurrence has been identified 
by the investigator and is confirmed by BICR. Sites should submit all scans to the third-party 
vendor on a rolling basis, preferably within 7 business days of scan acquisition, and submit any 
pertinent cytology/pathology results for central review. If recurrence (defined in Section 9.1.1) is 
assessed by the investigator, the site will inform the radiology vendor so that the BICR assessment 
of recurrence can be performed. The BICR assessment of recurrence will be completed, and the 
results provided to the site within 10 business days of receipt of final images and any pertinent
pathology results as specified in Section 9.1.3. BICR assessment of recurrence should only be 
requested upon recurrence diagnosis by the investigator per the criteria specified in Table 9.1.3.2-
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1. The first point of contact should be BMS Imaging Operations Lead and BMS Protocol Team if 
the site (the Investigator) disagrees with BICR results. The site should not contact the central 
imaging vendor to discuss or request any details of the BICR assessment.
Participants whose recurrence 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. Investigators are strongly encouraged to wait for BICR confirmation of 
recurrence prior to breaking the blind and initiating any subsequent therapy. If the investigator 
feels that the immediate initiation of subsequent therapy is clinically indicated and does not wish 
to wait for the confirmation of recurrence from the BICR, then the decision to break the blind must 
be discussed within the BMS Medical Monitor or designee prior to doing so. See Section 7.3 for 
additional information regarding unblinding. 
PK and immunogenicity samples will be collected according to Table 9.5-1. Adverse event 
assessments should be documented at each clinic visit. 
Quality of Life will be assessed using NCCN Functional Assessment of Cancer Therapy - Kidney 
Symptom Index (FKSI-19) and EuroQoL’s EQ-5D-3L. These questionnaires should be completed 
according to Table 2-2. 
The Treatment Phase ends when the participant is discontinued from study therapy. 
Follow-up Phase
The Follow-up Phase begins at the completion of 12 cycles, when the decision to discontinue a 
participant from study therapy is made (no further treatment with study therapy), or 36 weeks after 
the first dose, whichever comes first. Participants will have 2 follow-up visits (Follow-up 1 and 
Follow-up 2) for safety. Follow-up 1 will occur within 30 days from the last dose (± 7 days) or 
coincide with the date of discontinuation (± 7 days) if date of discontinuation is greater than 
30 days after last dose. Follow-up 2 will occur within 100 days (± 7 days) from the last dose of 
study therapy. Any ongoing treatment-related AEs will be followed until the toxicities resolve, 
return to baseline, or are deemed irreversible. The FKSI-19 and EQ-5D-3L will be completed as 
described in Table 2-3.
Participants who discontinued study treatment without BICR confirmed recurrence will continue 
to have tumor assessments performed according to the frequency described in Table 2-3, even if 
new anti-tumor therapy has been initiated prior to receipt of confirmation. If recurrence (defined 
in Section 9.1.1) is assessed by the investigator, the site will inform the radiology vendor, so that 
the BICR assessment of recurrence can be performed. Participants whose recurrence 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 BICR confirms 
recurrence on a subsequent tumor assessment (see Section 9.1.3.3 for additional details).
After the Follow-up 2 Visit, all participants will be followed for OS status every 12 weeks 
(± 1 week) until death, withdrawal of consent, lost to follow-up, or end of study. Survival status 
may be ascertained by telephone contact if the participant is unable to return to the site for a visit. 
If new anti-tumor therapy is initiated for either disease recurrence or a secondary malignancy at 
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any time during this period, this and all other pertinent data obtained should be recorded on the 
appropriate Case Report Form (CRF).
5.1.1
Data Monitoring Committee and Other External Committees
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
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be established to provide oversight of safety and 
efficacy considerations in protocol CA209914. Additionally, the DMC will provide advice to the 
sponsor regarding actions the committee deems necessary for the continuing protection of study 
participants. The DMC will be charged with assessing such actions in light of an acceptable 
benefit/risk profile for nivolumab and ipilimumab. The DMC will act in an advisory capacity to 
BMS and will monitor participant safety and evaluate the available efficacy data for the study. The 
oncology therapeutic area of BMS has primary responsibility for design and conduct of the study.
5.1.1.2
Blinded Independent Central Review 
The BICR will review tumor images and pertinent clinical data (cytology/pathology results) in all 
randomized participants to determine recurrence for the DFS analyses. Details of the BICR 
responsibilities, procedures, composition, and process will be specified in the BICR charter.
5.2
Number of Participants
Approximately 1600 participants in total (Parts A + B) will be randomized in this study. 
Approximately 600 participants have been randomized in Part A with approximately 200 more 
expected to be randomized (Figure 5.1-1). Approximately 800 participants are expected to be 
randomized in Part B of this study (Figure 5.1-2). Section 10.1 provides additional details. 
5.3
End of Study Definition
The start of the trial is defined as the first participant’s first visit. End of trial is defined as the last 
participant’s last study visit or phone call. 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
5.4.1
Rationale for Selection of Participants at Moderate to High Risk of 
Relapse
The current standard treatment for early stage (I-III) RCC is surgery. While the prognosis of stage 
I tumors is excellent, stage II and particularly stage III have a high risk of relapse and represent a 
high unmet medical need. The adjuvant treatment of patients with RCC remains an area of 
investigation, with patient selection being a key aspect. Several organizations have guidelines for 
follow-up surveillance of higher-risk disease. The American Urological Association (AUA) 
stratifies risk of recurrence on the basis of tumor size and nodal status (low risk: pT1 N0 Nx; 
moderate to high risk: pT2-4N0, Nx, or any stage N+-),38 while the European Association of 
Urology (EAU) bases risk on prognostic nomograms rather than TNM stage.39
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In study CA209914, the primary endpoint, DFS, will be evaluated in participants at moderate to 
high risk of recurrence as defined by the AUA. This population represents approximately 40% of 
the localized RCC population who has undergone surgery. Inclusion of this subset of participants 
for the primary endpoint of the study will allow for potential meaningful differences in efficacy to 
be detected earlier than if participants at lower risk of recurrence were included. Since 
approximately 90% of low risk participants will not have recurrence after nephrectomy, their 
exclusion will also avoid unnecessary treatment in the vast majority of these low risk participants. 
Efficacy will also be assessed in the high and moderate risk subgroups by using the following risk 
staging system:40
High risk: 
•
pT3, G3 or G4, N0M0
•
pT4, G any, N0M0
•
pT any, G any, N1M0
Moderate risk: 
•
pT2a, G3 or G4, N0M0
•
pT2b, G any, N0M0
•
pT3, G1 and G2, N0M0
Efficacy may also be assessed using a score based on stage, size, grade, and necrosis (the SSIGN 
score)41 in the intermediate (3-5) and high (≥6) SSIGN score defined groups.40
5.4.2
Rationale for 6 Month Treatment Duration
There is no consensus regarding the optimal treatment duration for patients in the adjuvant setting 
for localized RCC. Historic Phase 3 trials of adjuvant targeted antiangiogenic therapies have 
continued treatment for 12 months. Because immunotherapy engages the immune system to 
control the tumor, continuous treatment, as is required with targeted antiangiogenesis agents and
cytotoxic therapy, may not be necessary. Accumulating evidence from different clinical trials in 
different tumor types with nivolumab monotherapy or nivolumab combined with ipilimumab 
indicates that responses generally occur early, with a median time to response of 2-4 months, and 
are durable.42
In study CA209016, for example, responses in metastatic RCC participants receiving nivolumab 
3 mg/kg /ipilimumab 1 mg/kg combination (n=47) occurred within the first 3 months of treatment, 
and the median duration of response was 88.7 weeks.43
Since standard of care in localized RCC is observation post-nephrectomy and to minimize potential 
toxicity while maintaining expected efficacy, treatment with nivolumab and ipilimumab or placebo 
in study CA209914 will be given for 24 weeks in absence of disease recurrence or unacceptable 
toxicity. 
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5.4.3
Rationale for 30 min Infusion Duration for Nivolumab and Ipilimumab
The current US label for nivolumab is approved for advanced RCC at 240 mg flat dose
administered intravenously over 60 minutes every 2 weeks. Previous clinical studies of nivolumab 
monotherapy have used a 60-minute infusion duration, and 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-minute infusion was assessed in CA209153 
in participants (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 participants administered nivolumab over a 30 minute 
infusion compared with that reported for participants with the 60-minute infusion. Thus, it was 
shown that nivolumab can be safely infused over 30 minutes.
The risk/benefit profile for ipilimumab has primarily been investigated using a 90-minute infusion. 
Ipilimumab has 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. The shortened infusion duration of 30 minutes for ipilimumab is not expected to 
present additional safety concerns.44
Both agents given as single agent are uncommonly associated with infusion reactions: the 
incidence is less than 1% for ipilimumab45 and 3% for nivolumab.26 In the CA209069 study, 
hypersensitivity/infusion reactions were listed as 3.2% for the combination and 2.2% for 
ipilimumab. No Grade 3 or Grade 4 hypersensitivity/infusion reactions were observed in either the 
combination or single agent ipilimumab treatment groups.46 Participants should be carefully 
monitored for infusion reactions during nivolumab/ipilimumab administration.
In this study, nivolumab and ipilimumab will each be infused over 30 minutes. 
5.4.4
Rationale for Nivolumab Monotherapy
Nivolumab monotherapy was chosen as one of the treatment arms in Part B because of a favorable 
risk-benefit ratio assessed from 3 studies in participants with mRCC: CA209010, CA209009, and 
CA209025.
In CA209010, 168 participants who received at least 1 prior anti-angiogenic therapy were 
randomized to receive nivolumab 0.3 mg/kg (n = 60), 2 mg/kg (n = 54), and 10 mg/kg (n = 54). 18
Median PFS was 2.7 months, 4.0 months, and 4.2 months at 0.3, 2, and 10 mg/kg, respectively. 
The ORR ranged from 20% to 22% across dose levels. Median OS was 18.2 months at 0.3 mg/kg, 
but was not yet reached at the 2 highest dose levels. 
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CA209009 enrolled a similar population to CA209010, but also included 24 participants with 
treatment-naive RCC. Among treatment-naive participants, all of whom received nivolumab 10 
mg/kg Q3W, the ORR was 13% (3/23). CA209010 includes the largest safety database for 
nivolumab monotherapy in mRCC. All treated participants (n = 167) were included in the safety 
analyses. Drug-related AEs of any grade occurred in 74.6%, 66.7%, and 77.8% of participants 
treated at 0.3 mg/kg, 2 mg/kg, and 10 mg/kg, respectively. The most common (≥10% in any group) 
drug-related AEs included fatigue, dry skin, rash, pruritus, arthralgia, nausea, diarrhea, decreased 
appetite, dry mouth, and hypersensitivity. Grade 3 drug-related AEs occurred in 5.1%, 16.7%, and 
13% of participants treated at 0.3 mg/kg, 2 mg/kg, and 10 mg/kg, respectively. Related Grade 3 
events in at least 2 participants across dose levels included nausea, (AST)/ALT increased, and 
anemia. No drug-related Grade 4 or Grade 5 events occurred. No dose-toxicity relationship was 
identified except for hypersensitivity/infusion reaction, which occurred most frequently in the 10 
mg/kg treatment group.
Based on the clinical activity of nivolumab observed in these Phase 1 and 2 studies, a large Phase 
3 trial (CA209025) was conducted in 821 participants with advanced RCC previously treated with 
1 or 2 anti-angiogenic therapies who were randomized to receive nivolumab 3 mg/kg every 
2 weeks (Q2W) or everolimus 10 mg daily. A planned interim analysis, after a minimum follow-
up of 14 months, demonstrated a statistically significant and clinically meaningful improvement 
in OS of nivolumab monotherapy versus everolimus (median OS, 25.0 months vs 19.6 months, 
respectively; hazard ratio [HR] 0.73 [98.5% confidence interval (CI), 0.57 to 0.93, p-value (P) = 
0.002]). ORR was 25% for nivolumab versus 5% for everolimus. Among 756 participants with 
quantifiable PD-L1 tumor expression in pretreatment samples, 24% had PD-L1 expression ≥ 1%. 
Among participants with PD-L1 expression ≥ 1%, median OS was 21.8 months in the nivolumab 
group and 18.8 months in the everolimus group (HR 0.79 [95% CI, 0.53 to 1.17]). Among 
participants with PD-L1 expression < 1%, the median OS was 27.4 months in the nivolumab group 
and 21.2 months in the everolimus group (HR, 0.77 [95% CI, 0.60 to 0.97]). No new safety 
concerns were identified, and nivolumab monotherapy showed a favorable safety profile as 
compared to everolimus, evidenced by the lower rates of drug-related AEs (all grades, 79% vs 
88%; Grade 3-4, 19% vs 37%, respectively) and drug-related AEs leading to discontinuation (all 
grades, 8% vs 13%, respectively) in the nivolumab group. These results were the basis for 
regulatory approval of nivolumab monotherapy in advanced RCC.
As the treatment of RCC landscape continues to evolve, accumulative evidence showed a single-
agent activity for anti-PD-1 or anti-PD-L1 monotherapy in the 1L treatment of advanced RCC. If 
this observation is applicable then there could also be the potential for large improvements in DFS 
in the adjuvant RCC setting.47,48,49
Based upon the totality of the safety, efficacy, and exposure-response data, a dose of 240 mg Q2W 
was selected as the dose anticipated to achieve an appropriate balance of efficacy and risk in the 
monotherapy arm. In addition, by selecting the 240 mg Q2W, we are aligning the same nivolumab
dose and schedule as utilized in both the combination arm and the nivolumab monotherapy 
comparator arm.
For additional information on nivolumab monotherapy in RCC please refer to section 3.2.1.1
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5.5
Justification for Dose
There are 4 completed or ongoing studies of nivolumab monotherapy using body weight 
normalized dosing (mg/kg) in advanced RCC: MDX1106-03, CA209009, CA209010, and 
CA209025. In study MDX1106-03, previously-treated RCC participants were administered 
nivolumab monotherapy with 1 or 10 mg/kg Q2W. In studies CA209009 (which included both 
previously-treated and previously untreated RCC participants) and CA209010 (which included 
only previously-treated RCC participants), nivolumab doses of 0.3, 2, or 10 mg/kg were given 
Q3W. As detailed in Section 3.2.1, clinical activity was observed across all nivolumab dose levels 
in these studies, in both Q2W and Q3W schedules, and in both previously-treated and previously 
untreated participants. 
Nivolumab pharmacokinetics (PK) and exposures of participants in these studies have been 
characterized by population pharmacokinetics (PPK) analysis of data collected from these studies, 
together with PK data from several Phase 1, 2, and 3 clinical studies of nivolumab in solid tumors. 
Based on PK modeling and the long half-life (25 days) of nivolumab, the Q2W schedule was 
subsequently selected for CA209025 and resulted in sustained exposure between treatments. Study 
CA209025 demonstrated that nivolumab 3 mg/kg Q2W improved OS and had a favorable safety 
profile compared to everolimus in previously-treated mRCC, leading to regulatory approval in this 
population (see Section 3.2.1).
Nivolumab PK was determined to be linear, with dose proportional exposures over a dose range 
of 0.1 to 10 mg/kg. Nivolumab clearance and volume of distribution was 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. Conversely, given 
the relationship between nivolumab PK and body weight, a flat dose is expected to lead to lower 
exposures in heavier patients, relative to the exposures in lighter patients. Taken together, the PK, 
safety, and efficacy data indicate that the safety and efficacy profile of 240 mg nivolumab will be 
similar to that of 3 mg/kg nivolumab, regardless of tumor type. In the US, the 240 mg Q2W flat 
dose is now approved for the treatment of patients with unresectable or metastatic melanoma (as 
monotherapy or as maintenance therapy following nivolumab plus ipilimumab regimen), 
metastatic NSCLC, and advanced RCC.
The PK and safety of nivolumab have been evaluated in the Asian population. The comparison of 
PK parameters in global and Japanese participants suggests that the PK of nivolumab is similar in 
these populations. Nivolumab is shown to be safe and well tolerated in Japanese participants. The 
similar PK and safety profile of nivolumab between global and Japanese participants supports the 
use of similar dosing in the Asian population as is being used in global clinical studies.
5.5.1
Justification for Dosage in Combination Treatment of Nivolumab and 
Ipilimumab
The dose and schedule of nivolumab and ipilimumab for this study was selected based on the data 
observed in the CA209016 study and in the CA209012 study.50 As was previously mentioned in 
Section 3.2.1.3, Study CA209016 demonstrated antitumor activity of nivolumab 3 mg/kg + 
ipilimumab 1 mg/kg Q3W for 4 doses, followed by nivolumab 3 mg/kg Q2W (N3 + I1 schedule) 
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with an ORR of 36% in previously-untreated RCC participants, which is higher than the efficacy 
with either nivolumab monotherapy (CA209009) or ipilimumab monotherapy (MDX010-11). In 
CA209012, a multi-cohort Phase 1 study in participants with advanced NSCLC, multiple
nivolumab and ipilimumab combination schedules were evaluated in order to optimize safety and 
efficacy. In addition to evaluating the N3 + I1 schedule (identical to that given in CA209016) in 2 
cohorts, CA209012 evaluated nivolumab 3 mg/kg Q2W combined with ipilimumab 1 mg/kg either 
given Q6W or given Q12W in 2 other cohorts. Both the ipilimumab Q6W and Q12W cohorts were 
associated with improved and manageable tolerability compared to the cohort that received the N3 
+ I1 schedule. Both cohorts demonstrated encouraging efficacy, yielding ORR of 38% to 47%, 
which is higher than the ORR observed in the nivolumab monotherapy cohort (ORR 23%) or the 
N3 + I1 cohorts (ORR 20%, combining squamous and non-squamous cohorts) in the same study. 
The CA209012 study demonstrated activity of the combination of nivolumab 3 mg/kg Q2W plus 
ipilimumab 1 mg/kg Q6W in both PD-L1+ and PD-L1- tumors, coupled with a manageable safety 
profile, and this combination regimen in being further evaluated in the Phase 3 CA209227 in 
previously untreated advanced NSCLC. 
Given the demonstrated clinical activity of nivolumab monotherapy in advanced RCC from 
CA209025 and the similar PK, efficacy, and safety of nivolumab 240 mg Q2W to 3 mg/kg Q2W, 
CA209914 will use a nivolumab flat dose of 240 mg Q2W as the backbone for the combination 
regimen with ipilimumab. With both ipilimumab 1 mg/kg Q6W and Q12W schedules showing a 
similar safety and efficacy profile when combined with nivolumab 3 mg/kg Q2W in CA209012, 
the ipilimumab 1 mg/kg Q6W schedule was chosen to combine with the nivolumab 240 mg 
backbone to avoid any potential loss of efficacy with less frequent ipilimumab dosing.
5.5.2
Justification for Dose of Nivolumab Monotherapy Treatment in Part B
Nivolumab will be dosed at 240 mg Q2W in the monotherapy arm. Nivolumab is approved in the 
US and EU for advanced renal cell carcinoma at 240 mg Q2W or 480 mg Q4W.51 These doses 
have comparable time-averaged concentrations over the respective dosing intervals and were 
shown to have comparable benefit:risk to that of 3 mg/kg Q2W in advanced renal cell carcinoma. 
The dose of 240 mg Q2W was selected since this matches the same dose and frequency of 
administration as that in the nivolumab and ipilimumab combination arm. Having the same 
nivolumab dosing frequency for the monotherapy and combination arm will allow for a more 
complete assessment of contribution of ipilimumab to efficacy and safety. Additionally, having 
the same nivolumab dosing frequency will maintain the study blind by avoiding any operational 
challenges associated different dosing frequencies across treatment arms. 
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
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a) Participants must have signed and dated an IRB/IEC approved written ICF 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, 
and laboratory testing.
2) Type of Participant and Target Disease Characteristics
a) Kidney tumor has been completely resected with negative surgical margins obtained. The
randomization must occur greater than 4 weeks and less than (or equal to) 12 weeks from 
the date of nephrectomy. Partial nephrectomy is allowed provided all inclusion criteria are 
met. 
b) Post-nephrectomy tumor shows RCC with a predominantly clear cell histology, including 
participants with sarcomatoid features.
c) Pathological TNM staging per AJCC staging version 2010 (refer to Appendix 9 for 
correlations of classifications in cancer staging systems):
♦pT2a, G3 or G4, N0M0
♦pT2b, G any, N0M0
♦pT3 (a, b, c), G any, N0M0
♦pT4, G any, N0M0
♦pT any, G any, N1M0
Note 1: Excisional biopsy of all regional lymph node(s) which appear abnormal on pre-
operative scans or at surgery.
In order to properly stratify participants, it is required that the investigator designate the 
nodal status as either N0 or N1 according to the following criteria which will be captured 
in the eCRF: 
o
N0 requires that a participant have no abnormal regional lymph nodes on 
pre-operative scans or visualized at surgery, OR have regional lymph nodes 
biopsied with negative (no tumor present) result. 
o
N1 requires that a participant have regional lymph nodes biopsied with one or more 
regional lymph nodes having positive (tumor present) results.
Note 2: Participants with ipsilateral multicentric RCC are eligible if the most advanced 
lesion per pT stage fulfils the aforementioned combinations of pathologic staging and 
Fuhrman nuclear grading. 
d) Participants must have no clinical or radiological evidence of macroscopic residual disease 
or distant metastases (M0) after nephrectomy:
o
Baseline tumor assessment, performed 4 to approximately 12 weeks after 
nephrectomy, shows no metastasis or residual tumor lesions per local review and 
as confirmed by BICR. Results of BICR of the baseline tumor assessment 
confirming absence of metastasis or residual tumor lesions must be received before 
randomization. 
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o
If the Investigator is not certain the participant is disease free, the participant should 
1) not be consented or be enrolled into the study and 2) evaluation for eligibility 
should not be submitted to BICR.
Note: participants with one or more regional lymph nodes identified with short axis 
≥15 mm on the baseline (post-operative) tumor assessments are considered to have 
gross residual disease and are therefore ineligible. See Section 9.1.2 for guideline of 
imaging diagnosis for baseline disease-free status.
e) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 (Appendix 5).
f)
Either a FFPE tissue block or unstained tumor tissue sections, obtained within 3 months 
prior to enrollment, preferably from nephrectomy, with an associated pathology report, 
must be submitted to the central laboratory prior to randomization. FFPE block or
20 unstained slides is ideal, but a minimum of 10 unstained slides will be acceptable if 
tumor tissue is limited. Biopsy should be excisional, incisional, or core needle. Fine needle 
aspiration is unacceptable for submission. Sites will be notified if there is insufficient tissue 
for analysis by the central lab.
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.
i)
An extension up to 72 hours prior to the start of study treatment is permissible in 
situations where results cannot be obtained within the standard 24-hour window.
ii) Additional requirements for pregnancy testing during and after study intervention are 
located in Section 2, Schedule of Assessments.
iii) The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
c) Women must not be pregnant or breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception and use a 
contraceptive method that is highly effective (with a failure rate of <1% per year), with low 
user dependency (Appendix 4 and as described below and included in the ICF) for the 
duration of treatment with study treatment(s) nivolumab plus 5 half-lives of study treatment
plus 30 days (duration of ovulatory cycle) for a total of 5 months post-treatment 
completion.
i)
WOCBP are permitted to use hormonal contraception methods (as described in 
Appendix 4).
ii) WOCBP must agree not to donate eggs (ova, oocytes) for the purpose of reproduction 
during the intervention period and for at least 5 months.
iii) Women who are not of childbearing potential are exempt from contraceptive 
requirements. 
iv) Women participants must have documented proof that they are not of childbearing 
potential.
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e) Not Applicable per Revised Protocol 04: Males who are sexually active with WOCBP 
must agree to follow instructions for method(s) of contraception (Appendix 4) for the 
duration of treatment with study treatment(s) nivolumab 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. 
f)
Not Applicable per Revised Protocol 04: Azoospermic males are exempt from 
contraceptive requirements. Still applicable per Revised Protocol 04: 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 on the importance of pregnancy prevention, the implications 
of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of 
study drug to a developing fetus. Investigators shall advise on the use of highly effective methods 
of contraception (Appendix 4), which have a failure rate of < 1% when used consistently and 
correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at all sites where mandated by country or local regulations (see Appendix 7). 
b) Any severe or serious, acute or chronic medical or psychiatric condition, or laboratory 
abnormality that may increase the risk associated with study participation or study drug 
administration, including ongoing or active infection requiring parental antibiotics.
c) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days prior to the first dose of study drug. Topical, ocular, intra-articular, intranasal, 
inhaled steroids, and adrenal replacement steroid doses > 10 mg daily prednisone or the 
equivalent are permitted in the absence of active immune disease. 
d) Uncontrolled adrenal insufficiency.
e) Participants with an active known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. 
f)
Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.
Note: Participants with a history of RCC who have been considered cured with a nephrectomy
or other surgical procedure in the past, and now present with a new RCC, either on the same 
kidney or the contralateral kidney, should not be enrolled into the study.
g) Treatment with any live / attenuated vaccine within 30 days of first treatment.
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i)
The use of inactivated vaccines, such as the seasonal influenza (eg, Fluzone®) will be 
permitted on study without restriction.
h) Previous SARS-CoV-2 infection (either suspected or confirmed) within 4 weeks prior to 
screening.
Acute symptoms must have  resolved and based on investigator assessment in 
consultation with the medical monitor, there are no sequelae that would place the 
participant at a higher risk of receiving investigational treatment.
2) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways.
b) Prior systemic anti-cancer treatment, including chemotherapy, antiangiogenic agents or 
investigational agents, given in the neoadjuvant, adjuvant, or metastatic setting for RCC.
c) Treatment with complementary medications (eg, herbal supplements or traditional Chinese 
medicines) to treat the disease under study within 2 weeks prior to first study treatment. 
Such medications are permitted if they are used as supportive care. Refer to Section 7.7.1 
for prohibited therapies.
d) Participants currently in other interventional trials, including those for Coronavirus Disease 
2019 (COVID-19), may not participate in BMS clinical trials until the protocol specific 
washout period is achieved. If a study participant has received an investigational 
COVID-19 vaccine or other investigational product designed to treat or prevent COVID-19
prior to screening, enrollment must be delayed until the biologic impact of the vaccine or 
investigational product is stabilized, as determined by discussion between the investigator 
and the BMS Medical Monitor.
3) Physical and Laboratory Test Findings
a) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, Hepatitis B surface antigen (HBsAg) positive, or Hepatitis C antibody 
(anti-HCV) positive (except if HCV-RNA negative).
b) WBC < 2000/μL
c) Neutrophils < 1500/μL
d) Platelets < 100 x 103/μL
e) Hemoglobin < 9.0 g/dL
f)
Serum creatinine >1.5 x ULN unless creatinine clearance ≥ 40 mL/min (measured or using 
the Cockcroft-Gault formula)
g) AST/ALT > 3.0 x ULN
h) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 x ULN)
4) Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity to a monoclonal antibody.
b) History of allergy or hypersensitivity to study drug components.
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5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized/has not 
been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within the Screening or Lead-in 
period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Testing for asymptomatic SARS-CoV-2 infection, for example by RT-PCR or viral antigen is not 
required. However, some participants may develop suspected or confirmed symptomatic SARS-
CoV-2 infection, or be discovered to have asymptomatic SARS-CoV-2 infection during the 
screening period. In such cases, participants may be considered eligible for the study after meeting 
all inclusion/exclusion criteria related to active infection, and after meeting the following criteria: 
−
At least 10 days (20 days for severe/critical illness) have passed since symptoms first 
appeared or positive RT-PCR or viral antigen test result, and
−
At least 24 hours have passed since last fever without the use of fever-reducing 
medications, and
−
Symptoms (eg, cough, shortness of breath) have resolved, and
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−
In the opinion of the Investigator, there are no COVID-19-related sequelae that may place 
the participant at a higher risk of receiving investigational treatment, and
−
Negative follow-up test for SARS-CoV-2 RT-PCR or viral antigen test based on 
institutional, local or regional guidelines
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 (see Table 7-1), the following are considered IP/IMP:
•
Nivolumab (BMS-936558)
•
Ipilimumab (BMS-734016)
•
Nivolumab-Placebo (0.9% Sodium Chloride Injection or 5% Dextrose Injection)
•
Ipilimumab-Placebo (0.9% Sodium Chloride Injection or 5% Dextrose Injection)
The 0.9% normal saline or 5% dextrose to be used as placebo will not be provided by the Sponsor.
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 CA209914 
Product Description / 
Class and Dosage 
Form
Potency
IP/Non-
IMP
Blinded or 
Open Labela
Packaging / Appearance
Storage 
Conditions
(per label)
Nivolumab Solutionb
for Injection
100 mg (10 mg/mL)
or
40 mg (10 mg/mL)
IP
Open-label
5 or 10 vials per carton
Or 
240 mg kits (two 100 mg vials and one 40 mg vial) 
Clear to opalescent colorless to pale yellow liquid. 
May contain particles
2° to 8 °C. Protect 
from light and 
freezing
Ipilimumab
200 mg (5 mg/mL)
IP
Open-label
4 vials per carton
Clear to opalescent colorless to pale yellow liquid. 
May contain particles
2° to 8 °C. Protect 
from light and 
freezing
0.9% Sodium Chloride 
for Injection
NA
IP
Open-label
Various (local commercial product)
As per active IP
5%  Dextrose for 
Injection
NA
IP
Open-Label
Various (local commercial product)
As per active IP
a The term “open-label” refers to the medication as it is upon receipt at the pharmacy.  The trial will be conducted in a double-blinded fashion.
b Nivolumab is labeled as BMS-936558-01 Solution for Injection
Premedications used to treat infusion reactions should be sourced by the investigative sites if available and permitted by local regulations.
Solutions used as diluent or placebo (ie, 0.9% Sodium Chloride Injection or 5% Dextrose Injection) should also be sourced by 
investigative sites if available and permitted by local regulations  
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7.1
Treatments Administered
7.1.1
Administration
Participants should receive nivolumab at a dose of 240 mg as an approximately 30-minute infusion 
on Day 1 of each treatment cycle until recurrence, unacceptable toxicity, withdrawal of consent, 
Week 36, or a maximum of 12 doses, whichever occurs first. Starting with Cycle 1, ipilimumab 1 
mg/kg as an approximately 30-minute infusion should be administered every third cycle (ie, Cycles 
1, 4, 7, and 10). Table 7.1.1-2 provides the dosing schedule. Participants must begin study 
treatment within 3 calendar days of randomization. 
Treatment cycles should be given every 2 weeks (14 days). After Cycle 1, dosing for subsequent 
dosing should be based on the actual date of administration of the previous cycle. To permit 
scheduling flexibility (eg, to accommodate local holidays), doses may be given up to 2 days early 
(ie, no less than 12 days after the previous cycle) or up to 17 days after the previous cycle. Doses 
given more than 17 days after the previous dose will be considered delayed. 
For Cycles 1, 4, 7, and 10, when nivolumab and ipilimumab are to be administered on the same 
day, nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a 
0.9% normal saline or 5% dextrose flush to clear the line of nivolumab before starting the 
ipilimumab infusion. The second infusion will always be the ipilimumab study drug 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. Simultaneous infusions of nivolumab and ipilimumab 
will not be permitted.
Ipilimumab dosing calculations should be based on the body weight assessed at either the day of 
dosing or the last recorded weight, and if the participant’s weight on the day of dosing differs by 
> 10% from the weight used to calculate the dose, then the dose must be recalculated. All 
ipilimumab doses should be rounded to the nearest milligram. 
There will be no dose escalations or reductions of nivolumab or ipilimumab allowed. 
Premedications are not recommended for nivolumab or ipilimumab on the first cycle. Participants 
should be carefully monitored for infusion reactions during nivolumab and ipilimumab 
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.4.3.
Doses of nivolumab and ipilimumab may be interrupted, delayed, or discontinued depending on 
how well the participant tolerates the treatment. Dosing visits are not to be skipped/omitted, only 
delayed if any dose delay criteria are met. Dose delay criteria and criteria to resume treatment are 
discussed in Section 7.4.
Any cycles not given within 36 weeks after the first dose will be omitted. Participants who have 
not completed all 12 cycles will discontinue study treatment at Week 36 and begin the Post-
Treatment Follow-Up Phase. 
The strength and route of administration are described in Table 7.1.1-1 and the timing of each dose 
is described in Table 7.1.1-2.
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Table 7.1.1-1:
Strength and Route of Study Treatment Administration
Study Treatment
Unit dose strength(s)/Dosage level(s)
Route of Administration
Nivolumab
240 mg
IV
Ipilimumab
1 mg/kg
IV
Nivolumab-Placebo
0.9% Sodium Chloride or 5% Dextrose 
Injection)
IV
Ipilimumab-Placebo
0.9% Sodium Chloride or 5% Dextrose 
Injection)
IV
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Table 7.1.1-2:
Dosing Schedule for CA209914
Arm
Cycle 1
Day 1
Cycle 2 
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycle 5
Day 1
Cycle 6
Day 1
Cycle 7
Day 1
Cycle 8
Day 1
Cycle 9
Day 1
Cycle 10
Day 1
Cycle
11
Day 1
Cycle 
12
Day 1
Arm A (Parts 
A and B)
Nivolumab +
Ipilimumab
N240 
+
I1
N240
N240
N240 
+
I1
N240
N240
N240 
+
I1
N240
N240
N240 
+
I1
N 240
N 240
Arm B (Parts 
A and B)
Placebo
N Placebo 
+ 
I Placebo
N 
Placebo
N 
Placebo
N Placebo 
+
I Placebo
N 
Placebo
N 
Placebo
N Placebo 
+ 
I Placebo
N 
Placebo
N 
Placebo
N Placebo 
+ 
I Placebo
N 
Placebo
N 
Placebo
Arm C (Part B 
only)
Nivolumab + 
I Placebo
N240 +
I Placebo
N240
N240
N240 +
I Placebo
N240
N240
N240 +
I Placebo
N240
N240
N240 +
I Placebo
N240
N240
I1 = ipilimumab 1 mg/kg; I Placebo = ipilimumab placebo; N240 = nivolumab 240 mg; N Placebo = Nivolumab Placebo.
Note: Time between end of nivolumab infusion and start of ipilimumab infusion should allow time for flushing of line, changing of filters, and observation for 
infusion reaction.
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7.1.1.1
Nivolumab
Nivolumab Injection 100 mg/10 mL (10 mg/mL) and Nivolumab Injection 40 mg/4 mL 
(10 mg/mL) are to be administered as an approximately 30-minute IV infusion through a 0.2-
micron to 1.2-micron pore size, low-protein binding in-line filter at the protocol-specified doses. 
It is not to be administered as an IV push or bolus injection. Nivolumab injection can be infused 
undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection. 
For instructions on dilution and infusion of nivolumab injection, please refer to the clinical 
protocol, current IB, pharmacy manual/binder, or pharmacy reference sheet. Care must be taken 
to assure sterility of the prepared solution as the product does not contain any antimicrobial 
preservative or bacteriostatic agent. At the end of the infusion, flush the line with a sufficient 
quality of 0.9% normal saline or 5% dextrose solution. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
7.1.1.2
Ipilimumab
Ipilimumab injection can be used for IV administration without dilution after transferring to a 
PVC, non-PVC/non-DEHP or glass container and is stable for 24 hours at 2-8°C or room 
temperature/room light (RT/RL). For ipilimumab storage instructions and additional preparation 
instructions, refer to Ipilimumab IB and/or pharmacy manual/reference sheets.
Separate infusion bags and filters should be used when administering nivolumab and ipilimumab 
on the same day.
Ipilimumab is to be administered as an approximately 30-minute IV infusion after the completion 
of the nivolumab infusion. A volumetric pump with a 0.2 to 1.2 micron, low protein binding, in-
line filter is to be utilized. The drug can be diluted with 0.9% normal saline or 5% Dextrose 
Injection to concentrations between 1 mg/mL and 4 mg/mL. It is not to be administered as an IV 
push or bolus injections. Care must be taken to assure sterility of the prepared solutions, since the 
drug product does not contain any antimicrobial preservatives or bacteriostatic agents. At the end 
of the infusion, flush the line with a sufficient quantity of 0.9% normal saline or 5% dextrose 
solution. 
7.2
Method of Treatment Assignment
CA209914 is a double-blind, randomized trial. Participants with early stage localized RCC who 
underwent radical or partial nephrectomy will be eligible to participate. After the participant’s 
initial eligibility is established and informed consent has been obtained, the participant must be 
enrolled into the study by calling the IRT to obtain a participant number. Every participant that 
signs the ICF must be assigned a participant number in IRT. Specific instructions for using IRT 
will be provided to the investigational site in a separate document. The investigator or designee 
will register the participant for enrollment by following the enrollment procedures established by 
BMS.
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The following information is required for enrollment:
•
Date that informed consent was obtained
•
Date of birth, where applicable by local regulations
•
Gender at birth
Once enrolled in IRT participants who have met all eligibility criteria will be ready to be 
randomized through IRT. The following information is required for participant randomization:
•
Participant number
•
Date of birth, where applicable per local regulations
•
TNM staging per AJCC staging version 2010 and Fuhrman nuclear grading categories (refer 
to Appendix 9 for correlations of classifications in cancer staging systems):
−
pT2a, G3 or G4, N0, M0
−
pT2b, G any, N0, M0 
−
pT3, G any, N0, M0 
−
pT4, G any, N0, M0
−
pT any, G any, N1, M0
•
Type of nephrectomy procedure (partial versus radical, including total nephrectomy).
•
Date of nephrectomy 
•
Confirmation that tumor tissue has been sent to the central lab.
•
Confirmation of disease-free status by BICR (radiographic only)
Refer to Section 6.1 for the definition of node status. The exact procedures for using the IRT will 
be detailed in the IRT manual.
7.3
Blinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of the 
investigational product is critical to the participant's management, the blind for that participant
may be broken by the investigator. The participant’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, ie, that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the participant
is receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the BMS Medical Monitor or designee, but the investigator always has ultimate 
authority for the decision to unblind. The Principal Investigator should only call in for emergency 
unblinding AFTER the decision to discontinue the participant has been made.
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Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor or designee. 
For this study, the method of unblinding for emergency purposes is through the IRT. For 
information on how to unblind for emergency, please consult the IRT manual.
In cases of accidental unblinding, contact the Unblinded Monitor or designee and ensure every 
attempt is made to preserve the blind.
Designated staff of Bristol-Myers Squibb Research & Development may be unblinded prior to 
database lock to facilitate the bioanalytical analysis of pharmacokinetic samples and 
immunogenicity. A bioanalytical scientist in the Bioanalytical Sciences department of Bristol-
Myers Squibb Research & Development (or a designee in the external central bioanalytical 
laboratory) will be unblinded to the randomized treatment assignments in order to minimize 
unnecessary bioanalytical analysis of samples.
7.3.1
Unblinding at the Time of Disease Recurrence
If a participant is assessed by the investigator to have RCC disease recurrence (Section 9.1.3.2), 
the study treatment assignment for the participant can be obtained by the investigator through IRT 
for non-emergency unblinding in order to determine subsequent anti-cancer treatments. The 
investigator should follow the procedures outlined in the IRT manual to obtain the participant’s 
study treatment assignment.
Investigators are strongly encouraged to wait for confirmation of recurrence from the BICR prior 
to non-emergency unblinding for the purpose of initiating subsequent anti-cancer therapy, unless 
clinical considerations require immediate intervention (eg, symptomatic brain metastases). If a 
tumor biopsy collection at the time of suspected recurrence is planned, the request for unblinding 
should occur after pathology results are available. If subsequent anti-cancer therapy (including 
systemic cancer therapy, radiotherapy, or tumor-directed surgery) is planned prior to BICR 
confirmation of recurrence, the investigator must contact the BMS Medical Monitor or designee 
to discuss the case prior to the start of any of such therapy.
If a participant is diagnosed with a non-RCC secondary cancer, blinding should be preserved 
unless specific circumstances, to be discussed with the BMS Medical Monitor or designee, require 
that the blind be broken (eg, participant has metastases and could enroll on a clinical trial but would 
be ineligible if he or she had prior checkpoint inhibitor therapy). 
For this study, the method of unblinding for emergency purposes is through the IRT. For 
information on how to unblind in an emergency, please see Section 7.3.
7.4
Dosage Modification
Dose reductions or dose escalations are not permitted. All dose modifications rules apply to both 
Arms A and B given the blinded nature of this study.  
7.4.1
Dose Delay Criteria for Study Treatment
Regardless of whether or not the event is attributed to Arm A, Arm B, or Arm C, all study drugs 
must be delayed until criteria to resume treatment (Section 7.4.2) have been met, given the blinded 
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nature of this study. Tumor assessments for all participants should continue as per protocol even 
if dosing is delayed. If one drug is delayed, both study drugs must be delayed. 
Study drug administration should be delayed for any of the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section 8.1)
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
•
SARS-CoV-2 infection (either suspected or confirmed).
Participants who require delay of study drug should be re-evaluated weekly or more frequently if 
clinically indicated and resume study drug dosing when re-treatment criteria are met. If a 
participant is delayed beyond 36 weeks of the first dose, treatment will discontinue. 
7.4.2
Criteria to Resume Treatment
All criteria to resume study therapy apply to nivolumab, ipilimumab, and placebo, given the 
blinded nature of the study. Participants may resume treatment with study drug when the 
drug-related AE(s) resolve to Grade ≤1 or baseline value and any systemic corticosteroids have 
been tapered to ≤ 10 mg prednisone equivalent. (See Section 7.7.3 for exception regarding adrenal 
replacement steroids.)
The following are exceptions to the above:
•
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.
•
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 or designee.
•
Participants with SARS-CoV-2 infection (either suspected or confirmed) may resume 
treatment after all of the following: 1) at least 10 days (20 days for severe/critical illness) have 
passed since symptoms first appeared or positive test result (eg, RT-PCR or viral antigen), 2)
resolution of acute symptoms (including at least 24 hours has passed since last fever without 
fever-reducing medications), 3) evaluation by the Investigator with confirmation that there are 
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no sequelae that would place the participant at a higher risk of receiving investigational 
treatment, and 4) consultation by the Medical Monitor. For suspected cases, treatment may 
also resume if SARS-CoV-2 infection is ruled out and other criteria to resume treatment are 
met.
If the criteria to resume treatment are met after a delay of Cycle 4, 7, or 10, then both nivolumab 
and ipilimumab must be resumed on the same day when the cycle is given. 
If treatment is delayed > 6 weeks from the previous dose, the participant must be permanently 
discontinued from study therapy, except as specified in Section 8.1.1.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor or 
designee. Grade 3 or 4 drug-related adrenal insufficiency requires discontinuation regardless of 
control with hormone replacement.
7.4.3
Treatment of Study Treatment-related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. Regardless 
of whether or not the event is attributed to the study drugs, all Grade 3 or 4 infusion reactions 
should be reported within 24 hours to the study BMS Medical Monitor or designee and reported 
as an SAE if it meets the criteria, given the blinded nature of the study. 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 study drug administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for ≤24 
hours):
•
Stop the study drug 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 
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infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms recur, 
then no further study drug 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 study drug infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (eg, renal impairment, 
pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory support indicated):
•
Immediately discontinue infusion of study drug. 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 drugs will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
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 (eg, required diluents, administration sets).
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•
Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2 and the CA209914 Pharmacy Manual.
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
7.6
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and eCRF. This will be source data verified by the BMS Unblinded Site Monitor 
through regularly scheduled monitoring visits.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.3)
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
or standard or investigational agents given prior to discontinuation of study treatment)
•
Any complementary medications (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such medications are permitted if they are used as
supportive care.   
•
Any live/attenuated vaccine (eg, varicella; zoster; yellow fever; rotavirus; oral polio; and 
measles, mumps, rubella [MMR]) during treatment, and until 100 days post last dose. 
−
Note: The use of inactivated vaccines, such as seasonal influenza (eg, Fluzone), will be 
permitted on study without restriction.
Supportive care for disease-related symptoms may be offered to all participants on the trial.
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 disease.
Investigators are strongly encouraged to wait for confirmation of recurrence from the BICR prior 
to initiating subsequent systemic cancer therapy, radiotherapy, or tumor-directed surgery for 
suspected 
recurrence 
unless 
clinical 
considerations 
require 
immediate 
intervention 
(eg, symptomatic brain metastases). If subsequent systemic cancer therapy, radiotherapy, or 
tumor-directed surgery is planned prior to BICR confirmation of recurrence, the investigator must 
contact the BMS Medical Monitor or designee to discuss the case prior to the start of any of these 
procedures.  
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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, even if 
> 10 mg/day prednisone equivalents, are permitted. A brief (less than 3 weeks) course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Concomitant medications are recorded at baseline, throughout the treatment phase of the study and 
within 100 days of the last dose date of study drug should be recorded in the appropriate section 
of the CRF. All medications (prescriptions or over the counter medications) continued at the start 
of the study or started during the study and different from the study drug must be documented in 
the concomitant therapy section of the CRF.
7.8
Treatment After the End of the Study
At the end of the study/Period (24 weeks), BMS will not continue to provide BMS supplied study 
treatment to participants/investigators unless BMS chooses to extend the study. The investigator 
should ensure that the participant receives appropriate standard of care to treat the condition under 
study.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue 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 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
•
Criteria listed in Section 8.1.1
•
Disease recurrence or occurrence of a secondary malignancy which requires systemic therapy 
or radiotherapy for treatment 
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 
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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 or designee within 24 hours 
of awareness of the pregnancy. If the investigator determines a possible favorable benefit/risk ratio 
that warrants continuation of study treatment, a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate CRF page.
8.1.1
Study Treatment Discontinuation Criteria
•
All discontinuation criteria apply to nivolumab, ipilimumab, and placebo given the blinded 
nature of the study. Treatment should be permanently discontinued for any of the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. 
−
Grade 3 drug-related adrenal insufficiency requires discontinuation . 
−
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*
* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be 
permanently discontinued. If the investigator determines a possible favorable 
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benefit/risk ratio that warrants continuation of study drug(s), a discussion between 
the investigator and the BMS Medical Monitor/designee must occur.
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or Total Bilirubin), requires discontinuation 
•
Grade 4 drug-related adrenal insufficiency or hypophysitis requires discontinuation 
•
The following Grade 4 events are exceptions and 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 AE, 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 or designee.
•
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related AE 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 or designee.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the BMS 
Medical Monitor or designee must be consulted. Tumor assessments should continue per protocol 
schedule even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
should also continue every 4 weeks or more frequently if clinically indicated during such dosing 
delays.
Study treatment must be discontinued within 36 weeks after the first dose. Any cycles not given 
within 36 weeks after first dose will be omitted. 
8.1.2
Post Study Treatment Study Follow-up
In this study, DFS is a key endpoint of the study. Post study follow-up is of critical importance 
and is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 5 until death or the conclusion of the study.
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BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window (see Table 2-3). At the time of this request, each participant will be 
contacted to determine their survival status unless the participant has withdrawn consent for all 
contacts or is lost to follow-up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
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.
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9
STUDY ASSESSMENTS AND PROCEDURES
•
Study CT/MRI procedures and timing are summarized in the Section 9.1.2.
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
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 AE, the participant should be immediately evaluated to 
rule out pulmonary toxicity, according to the suspected pulmonary toxicity management algorithm 
in the BMS-936558 (nivolumab) IB and in Appendix 6.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the Schedule of Activities in Section 2.
9.1.1
Definitions of Recurrence
•
The primary endpoint of DFS is defined as time from randomization until death from any cause 
or recurrence of tumor as defined by either of the following:
•
Local disease recurrence refers to relapse of the primary tumor in-situ (site of original resected 
primary RCC tumor, either in the surgical bed of the resected kidney or in the residual kidney 
in partial nephrectomy) or occurrence of a secondary RCC primary cancer
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•
Distant recurrence: any non-local metastatic sites
•
The date of recurrence is defined as the date of the tumor assessment that demonstrated 
unequivocal recurrence. 
For participants with suspected diagnosis of secondary non-RCC primary tumor, the investigator 
should clearly document the tumor site(s). These events will not be counted as an event under the 
primary study endpoint. 
9.1.2
Methods of Measurements
CT and MRI are an essential part of the work-up to establish recurrence. Contrast-enhanced CT of 
the chest, abdomen, and pelvis should be performed. Images should be acquired with slice 
thickness of 5 mm or less with no intervening gap (contiguous). 
•
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of 
the chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected 
sites of disease should be obtained.  
•
Should a participant have contraindication for both MR and CT intravenous contrasts, a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
•
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition 
to contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, 
and other known/suspected sites of disease is acceptable. 
•
Every attempt should be made to image each participant using an identical acquisition protocol 
on the same scanner for all imaging time points. 
•
PET alone will not be considered adequate for the disease assessment. Complementary CT 
and/or MRI or biopsy must be performed in such cases. 
Note: Use of CT component of a PET/CT scanner: Combined modality scanning, such as 
with FDG-PET/CT, is increasingly used in clinical care and is a modality/technology that 
is in rapid evolution; therefore, the recommendations outlined here may change rather 
quickly with time. At present, low-dose or attenuation correction CT portions of a 
combined FDG-PET/CT are of limited use in anatomically-based efficacy assessments,
and it is, therefore, suggested that they should not be substituted for dedicated diagnostic 
contrast enhanced CT scans. However, if a site can document that the CT performed as part 
of a FDG-PET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the FDG-PET/CT can be used. Note, however, that the 
FDG-PET portion of the CT introduces additional data which may bias an investigator if it 
is not routinely or serially performed.
•
Histology or cytological evidence of recurrence should be attempted in all cases except for 
brain metastases. Cytology and/or histology are mandatory to confirm recurrence in solitary or 
in equivocal lesions, any new lesions occurring in the kidney, and lymph nodes unless the 
lesion is too small to biopsy or the risk of biopsy is substantial (eg, inter-aortal node with risk 
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of bleed after biopsy because of close proximity to the aorta and IVC) in which case the 
recurrence must be confirmed with a repeat scan 4 weeks later. 
9.1.3
Imaging and Clinical Assessment 
9.1.3.1
Assessment of Baseline Disease-free Status
Screening/baseline imaging is to be performed greater than 4 weeks post-nephrectomy and 
submitted to the radiology vendor for BICR confirmation of disease-free status. Pre-nephrectomy 
images are also requested, if available.
Participant eligibility must be confirmed by BICR prior to randomization, and randomization must 
occur within 12 weeks post-nephrectomy.
Therefore, sites are strongly encouraged to submit pre-nephrectomy scans (if available) and 
baseline scans to BICR preferably prior to 8 weeks after the nephrectomy to allow for return of 
the results from the BICR.
9.1.3.2
Investigator Assessment of Recurrence 
The same method of assessment used at Screening should be used for on-study time points. 
Post-baseline assessments will be performed at the time points described below until disease 
recurrence confirmed by BICR, death, or withdrawal from the study. 
Timing for scans should be based on the date of first treatment, which is considered Week 1.
Tumor assessments for ongoing study treatment decisions will be completed by the investigator.
1) First tumor assessment post-baseline should be performed at Week 23 (± 1 week). Use same 
imaging method as was used at screening/baseline.
2) Subsequent tumor assessments should occur at Weeks 36 and 52. Allowable window for 
assessments is ± 1 week. After Week 52 (first year), tumor assessments should occur every 
6 months (± 2 weeks) until Year 6 and then annually (± 2 weeks) for Year 6 to Year 10. 
3) Additional imaging of potential disease sites should be performed whenever disease recurrence 
or occurrence of a secondary malignancy is suspected. Brain CT or MRI with contrast or bone 
imaging during on-study treatment and follow-up periods should be obtained if clinically 
indicated.
4) Tumor assessments can be discontinued when recurrence has been confirmed by BICR.  
General Considerations for Determining Recurrence:
1) The goal is to identify lesions suspicious for recurrence of RCC. If it is believed that a lesion 
is NOT malignant in nature (eg, infection, trauma), it should be noted in the medical records. 
The specified minimum size criteria should be combined with radiographic appearance 
consistent with recurrent tumor in the assessment of all suspicious lesions.
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2) Equivocal recurrence is upgraded to unequivocal recurrence (except in cases of central nervous 
system [CNS] recurrence) by one or more of the following:
a) A subsequent scan not earlier than 4 weeks from the time when recurrence was first 
suspected demonstrates that the lesion size is ≥5 mm over the size previously recorded, or 
the radiographic appearance of the lesion has become consistent with tumor recurrence. If 
this occurs, the date of recurrence will be the date when the lesion was first suspected.
b) FDG PET demonstrates qualitative uptake consistent with malignancy.
c) Positive histology/cytology.
3) Appearance of multiple new lesions in the same time point generally constitutes unequivocal 
recurrence, even though they may be from different organs (eg, one liver lesion, one lung 
lesion, and one enlarged lymph node).
The diagnosis by radiographic recurrence of localized RCC or distant metastasis or occurrence of 
a secondary malignancy can be made only when the imaging findings meet the acceptance criteria 
in Table 9.1.3.2-1. Positive cytology or histology of a suspected lesion will also confirm 
recurrence.
Table 9.1.3.2-1:
Criteria for Diagnosis of Radiographic Recurrence
Anatomic Sites
Criteria
Kidney
1)
Equivocal renal lesions include:
d)
Equivocal secondary RCC primary tumor (eg, in contralateral kidney):
Any renal lesion measuring < 40 mm in LD or with radiographic appearance 
equivocal for new primary RCC tumor noted by the reader.
e)Equivocal recurrent lesions:
Any new lesion of any size in the ipsilateral kidney (after partial nephrectomy) or 
nephrectomy bed (after radical nephrectomy).
2)
Unequivocal renal lesions include:
a)Unequivocal secondary RCC primary tumor (eg, in contralateral kidney):
One or more renal lesions measuring ≥40 mm in LD and with radiographic 
appearance consistent with a new primary or recurrent tumor.
3)
Unequivocal recurrent lesions:
a)Refer to the second bullet under the previous section, “General Considerations 
for Determining Recurrence.”
Non-Nodal Soft 
Tissue (including 
visceral lesions)
2)
Equivocal lesions include:
b)
Solitary lesion measuring ≤10 mm in LD or with radiographic 
appearance equivocal for tumor recurrence.
c) One or more lesions suggestive of intraperitoneal seeding/implants or port site 
recurrence (eg, in subjects who underwent prior laparoscopic or robotic surgery).
4)
Unequivocal lesions include:
One or more new lesions > 10 mm in LD with radiographic appearance consistent 
with tumor recurrence (excluding intraperitoneal lesions).
Bone Lesions
3)
Equivocal lesions include:
a) Solitary lesion.
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Table 9.1.3.2-1:
Criteria for Diagnosis of Radiographic Recurrence
Anatomic Sites
Criteria
b) Lesions identified on radionuclide bone scan. Findings on radionuclide bone scan 
must be confirmed by CT, MRI, or plain films in order to be upgraded to 
unequivocal.
5)
Unequivocal lesions include:
Two or more new lesions consistent with tumor recurrence.
Lymph Nodesa
4)
Normal lymph nodes are defined as < 10 mm in the short-axis diameter (SAD).
6)
Equivocal lymph nodes include
a)Lymph nodes measuring 10 – 14 mm SAD with radiographic appearance 
consistent with RCC recurrence.
b)
Lymph nodes ≥15 mm SAD without radiographic appearance 
consistent with RCC recurrence.
7)
Unequivocal proof of nodal recurrence includes:
One or more previously normal or equivocal lymph nodes that enlarge to ≥15 mm 
SAD and with radiographic appearance consistent with RCC recurrence.
Fluid Collections
(eg, ascites, 
pleural/pericardial 
effusions)
5)
Presence of fluid alone, without pathological confirmation, does not constitute 
equivocal or unequivocal recurrence.
8)
Unequivocal proof of recurrence is positive pathology of malignant cells from 
fluid(s).
CNS
Unequivocal recurrence is defined as any new CNS lesion of any size on CT or MRI 
with a radiographic appearance consistent with tumor recurrence.
a For lymph node with short axis 10-15 mm, consider biopsy when lymph node is progressively enlarged as evidenced 
by 2 CT or MRI imagings separated by at least a 4-week interval.
9.1.3.3
BICR Assessment of Recurrence
Sites should submit all scans to a third-party vendor on a rolling basis, preferably within 5 business 
days of scan acquisition throughout the duration of the study. When recurrence is diagnosed by 
the investigator per the criteria specified in Table 9.1.3.2-1, the site will inform the radiology 
vendor by indicating on the submission form that recurrence has been identified, so that the BICR 
assessment of recurrence can be performed. Any relevant cytology/pathology results that support 
a diagnosis of recurrence should be promptly submitted to ICON Central Lab so they can be 
translated and de-identified before being sent to BICR. The BICR review will be completed and 
the results provided to the same site within 10 business days of receipt of the scans and any relevant 
cytology/pathological data, provided there are no pending imaging queries to the site. 
Participants whose recurrence 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 recurrence on a subsequent tumor assessment. 
If the investigator feels that the immediate initiation of subsequent therapy is clinically indicated 
and does not wish to wait for the results of the BICR, then the decision to break the blind must be 
discussed with the BMS Medical Monitor or designee prior to doing so. When the blinding code 
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is broken, the reason must be fully documented in the site source document. Please see Section 7.3
for additional information regarding unblinding. 
9.1.3.4
Date of Recurrence 
The first date when recurrence was observed should be taken into account regardless of the method 
of assessment. Please note the following general rules regarding the assessment of recurrence:
•
If recurrence is unequivocal (eg, multiple measurable lesions),
confirmation with 
histology/cytology should be attempted, but not required.
•
If recurrence is equivocal (eg, lymph node only, solitary lesion, or in the kidneys), confirmation 
with histology/cytology must be attempted. If risk of biopsy is too high or biopsy not feasible, 
either a follow-up CT or MRI scan showing progressive and measurable disease or PET/CT 
demonstrating unequivocal FDG uptake must confirm recurrence. If confirmed, the date of 
initial scan showing recurrence will be recorded as the recurrence date.
•
Any pathological evidence of malignancy denotes recurrence (even if scans are equivocal or
not available).
•
If both pathology and imaging are available and meet the criteria for recurrence, specified in
Table 9.1.3.2-1, the date of recurrence is the date of which ever examination came first.
9.1.4
Imaging Restriction and Precautions
Table 9.1.4-1 provides a summary of the alternative methods, acceptable per protocol, in the event 
of contraindications for use of IV and oral contrast, and or/MRI. 
Table 9.1.4-1:
Acceptable Imaging Assessment Methods for Different Anatomic 
Regions
Anatomic Region
Preferred Method
Alternative Methods
Chest, abdomen, and 
pelvis
Note: Scan must cover 
lung apices to 
diaphragm, diaphragm 
through entire liver,
and to below the pubic 
symphysis
CT with IV 
contrast
For chest:
•
CT without contrast can be used only if the participant has a 
clinical contraindication for iodine-based IV contrast (eg, 
hypersensitivity, renal insufficiency)
For abdomen and pelvis:
•
MRI with gadolinium-based IV contrast is the first alternative 
method if the participant has a clinical contraindication for 
iodine-based IV contrast
•
MRI without contrast can be used as the second alternative 
method only if the participant has a clinical contraindication 
for both contrast-enhanced CT and MRI.
•
CT without contrast can be used as the third alternative 
method only if the participant has a clinical contraindication 
for both contrast-enhanced CT and MRI.
Brain
MRI with IV 
contrast
•
CT with IV contrast is the first alternative method if IV 
gadolinium is clinically contraindicated. 
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Table 9.1.4-1:
Acceptable Imaging Assessment Methods for Different Anatomic 
Regions
Anatomic Region
Preferred Method
Alternative Methods
•
MRI without contrast can be used as a second alternative 
method if a participant has clinical contraindications for both 
contrast-enhanced CT and MRI
Bone
Bone scintigraphy
PET (18F-fluoride NaF or FDG) and 99m Technetium SPECT
Notes:
1. CT scans must be performed with slice thickness of ≤5 mm. The reconstruction interval should be equal to slice 
thickness to avoid gap. 
2. The same modality for a given anatomical coverage and the same scanning procedure (most importantly: 
reconstruction slice thickness, anatomic coverage, use of IV contrast) should be consistent between baseline and 
all subsequent follow-up scanning. If possible, the same scanner or an equivalent scanners should be used 
throughout the study. 
3. For abdomen and pelvis CT scans, oral contrast is recommended as per institutional standards. 
4. MRI should include both T1 and T2-weighted sequences with T1-weighted both and pre- and post-contrast. 
5. If bone scan shows hotspots indicative of metastases, further investigation with X-ray, CT, or MRI is warranted. 
6. All scans generated should be exportable in electronic format (DICOM) to enable secure and rapid electronic 
transmission to the designated central imaging laboratory. 
The use of gadolinium-based contrast agents in participants with acute or chronic renal 
insufficiency, with a glomerular filtration rate (GFR) less than 30 mL per minute per 1.73 m2 or 
with any acute renal failure caused by hepatorenal syndrome or perioperative liver transplantation, 
is not recommended.
If gadolinium is contraindicated, proceed without contrast, but the reason for not using contrast 
must be documented. 
9.1.5
Outcomes Research Assessments 
The evaluation of patient-reported outcomes is an increasingly important aspect of clinical efficacy 
in oncology trials. Such data provide an understanding of the impact of treatment from the 
participant’s perspective and offer insights into participant experience that may not be captured 
through physician reporting. Additionally, generic health-related quality of life measures provide 
data needed for calculating utility values to inform health economic models. Patient-reported 
outcomes will be captured through the use of 2 validated self-reported questionnaires: the NCCN 
Functional Assessment of Cancer Therapy - Kidney Symptom Index (FKSI-19) and the EuroQoL 
Group’s 3-level version of the EQ-5D (EQ-5D-3L). The questionnaires will be provided in the 
participant’s preferred language and may be administered by telephone during follow-up visits 1 
and 2 and subsequent survival follow-up visits. All patient-reported outcome assessments should 
be completed prior to study-related procedures, if possible. There exists a standardized guide that 
can be used to facilitate telephone administration of the EQ-5D-3L, though a similar guide does 
not exist for the FKSI-19. Participants will be provided with a hard copy of the latter scale to take 
home and use as a visual aid during telephone interviews.
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The NCCN FKSI-19 is a 19-item scale that measures tumor specific HrQoL in kidney cancer 
participants.52 The symptom index questionnaire is broken into 4 subscales: disease-related 
symptoms-physical (DRS-P), disease-related symptoms-emotional (DRS-E), treatment side-
effects (TSE), and general function and well-being (FWB). Additionally, a 9-item subset of 
disease-related symptoms knows as the FKSI-DRS will be examined. The FKSI-19 uses 5 Likert-
type response categories that range from “not at all” to “very much.” Participants are asked to 
circle the response category that best characterizes their response over the last 7 days on 19 items 
that include symptoms such as lack of energy, fatigue, appetite, coughing, shortness of breath, 
pain, nausea, and ability to work. The FKSI-19 uses a recall period of the past 7 days.
The EQ-5D-3L is a standardized instrument used to measure self-reports of health status and 
functioning.53 The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting 
"no health problems," "moderate health problems," and "extreme health problems." A dimension 
for which there are no problems is said to be at level 1, while a dimension for which there are 
extreme problems is said to be at level 3. Thus, the vectors 11111 and 33333 represent the best 
health state and the worst health state, respectively, described by the EQ-5D. Altogether, the 
instrument describes 35 = 243 health states. Empirically derived weights can be applied to an 
individual’s responses to the EQ-5D descriptive system to generate an index measuring the value 
to society of his or her current health. Such preference-weighting systems have been developed 
for Japan, UK, US, Spain, Germany, and numerous other populations. In addition, the EQ-5D 
includes a visual analog scale that allows respondents to rate their own current health on a 101-
point scale ranging from “best imaginable” to “worst imaginable” health. The EQ-5D is available 
for use in over 150 languages.
Table 2-2 and Table 2-3, provide information regarding the timing of patient-reported outcomes 
assessments.
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. 
Contacts for SAE reporting are specified in Appendix 3.
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 CRF.
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9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Non-serious AE Collection
The collection of non-serious AE information (with the exception of non-serious AEs related to 
SARS-CoV-2 infection, which should begin collection at the time of consent) should begin at 
initiation of study treatment until 100 days after the last dose 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.
SAE Collection
Sections 5.6.1 and 5.6.2 in the IB represent the Reference Safety Information to determine 
expectedness of SAEs for expedited reporting. Following the participant’s written consent to 
participate in the study, all SAEs, whether related or not related to study drug, must be collected, 
including those thought to be associated with protocol-specified procedures.
All SAEs must be collected that occur during the Screening Phase 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). For participants randomized/assigned 
to treatment and never treated with study drug, SAEs should be collected for 30 days from the date 
of randomization.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
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.
SARS-CoV-2 Infection-related AE Collection
All SAEs, and all AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection must be collected from the date of the participant’s written consent until 
100 days following discontinuation of dosing.
Extended Collection of Study Treatment-related Non-Serious AEs
The time period for collection for study treatment-related AEs is being extended to better 
characterize and understand late-onset AEs considered related to study treatment. This will provide 
important safety data in the adjuvant setting and better understand the safety profile. The collection 
of non-serious AEs considered related to the study treatment should continue to be collected 
through Survival Follow-up visits until approximately 1 year following discontinuation of study 
treatment. 
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However, if the non-serious AE has an onset date after 100 days since the last dose of study 
treatment and it occurs on or after the initiation of subsequent anti-cancer therapy, it should not be 
reported.
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
All non-serious AEs (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
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 9.2.1) and AEs (SAEs and non-serious AEs) associated with confirmed or suspected
SARS-CoV-2 infection 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)
or for suspected cases, until SARS-CoV-2 infection is ruled out.
After Follow-up visit 2 and through the survival follow-up phase, all study treatment-related AEs 
(non-serious and SAEs) should be collected during the survival follow-up visits. However, if the 
non-serious AE has an onset date after 100 days since the last dose of study treatment and it occurs
on or after the initiation of subsequent anti-cancer therapy, it should not be reported. After the 
initial AE/SAE report, the investigator is required to proactively follow each participant at 
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subsequent visits/contacts. All AEs (SAEs and non-serious) considered related to study treatment 
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 IB and will notify the IRB/IEC, if appropriate according to local requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor/designee
within 24 hours of awareness of the pregnancy.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Note: The following paragraph is no longer applicable per Administrative Letter 10. 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.
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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).
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.
9.2.9
Management Algorithms
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology agent 
in this protocol. Early recognition and management of AEs associated with immuno-oncology 
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agents may mitigate severe toxicity. Management Algorithms have been developed to assist 
investigators in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
•
Myocarditis
The above algorithms are found in the Nivolumab IB and in Appendix 6. 
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 Appendix 3).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report. See the Schedule of 
Activities for specific assessments and time points. 
9.4.2
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.5
Pharmacokinetics
Samples for PK and immunogenicity assessments will be collected for all participants as described 
in Table 9.5-1. All time points are relative to the start of study drug administration. Placebo 
samples will not be analyzed. 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 pre-dose 
sample should be collected just prior to the delayed dose. However, if a pre-dose sample is 
collected but the dose is subsequently delayed, an additional pre-dose 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, 
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the interruption details will also be documented on the CRF. Blood samples will be processed to 
collect serum and stored according to the Laboratory Manual. 
Serum concentration analyses for nivolumab and/or ipilimumab will be performed by validated 
immunoassay bioanalytical method(s) for nivolumab and ipilimumab.
Samples collected from participants will be evaluated for the development of Anti-Drug Antibody 
(ADA) for nivolumab and/or ipilimumab by validated immunoassays. Samples with a positive 
ADA response may also be analyzed for neutralizing ADA response to nivolumab and/or 
ipilimumab. 
In addition, selected serum samples may be analyzed by an exploratory method that measures 
nivolumab and ipilimumab, or detect anti-drug antibodies for technology exploration purposes; 
exploratory results will not be reported. The corresponding serum samples designated for either 
PK, immunogenicity or biomarker assessments may also be used for any of those analyses, if 
required (eg, insufficient sample volume to complete testing or to follow up on suspected 
immunogenicity related AE).
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Table 9.5-1:
Pharmacokinetic and Immunogenicity Sampling Schedule for Nivolumab,  Ipilimumab 
and Placebo for all Study Parts and Arms
Study Daya
(1 Cycle = 2 
weeks)
Event
(Relative 
to 
Dosing)
Hour
Time
(Relative To 
Dosing)
Hour: Min
Pharmacokinetic 
Blood Sample for 
Nivolumab/Placebo
Immunogenicity 
Blood Sample for 
Nivolumab/Placeb
o
Pharmacokinetic 
Blood Sample for 
Ipilimumab/Place
bo
Immunogenicity 
Blood Sample for 
Ipilimumab/Placebo
C1D1 
Predoseb
00:00
X
X
X
X
C1D1
(EOI-
PK)c
00:30
X
X
C2D1 
Predoseb
00:00
X
X
X
X
C5D1 
Predoseb
00:00
X
X
X
X
C8D1 
Predoseb
00:00
X
X
X
X
C11D1 
Predoseb
00:00
X
X
X
X
Follow-up 
Samples 
(Follow-up 1 and 
Follow-up 2)- 30 
and 100 days, 
respectively,
from the last 
dose of study 
therapy (see 
Table 2-3 for 
additional 
details)
NA
NA
X
X
X
X
a If a participant discontinues study drug treatment during the sampling period, they will move to sampling at the follow-up visits.
b Predose: All predose samples for nivolumab (or placebo) and ipilimumab (or placebo) should be taken prior to the start of nivolumab (or placebo) infusion. It is 
acceptable to obtain predose samples with routine lab work if done on the same day as the infusion, provided accurate collection time is indicated for the sample. 
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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.
c EOI-nivo and EOI-ipi: End of Infusion samples for nivolumab and ipilimumab, respectively. EOI-PK collection instructions apply to the placebo arm as well.
. Since the end of infusion-PK (EOI-PK) sample is drawn with the intent of accurately estimating the maximum concentration (Cmax) of the drug, draw the EOI-PK 
for both nivolumab and ipilimumab when all of the ipilimumab study drug (which is administered after nivolumab) has been infused. If the site infuses drug 
without a flush, then collect the EOI-PK samples within approximately 5 minutes after end of infusion of ipilimumab. If a subsequent flush is administered to 
clear the IV lines of ipilimumab and to ensure delivery of the entire drug dose, then draw the EOI-PK sample within approximately 5 minutes after end of the 
flush. 
Do not draw EOI samples from the same IV access that the drug was administered.
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9.6
Pharmacodynamics
Refer to Section 9.8.
9.7
Pharmacogenomics
Refer to Section 9.8.
9.8
Biomarkers
A variety of factors that could potentially predict clinical response and incidence of AEs to 
nivolumab + ipilumimab combined therapy and/or nivolumab monotherapy will be investigated in 
peripheral blood and in tumor specimens taken from all participants prior to treatment and as 
outlined in the protocol. Data from these investigations will be evaluated for associations with 
efficacy endpoints. In addition, these analyses will provide the necessary data to identify and 
validate biomarkers with predictive versus prognostic value. The biomarker-sampling schedule for 
this study is provided in Table 9.8-1. A separate manual outlining details of biomarker sample 
collection and handling will be provided to participating sites.
Table 9.8-1:
Biomarker Sampling Schedule for Nivolumab, Ipilimumab, and 
Placebo for All Study Parts and Arms
Study Day
(1 Cycle = 2 Weeks)
Event
(Relative to 
Dosing)
Hour
aTumo
r 
Biopsy
Whol
e 
Blood 
DNA
Periphera
l 
Blood 
RNAb
MDS
C
Serumb
ctDNA
c
Anti-
SARS-
CoV-2
serolo
gyd
Screening 
X
C1D1 
Predose
X
X
X
X
X
X
C2D1 
Predose
X
C4D1
Predose
X
C5D1 
Predose
X
C7D1
Predose
X
X
C9D1 
Predose
X
C12D1
Predose
X
Follow-up Visit 2
X
AE, adverse event; ctDNA, circulating tumor DNA; C, cycle; D, day; MDSC, myeloid-derived suppressor cells; SAE, 
serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
a Baseline tumor samples are mandatory and an optional tumor sample will be collected upon recurrence.
b Sample collection upon > Grade 3 non-laboratory drug-related AE and/or laboratory abnormalities regarded as a 
drug-related SAE, to be collected when clinically safe and feasible.
c Subsequent ctDNA sample collections will be aligned with tumor assessments performed on Weeks 23, 36, and 52 
(+/- 1 week window). If a tumor assessment is not performed, ctDNA sampling is not required.
d A sample is also collected approximately 4 weeks after a suspected or confirmed SARS-CoV-2 infection to be used 
for potential future measurements of anti-SARS-CoV-2 serology (anti-SARS-CoV-2 total or immunoglobulin G 
(IgG)
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9.8.1
Additional Research Collection
This protocol will include residual sample storage for additional research (AR).
For All US sites:
Additional research is mandatory for all investigational sites in the US.
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 
understanding of disease and options for treatment. It may also be used 
 
 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. 
Sample Collection and Storage
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 DNA from whole blood, serum, circulating tumor DNA (ctDNA), peripheral blood 
RNA, and DNA and RNA from tumor biopsy tissue, (see Table 9.8.1-1) will also be retained 
for additional research purposes
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.
A variety of factors that could potentially predict clinical response and incidence of AEs to 
nivolumab and ipilimumab will be investigated in peripheral blood and in tumor specimens taken 
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from all participants prior to randomization. Data from these investigations will be evaluated for 
associations with DFS, OS, and distant metastasis-free survival and/or safety (adverse event) data. 
In addition, analyses of markers between the 2 treatment arms 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 RCC 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.
Table 9.8.1-1:
Residual Sample Retention for Additional 
Research Schedule
Sample Type
Timepoints for which residual samples will be retained
Whole blood (DNA) 
All
Serum
All
ctDNA
All
Peripheral Blood 
RNA
All
Tumor Biopsy (DNA 
and RNA)
Screening and recurrence
9.8.2
Tissue Specimens
Sufficient tumor tissue specimens collected within 3 months prior to enrollment, preferably at the 
time of nephrectomy, will be required in the form of a FFPE tissue block or 20 unstained slides. A 
minimum of 10 slides will be acceptable if tumor tissue is limited. In these situations, it is 
recommended to consult with the protocol team to discuss the specifics of the case.
The tumor sample may be used to assess putative predictive biomarkers of nivolumab and 
ipilimumab efficacy and/or to better characterize the tumor-immune microenvironment. Various 
molecular markers with potential predictive value for the treatment of RCC 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-L1, PD-1, PD-L2, 
TILs or subpopulations of TILs, a Th1 immune mRNA expression signature. In addition, tumor 
samples will also be used for assessment of tumor recurrence score based on gene signature 
analysis.54 These 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 and ipilimumab, including but not limited to other T cell checkpoint receptors and 
ligands (eg, Lag-3, Tim-3), and intratumoral immune cell subsets, including macrophages, natural 
killer (NK) cells and B cells.
In addition, it is recommended, although optional, for tumor tissue samples to be collected upon 
recurrence. These samples 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 
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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 and ipilimumab on the expression of potentially relevant 
predictive and/or prognostic RCC biomarkers. Both the nephrectomy tumor sample and the sample 
collected upon recurrence may be retrospectively assessed for the expression of other 
immune-related genes, RNAs and/or 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).
9.8.3
Exploratory Serum Biomarkers
Blood samples for exploratory serum biomarker analyses will be drawn at the time points specified 
in Table 2-2 and Table 2-3. 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 SAE, and upon recurrence. Blood samples will be collected and processed for serum 
and then put in frozen storage. Serum samples may be assessed by ELISA, seromics, microRNA 
profiling, ctDNA measurements, metabolomics and/or other relevant multiplex-based protein 
assay methods for immune or RCC-related factors that will predict for nivolumab or ipilimumab 
benefit or correlate with nivolumab or ipilimumab-related AEs. Numerous potential serum-based 
biomarkers are currently under investigation for their potential to predict or correlate with safety 
or efficacy to nivolumab, ipilimumab 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), ctDNA, and microRNAs (such as, but not limited to, miR-513 and 
miR19b).
9.8.4
Peripheral Blood RNA
Gene expression analyses of RNA derived from whole blood may provide information on the 
broad effects of nivolumab and ipilimumab on immune modulation. Thus, genomic expression 
patterns of whole blood collected at the time points in specified in Table 2-2 and Table 2-3 may 
be assessed by Affymetrix microarray profiling, qRT-PCR or other gene expression profiling 
technology, with a particular emphasis on genes with relevant immune function. 
9.8.5
Myeloid-Derived Suppressor Cells
Myeloid-derived suppressor cells (MDSCs) are an immune cell population capable of suppressing 
T cell activation and proliferation. MDSCs will be measured at baseline and on-treatment as 
described in Table 9.8-1 to assess pharmacodynamic changes or associations with outcome. 
9.8.6
Peripheral Blood DNA Mutation Research
The presence of cell-free DNA in circulating peripheral blood is a well-documented phenomenon. 
Fragments of DNA are shed into the blood stream from proliferating cells or from cells undergoing
apoptosis or other forms of cell death. In patients with cancer, a fraction of this DNA is tumor-
derived and is termed ctDNA. Small fragments of DNA, averaging between 180 to 200 base-pairs 
and representing segments of specific genes, can be amplified with PCR and then sequenced. 
Moreover, several studies have detected mutations in ctDNA that exactly correspond to mutations 
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from the parent tumor, using tissue and plasma from participants with known driver mutations in 
melanoma or head and neck cancer. Beaming technology may be utilized to count the frequency 
of mutations in the circulation. Correlation analyses with tumor will be warranted where the data 
are available. ctDNA will be investigated as a prognostic and predictive biomarker and will be 
used to monitor changes in tumor mutations during treatment.
9.8.7
Whole Blood for Genotyping
Whole blood samples for exploratory pharmacogenetic assessment will be collected from all 
participants. Genomic DNA will be extracted and subsequently assessed for SNPs and other 
genetic variations in candidate genes that may predispose participants to nivolumab or ipilimumab 
benefit or AEs (unless restricted by local requirements.) Such genes include, but are not limited 
to, PD-1, PD-L1, PD-L2 and CTLA-4. Additional use of these data may include correlative 
analyses aimed at identifying genotypic associations with clinically relevant biomarkers identified 
by other methodologies described in this section. This sample may be assessed for whole exome 
sequencing (WES) and rearrangements in the TCR in T cells within the peripheral blood. WES is 
an efficient way to identify genetic variants that alter protein sequences. An assessment of somatic 
TCR rearrangements by PCR, sequencing or NextGen sequencing approach will provide 
information regarding the clonality of a T cell repertoire, which may change with nivolumab and/or 
ipilimumab treatment. In addition, baseline T cell repertoire may be predictive of nivolumab and/or 
ipilimumab benefit.
9.8.8
Immunogenicity Assessments 
Blood samples for immunogenicity analysis will be collected. Samples collected from participants 
receiving nivolumab and/or ipilimumab will be evaluated for development of Anti-Drug Antibody 
(ADA) by a validated electrochemiluminescent (ECL) immunoassays.
Samples may also be analyzed for neutralizing antibodies and PK samples (please refer to Table 
9.5-1 for immunogenicity sampling schedule) 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.
9.8.9
Other Assessments
Serum will be collected for potential future measurements of anti-SARS-CoV-2 antibodies by 
serology (anti-SARS-CoV-2 total or immunoglobulin G [IgG]) to explore potential association 
with safety, efficacy, and/or immune biomarkers.
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.
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10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The modification to the study design outlined in revprot03 adds a monotherapy arm (nivolumab) 
and roughly doubles the total sample size with the first approximately 800 randomized 1:1 
participants (Part A) to nivolumab + ipilimumab and placebo and the approximately 
800 randomized 1:1:2 participants (Part B) to nivolumab + ipilimumab, placebo and nivolumab. 
Part A participants will be mutually exclusive from Part B participants. The combination analysis 
in Part A is preserved comparing the nivolumab + ipilimumab arm to the placebo arm in the first 
approximately 800 nivolumab + ipilimumab and placebo randomized 1:1 participants. Part B is 
added for the purposes 1) to compare monotherapy nivolumab to placebo and 2) to estimate the 
contribution of components for the combination of nivolumab + ipilimumab and monotherapy 
nivolumab.
This section is organized as follows. First, sample size calculations for Part A are presented. 
Second, the sample size calculations for Part B are presented. The Part B monotherapy comparison 
is between the nivolumab (approximately 400 participants) and placebo (approximately 200 
participants) arms. The additional approximately 200 participants randomized to the nivolumab + 
ipilimumab arm in Part B will be included in the combination OS analysis hierarchically if the 
DFS monotherapy test is successful (for more details, see Section 10.3.4). In addition, these 
nivolumab + ipilimumab Part B participants will be compared to the nivolumab participants to 
assess the contribution of components (CoC), i.e. to directly estimate the hazard ratio and variance 
for the contemporaneously randomized nivolumab + ipilimumab versus nivolumab arms.
10.1.1
Part A: Combination Comparison of DFS
The combination comparison sample size is driven by the comparison of DFS between participants 
randomized to receive nivolumab + ipilimumab versus placebo. Approximately 800 participants 
will be randomized to the nivolumab + ipilimumab and placebo treatment arms in a 1:1 ratio with 
DFS medians of 111 and 72 months, respectively, rendering a 62-month study. Note the invocation 
of revprot03 will initiate the 1:1:2 (i.e. nivolumab + ipilimumab, placebo, nivolumab) 
randomization (see next section on Monotherapy Comparison of DFS). 
Approximately 232 events among the approximately 800 contemporaneously randomized 1:1 
participants are expected, ensuring 90% power to detect an average hazard ratio of 0.65 with an 
overall type I error of 0.05 (two-sided). The number of events and power were calculated assuming 
an exponential distribution and a delayed treatment effect of 3 months. This design yields a 
minimal HR of 0.764 (P<0.041) when adjusting for interim analyses using Lan-DeMets alpha 
spending function.
Given accrual rates of 22 participants per month on average for the entire enrollment period, it is 
estimated that accrual of 800 participants (ie, 400 participants in each arm) will take approximately 
36 months; it will take an additional approximately 26 months to observe the required number of 
events for the final DFS analysis.
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There is 1 planned interim analysis of DFS. Stopping boundaries at the interim analyses will be 
derived based on the exact number of events using Lan-DeMets alpha spending function with 
O’Brien-Fleming boundaries. The DFS interim analysis is expected to occur at approximately 
56 months when approximately 204 events are expected to have occurred. This will provide 83% 
power to detect an overall interim DFS HR of 0.743 (P<0.034) at the pre-specified alpha level 
using the Lan-DeMets alpha spending function.
In the event that Part B enrollment is still ongoing at the time of observing the required number of 
events for the interim analysis and target number of events needed for the final analysis is projected 
in a shorter time interval (approximately within 4 months), then the interim analysis of DFS will
not be performed and only one final analysis of DFS will be conducted after observing 
approximately 227 DFS events (required number of events since there is no alpha spending for 
DFS interim analysis) among all randomized participants. The 227 events are expected to provide 
90% power to detect a DFS HR of 0.65 at alpha 0.05 (two-sided).
Table 10.1.1-1 summarizes sample size design parameters and schedule of primary endpoint 
analysis accounting for an interim and final analyses.
Table 10.1.1-1:
Part A Summary of Sample Size Parameters and Schedule of 
Combination Analyses (with an Interim Analysis)
Primary Endpoint
DFS
Primary analysis population
All Randomized Participants
Accrual rate per month
22
Power
90%
Alpha
0.05 2-sided (0.034 at interim analysis, 
0.041 at FA)
Hypothesized Median Control vs Experimental (Months) 
72 vs 111
Hypothesized Hazard Ratio
0.65
Critical HR (HR at which a statistically significant difference would 
be observed) / Difference in median corresponding to a minimally 
significant effect size (Months)
0.764 / 22 
Critical HR at interim analysis / Effect size (Months)
0.743 / 25
Expected events for interim analysis (percentage of target events)
204 (88%)
Timing of interim analysis from FPFV (Months)
56
Accrual Duration (Months)
36
Timing of final analysis (FA) from FPFV (Months)
62
Sample sizea
800
Target number of events (Event Goal)
232
a East version 5.4 was used for sample size / power computation
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Table 10.1.1-2 summarizes sample size design parameters and schedule of primary endpoint
analysis with one final analysis alone.
Table 10.1.1-2:
Part A Summary of Sample Size Parameters and Schedule of 
Combination Analysis (without an Interim Analysis)
Primary Endpoint
DFS
Primary analysis population
All Randomized Participants
Accrual rate per month
22
Power
90%
Alpha
0.05 
Hypothesized Median Control vs Experimental (Months) 
72 vs 111
Hypothesized Hazard Ratio
0.65
Critical HR (HR at which a statistically significant difference would 
be observed) / Difference in median corresponding to a minimally 
significant effect size (Months)
0.771 / 21.4
Accrual Duration (Months)
36
Timing of final analysis (FA) from FPFV (Months)
61
Sample sizea
800
Target number of events (Event Goal)
227
a East version 5.4 was used for sample size / power computation
10.1.2
Part B: Monotherapy Comparison of DFS
The monotherapy comparison sample size is driven by the comparison of DFS between 
participants randomized to receive nivolumab versus placebo. Approximately 600 participants will 
be randomized to the nivolumab and placebo treatment arms in a 2:1 ratio (i.e. as part of the 1:1:2
ratio to nivolumab + ipilimumab, placebo, nivolumab) with DFS medians of 106 and 72 months, 
respectively, for a total accrual of approximately 56 months (20 additional months from the end of 
the combo test accrual).
Approximately 91 additional events are expected in the nivolumab arm for a total of 153 events 
among the 600 participants, ensuring 60% power to detect an average hazard ratio of 0.68 with an 
overall type I error of 0.05 (two-sided). Note that since the Part B participants are mutually 
exclusive from Part A participants no hierarchical testing for the primary endpoint is necessary 
(for more details, see Section 10.3.4). The number of events and power were calculated assuming 
an exponential distribution and a delayed treatment effect of 3 months. This design yields a 
minimal HR of 0.71 (P<0.043) when adjusting for interim analyses using Lan-DeMets alpha 
spending function.
Given accrual rates of 40 participants per month on average for the entire monotherapy enrollment 
period (1:1:2, thus 30 per month for only the monotherapy and placebo arms), it is estimated that 
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accrual of 600 participants (i.e., 400 participants to the nivolumab arm and 200 to the placebo arm) 
will take approximately 20 months; it will take an additional approximately 28 months (84 months 
from study initiation) to observe the required number of events for the final monotherapy DFS 
analysis.
There is 1 planned interim monotherapy analysis of DFS. Stopping boundaries at the interim 
monotherapy analysis will be derived based on the exact number of events using Lan-DeMets 
alpha spending function with O’Brien-Fleming boundaries. The DFS interim monotherapy 
analysis is expected to occur at approximately 76 months when approximately 122 events in the 
monotherapy and contemporaneous placebo arms are expected to have occurred. This will provide 
40% power to detect an overall interim DFS HR of 0.65 (p<0.025) at the pre-specified alpha level 
using the Lan-DeMets alpha spending function.
In the event that the target number of events for the interim analysis and final analysis are projected 
in a shorter time interval (approximately within 6 months), then the interim analysis of DFS will 
not be performed and only one final analysis of DFS will be conducted after observing 
approximately 149 DFS events among the randomized participants in the nivolumab and placebo 
arms (required number of events since there is no alpha spending for DFS interim analysis). The 
149 events are expected to provide 60% power to detect a DFS HR of 0.68 at alpha 0.05 (two-
sided).
Table 10.1.2-1 summarizes sample size design parameters and schedule of primary endpoint 
analyses planned in this study.
Table 10.1.2-1:
Part B Summary of Sample Size Parameters and Schedule of 
Monotherapy Analyses (with an Interim Analysis)
Primary Endpoint
DFS
Primary analysis population
All Randomized Participants in 
Nivolumab and Placebo Arms
Accrual rate per month
40 (or 30 2:1 to N and P)
Power
60%
Alpha
0.05 2-sided (0.025 at mono interim 
analysis and 0.043 at mono final 
analysis)
Hypothesized Median Control vs Experimental (Months) 
72 vs 106
Hypothesized Hazard Ratio
0.68
Critical HR (HR at which a statistically significant difference would 
be observed) / Difference in median corresponding to a minimally 
significant effect size (Months)
0.71 / 29 
Critical HR at mono interim analysis / Effect size (Months)
0.65 / 39
Expected events for mono interim analysis (percentage of target 
events)
122 (80%)
Timing of mono interim analysis from FPFV (Months)
76
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Table 10.1.2-1:
Part B Summary of Sample Size Parameters and Schedule of 
Monotherapy Analyses (with an Interim Analysis)
Primary Endpoint
DFS
Accrual Duration (Months)
20
Timing of final analysis (FA for mono) from FPFV (Months)
84
Sample sizea
600
Target number of events (Event Goal)
153
a East version 5.4 was used for sample size / power computation
Table 10.1.2-2 summarizes sample size design parameters and schedule of primary endpoint 
analysis with one final analysis alone.
Table 10.1.2-2:
Part B Summary of Sample Size Parameters and Schedule of 
Monotherapy Analyses (without an Interim Analysis)
Primary Endpoint
DFS
Primary analysis population
All Randomized Participants in
Nivolumab and Placebo Arms
Accrual rate per month
40 (or 30 2:1 to N and P)
Power
60%
Alpha
0.05 2-sided
Hypothesized Median Control vs Experimental (Months) 
72 vs 106
Hypothesized Hazard Ratio
0.68
Critical HR (HR at which a statistically significant difference would 
be observed) / Difference in median corresponding to a minimally 
significant effect size (Months)
0.71 / 29 
Accrual Duration (Months)
20
Timing of final analysis (FA for mono) from FPFV (Months)
84
Sample sizea
600
Target number of events (Event Goal)
149
a
East version 5.4 was used for sample size / power computation
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10.1.3
Contribution of Components Analysis of DFS:
The contribution of components (CoC) will be assessed. The manner in which CoC will be 
measured is based on the hazard ratio and variance estimates computed for the contemporaneously 
randomized (approximately 200 vs 400) nivolumab + ipilimumab arm versus the nivolumab arm.
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 enrolled Part A participants
•
All Part A participants who signed an informed consent form and were 
registered into the IRT.
All enrolled Part B participants
•
All Part B participants who signed an informed consent form and were 
registered into the IRT.
All treated participants 
•
All participants who received at least 1 dose of study drug.
All treated Part A participants 
•
All Part A participants who received at least 1 dose of study drug. This is 
the primary dataset for the Part A drug exposure and safety analysis.
All treated Part B participants 
•
All Part B participants who received at least 1 dose of study drug. This is 
the primary dataset for the Part B drug exposure and safety analysis.
All randomized participants
•
All participants who were randomized to any treatment arm in the study. 
This population is considered the population for the combination overall 
survival analysis contingent on the primary DFS monotherapy analysis (for 
more details, see Section 10.3.4). 
All randomized Part A 
participants
•
All Part A participants who were randomized to any treatment arm in the 
study. This population is considered for Part A as the primary efficacy 
analysis population. Analysis of demography, protocol deviations, baseline 
characteristics, efficacy analysis and outcome research analysis will be 
performed in this population.
All randomized Part B 
participants
•
All Part B participants who were randomized to any treatment arm in the 
study. This population is considered for Part B as the primary efficacy 
analysis population. Analysis of demography, protocol deviations, baseline 
characteristics, efficacy analysis and outcome research analysis will be 
performed in this population.
PK participants
•
All randomized participants with available serum time-concentration data.
PK Part A participants
•
All Part A randomized participants with available serum time-
concentration data.
PK Part B participants
•
All Part B randomized participants with available serum time-
concentration data.
Immunogenicity Evaluable 
Participants 
•
Nivolumab ADA Evaluable Participants: all treated participants with 
baseline 
and 
at 
least 
1 post-baseline 
pre-infusion
nivolumab 
immunogenicity assessment. 
•
Ipilimumab ADA Evaluable Participants: all treated participants with 
baseline 
and 
at 
least 
1 post-baseline 
pre-infusion
ipilimumab 
immunogenicity assessment. 
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Population
Description
Immunogenicity Part A 
Evaluable Participants 
•
Nivolumab ADA Part A Evaluable Participants: all Part A treated 
participants with baseline and at least 1 post-baseline pre-infusion
nivolumab immunogenicity assessment. 
•
Ipilimumab ADA Part A Evaluable Participants: all Part A treated 
participants with baseline and at least 1 post-baseline pre-infusion
ipilimumab immunogenicity assessment. 
Immunogenicity Part B 
Evaluable Participants 
•
Nivolumab ADA Part B Evaluable Participants: all Part B treated 
participants with baseline and at least 1 post-baseline pre-infusion
nivolumab immunogenicity assessment. 
•
Ipilimumab ADA Part B Evaluable Participants: all Part B treated 
participants with baseline and at least 1 post-baseline pre-infusion
ipilimumab immunogenicity assessment. 
Biomarker participants:
All randomized participants with available biomarker data (PD-L1 expression 
status and other assays).
Biomarker Part A participants:
All Part A randomized participants with available biomarker data (PD-L1 
expression status and other assays).
Biomarker Part B participants:
All Part B randomized participants with available biomarker data (PD-L1 
expression status and other assays).
All analyses will be performed using the treatment arm as randomized (intent to treat), with the 
exception of dosing and safety, for which the treatment arm as received will be used:
•
All randomized participants who take at least 1 dose of double-blind study treatment.
•
Participants will be included in the treatment group they were randomized to, eg, data in this 
data set will be analyzed based on randomized treatment, except in the following cases:
−
If a participant received the same incorrect treatment throughout the study, then the 
participant will be analyzed based on the treatment received.
−
If a participant received study drug from more than 1 treatment group, and none of the 
administrations were consistent with the assigned randomized treatment group, then the 
participant will be analyzed based on the first treatment received.
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10.3
Statistical Analyses
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary DFS analyses will be conducted using a 2-sided log-rank test stratified by 
pathological T Stage and N Stage status and type of nephrectomy at screening in randomized 
participants. The hazard ratio and corresponding 2-sided (1- α)% CI (adjusted for interim) will 
be estimated using a Cox proportional hazards model, with treatment group as a single 
covariate, stratified by the above factors. DFS curves, DFS medians with 95% CIs, and DFS
rates at 6, 12, 18, 24, and 60 months with 95% CIs will be estimated using Kaplan-Meier 
methodology.
Note that upon completion of study enrollment, 2 of the 6 strata levels have less than 20 
participants. To avoid unreliable estimates, the strata levels with partial and radical 
nephrectomy will be combined for stratified analysis purposes. In other words, stratified 
analysis will be conducted based only on 1 stratification factor (pathological T Stage and N 
Stage status).
For censoring rules, please refer to Table 10.3.1-1.
Secondary
The secondary OS analysis will be conducted using a 2-sided log-rank test stratified by 
pathology status and histology at screening in randomized participants. The hazard ratio and 
corresponding 2-sided (1- α)% CI (adjusted for interim) will be estimated using a Cox 
proportional hazards model, with treatment arm as a single covariate, stratified by the above 
factors. OS curves, OS medians with 95% CIs and OS rates at 12, 24, 36, 48, and 60 months 
with 95% CIs will be estimated using Kaplan Meier methodology.
Note that upon completion of study enrollment, 2 of the 6 strata levels have less than 20 
participants. To avoid unreliable estimates, the strata levels with partial and radical 
nephrectomy will be combined for stratified analysis purposes. In other words, stratified 
analysis will be conducted based only on 1 stratification factor (pathological T Stage and N 
Stage status).
Exploratory
Will be described in the statistical analysis plan finalized before database lock.
Censoring rules for the primary definition of DFS are presented in Table 10.3.1-1. Sensitivity 
analyses of DFS will be described in the statistical analysis plan. 
Table 10.3.1-1:
Censoring Scheme Used in Primary Definition of DFS
Situation
Date of Progression or Censoring
Outcome
Recurrence
Date of first recurrence
Event
Death from any cause without recurrence
Date of death
Event
No baseline disease assessment
Date of randomization
Censored
No on-study disease assessments and no 
death
Date of randomization
Censored
No recurrence and no death
Date of last evaluable disease 
assessment
Censored
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Table 10.3.1-1:
Censoring Scheme Used in Primary Definition of DFS
Situation
Date of Progression or Censoring
Outcome
New systemic anticancer therapy, tumor-
directed radiotherapy, or tumor-directed 
surgery received without recurrence 
reported prior to or on the same day
Date of last evaluable disease 
assessment prior to or on the same 
date of initiation of subsequent 
therapy
Censored
Second non-RCC primary cancer reported 
without recurrence reported prior to or on 
the same day
Date of last evaluable disease 
assessment prior to or on the same 
date of diagnosis of secondary non-
RCC primary cancer
Censored
10.3.2
Safety Analyses
Endpoint
Statistical Analysis Methods
Secondary
Safety analyses will be performed in all treated participants. Descriptive statistics of safety will 
be presented using NCI CTCAE version 4.0 by treatment group. All on-study AEs, treatment-
related AEs, SAEs, and treatment-related SAEs up to 30 and 100 days of last dose of study 
therapy will be tabulated using worst grade per NCI CTCAE v 4.0 criteria by system organ 
class and preferred term. On-study lab parameters including hematology, chemistry, liver 
function, and renal function will be summarized using worst grade NCI CTCAE v 4.0 criteria.
Exploratory
Will be described in the statistical analysis plan, which will be finalized before database lock.
10.3.3
Other Analyses 
10.3.3.1
Pharmacokinetic Analyses
The nivolumab and ipilimumab concentration versus time data obtained in this study will be 
combined with data from other studies in the clinical development program to develop a population 
PK model. This model will be used to evaluate the effects of intrinsic and extrinsic (if applicable) 
covariates on the PK of nivolumab and ipilimumab to determine measures of individual exposure 
(such as peak, trough and time-averaged concentration following a single dose or at steady state). 
Pharmacokinetic drug-drug interaction between nivolumab and ipilimumab will be studied by
population PK approach as appropriate. Model determined exposures may be used for 
exposure -response analyses of selected efficacy and safety endpoints, if appropriate. The results 
of population PK, pharmacokinetic drug interaction and exposure response analyses will be 
reported separately, as needed.
10.3.3.2
Biomarker Analyses
Methodology for exploratory biomarker analyses will be described in the statistical analysis plan.
10.3.3.3
Outcomes Research Analyses
Descriptive summary statistics of quality of life assessments will be presented at baseline and each 
on-study time points unless otherwise specified. Mean changes from baseline for each of the 
2 assessments and all associated subscores will be calculated for each treatment arm at each on-
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study time point. More specifically, summary scores of the FKSI-19 subscale and total scores, the 
9-item FKSI-DRS score, and the EQ-5D-3L utility index and VAS at baseline and on-study time 
points and the 95% CIs will be conducted. For the EQ-5D-3L utility index, the UK preference 
weightings will be analyzed.55 In addition, participant compliance will be described per time point 
by the proportion of participants who filled out the QoL assessments over the numbers of 
participants known to be alive and eligible for assessment at these time points. 
Additionally, t-tests will be conducted to evaluate the differences between nivolumab combined 
with ipilimumab versus placebo infusions treatment arms as well as the nivolumab versus placebo 
infusions treatment arms at each time point, and 95% CIs will also be presented.
10.3.4
Interim Analyses and Hierarchical Testing
The Statistical Analysis Plan will further describe the planned interim analyses.
Part A Combination Analyses Timing
One formal DFS interim combination analysis will be conducted at the time when approximately 
88% (204) of the total DFS events in the combination and placebo arms have occurred and the 
time when the total enrollment of both Part A and Part B is expected to be complete. This formal 
comparison of DFS will allow for early stopping for superiority. The stopping boundaries at the 
interim and final analyses will be derived based on the exact number of DFS events using Lan-
DeMets alpha spending function with O’Brien-Fleming boundaries. Note that if Part B enrollment 
is still ongoing at the time of observing the required number of events for the interim analysis and 
target number of events needed for the final analysis is projected to occur in a shorter time interval
(approximately within 4 months), then the interim analysis of DFS will not be performed and only 
one final analysis of DFS will be conducted after the completion of enrollment in Part A and Part 
B (statistical significance of only one final analysis of DFS is 0.05 [two-sided]).
If the DFS combination analysis is significant, the OS combination analysis will be tested 
hierarchically. Formal OS interim combination analyses will be conducted at the time when the 
interim or final DFS combination analysis is significant. This formal comparison of OS will allow 
for early stopping for superiority. 
The OS combination analyses occurring at the time when the DFS combination analysis is 
significant either after the Part A (approximately 800) participants randomized to the nivolumab 
+ ipilimumab and placebo arms have a minimum of 20 or 26 months of follow-up, which are 
expected to occur at approximately 56 (62% of the total events) and 62 (70% of the total events) 
months from study initiation, respectively. These are at equivalent times when the DFS 
combination analyses of Part A are expected to occur. However, in the situation when the DFS 
combination analysis is significant at 56 months but OS is not significant at that time, the 62 month 
DFS analysis will not be necessary and so the second OS combination interim analysis will occur 
at 70 months (82% of the total events) rather than 62 months (70% of the total events). At the 56-
and 62-month (or 70-month) OS combination analyses, approximately 178 and 201 (or 235) events 
are expected providing 41% and 53% (or 68%) power to detect overall interim OS HRs of 0.68 (P 
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< 0.009) and 0.70 (P < 0.012) (or 0.74, P < 0.023), respectively, at the pre-specified alpha level 
using the Lan DeMets alpha spending function.
The final OS combination analysis will take place after the Part A (approximately 800) participants 
randomized to the nivolumab + ipilimumab and placebo arms have a minimum of 48 months of 
follow-up, which is expected to occur approximately 84 months from the start of the study. At the 
time of the final OS combination analysis, approximately 287 events are expected ensuring 85% 
overall power to detect a final OS hazard ratio of 0.79 (P<0.045).
Part B Monotherapy Analyses Timing
Similarly, 1 formal DFS interim monotherapy analysis will be conducted at the time when 
approximately 80% (122) of the total DFS events in the monotherapy and contemporaneous 
placebo arms have occurred. This formal comparison of DFS will allow for early stopping for 
superiority. The stopping boundaries at the interim and final analyses will be derived based on the 
exact number of DFS events using Lan-DeMets alpha spending function with O’Brien-Fleming 
boundaries. Note that if the target number of events for the interim analysis and final analysis are 
projected to occur in a shorter time interval (approximately within 6 months), then the interim 
analysis of DFS will not be performed and only one final analysis of DFS will be conducted 
(statistical significance of only one final analysis of DFS is 0.05 [two-sided]).
If the interim or final DFS monotherapy analysis is significant, the OS monotherapy analysis will 
be tested hierarchically. The final OS analysis will take place with approximately 182 events 
among all randomized Part B participants in nivolumab and placebo arms, which is expected to be 
at approximately 104 months from the start of the study, providing a minimum of 48 months of 
follow-up. Approximately 182 events are expected, ensuring 44% overall power to detect a HR of 
0.73 (P < 0.045). Two formal OS interim monotherapy analyses will be conducted, which will 
allow for early stopping for superiority. The first and second interim analyses of OS are planned 
to occur with 102 events (56% of the targeted OS events) and 146 events (80% of the targeted OS 
events) among the randomized participants in nivolumab and placebo arms, which are expected to 
be at approximately 76 months and 90 months from the start of the study. Approximately 102 and 
146 events are expected providing 8% and 27% power to detect overall interim OS HRs of 0.56 
(P < 0.006) and 0.67 (P < 0.023), respectively, at the pre-specified alpha level using the Lan 
DeMets alpha spending function.
In addition to the formal planned interim analyses for DFS and OS, the DMC will have access to 
periodic unblinded 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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19 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, Activity, and Immune Correlates of Anti-
PD-1 Antibody in Cancer. N Engl J Med 2012.
20 Choueiri TK FM, Escudier BJ, Kim JJ,et al. ;. Immunomodulatory activity of nivolumab in 
previously treated and untreated metastatic renal cell carcinoma (mRCC): Biomarker-based 
results from a randomized clinical trial. J Clin Oncol 32:5s, 2014 (suppl; abstr 5012)
21 Ref Keynote 427: Pembrolizumab monotherapy as first-line therapy in advanced clear cell 
renal cell carcinoma: Results from cohort A of KEYNOTE-427. McDermott DF, Lee JL, 
Szczylik 
C, 
et 
al 
J 
Clin 
Oncol. 
2018;36S:ASCO 
#4500. 
https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.4500
22 Ref 
TITAN: 
ESMO 
2019, 
https://www.urotoday.com/conference-highlights/esmo-
2019/esmo-2019-kidney-cancer/115250-esmo-2019-tailored-immunotherapy-approach-with-
nivolumab-for-advanced-renal-cell-carcinoma-titan-rcc.html
23 A Phase 2 Open-label Study of Single Agent Ipilimumab for the Treatment of IL-2 Refractory 
or IL-2 Ineligible Patients with Stage IV Renal Cancer; NCT00057889; Final Clinical Study 
Report 930025954 v1.0 (28-January-2008)
24 Yang JC, Hughes M, Kammula U et al. Ipilimumab (Anti-CTLA4 Antibody) causes regression 
of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 2007; 
30(8): 825-830
25 A Phase 2 Open-label Study of Single Agent Ipilimumab for the Treatment of IL-2 Refractory 
or IL-2 Ineligible Patients with Stage IV Renal Cancer; NCT00057889; Final Clinical Study 
Report 930025954 v1.0 (28-January-2008)
26 Nivolumab Investigator Brochure. Version 15. Bristol-Myer Squibb Research and 
Development. Princeton, NJ. June 206. Document Control No. 930038243.
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27 VOLUME 20, ISSUE 2, P297-310, FEBRUARY 01, 2019 Patient-reported outcomes of 
patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus 
sunitinib 
(CheckMate 
214): 
a 
randomised, 
phase 
3 
trial. 
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30778-2/fulltext
28 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39.
29 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27.
30 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
31 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2004;23:515-48.
32 Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
2000; 192(7): 1027-34.
33 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45.
34 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.
35 Postow MA,  Harding J, Wolchok JD. Targeting immune checkpoints: Releasing  the  restraints 
on anti-tumor immunity for patients with melanoma. Cancer J 2012; 18:153-159.
36 McDermott DF, Lee JL, Szczylik C, et al. Pembrolizumab monotherapy as first-line therapy 
in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-
427. J Clin Oncol 2018;36 (suppl; abstr 4500).
37 Atkins MB, McDermott DF, Powles T, et al. IMmotion150: a phase II trial in untreated 
metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and 
bevacizumab (bev) vs and following atezo or sunitinib. J Clin Oncol. 2017;35 (suppl; abstr 
4505).
38 Donat SM, Diaz M, Bishoff JT, et al. Follow-up for Clinically Localized Renal Neoplasms: 
AUA Guideline. J Urol. 2013; 19: 407-416.
39 Ljungberg B, Bensalah K, Bex A, et al: Guidelines on renal cell carcinoma. 
http://uroweb.org/wp-content/uploads/EAU-Guidelines-Renal-Cell-Cancer-2015-v2.pdf
40 Francesco Massari, Vincenzo Di Nunno, Veronica Mollica, Jeffrey Graham, Lidia Gatto, 
Daniel Heng: Adjuvant Tyrosine Kinase Inhibitors in Treatment of Renal Cell Carcinoma: A 
Meta-Analysis of Available Clinical Trials. Clinical Genitourinary Cancer: 2019.
41 Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical 
nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for 
prospective clinical trials. Cancer 2003; 97:1663-71.
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42 Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and Ipilimumab versus Ipilimumab in 
Untreated Melanoma. N Engl J Med 2015;372:2006-17.
43 Hammers HA, Plimack ER, Infante JR, et al. Updated Results from a Phase 1 Study of 
Nivolumab in Combination with Ipilimumab in Metastatic Renal Cell Carcinoma: The 
CheckMate 016 Study. Presented at the 2016 Annual Meeting of the European Society of 
Medical Oncologists, October 7-11, 2016, Copenhagen, Denmark. 
44 Momtaz P, Park V, Panageas KS, et al. Safety of Infusing Ipilimumab Over 30 Minutes.
Journal of Clinical Oncology 2015 33:30, 3454-3458.
45 Yervoy prescribing information. Bristol-Myers Squibb Research and Development. Princeton, 
NJ. October 2015.
46 Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and Ipilimumab versus Ipilimumab in 
Untreated Melanoma.  N Engl J Med. 2015;372(21):2006-17.
47 https://www.urotoday.com/conference-highlights/esmo-2019/esmo-2019-kidney-
cancer/115245-esmo-2019-a-tailored-immunotherapy-approach-with-nivolumab-in-
advanced-renal-cell-carcinoma-in-the-titan-
trial.html?utm_source=newsletter_7020&utm_medium=email&utm_campaign=esmo-2019-
breaking-genitourinary-malignancy-highlights-impacting-clinical-care Ref for KN427
48 Ref Keynote 427: Pembrolizumab monotherapy as first-line therapy in advanced clear cell 
renal cell carcinoma: Results from cohort A of KEYNOTE-427. McDermott DF, Lee JL, 
Szczylik C, et al J Clin Oncol. 2018;36S:ASCO #4500. 
49 Ref 
TITAN: 
ESMO 
2019, 
https://www.urotoday.com/conference-highlights/esmo-
2019/esmo-2019-kidney-cancer/115250-esmo-2019-tailored-immunotherapy-approach-with-
nivolumab-for-advanced-renal-cell-carcinoma-titan-rcc.html
50 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).
51 OPDIVO prescribing information. Bristol-Myers Squibb Company. Princeton, NJ. Updated 
March 2019. 
52 Rothrock, N. E., Jensen, S. E., Beaumont, J. L., Abernethy, A. P., Jacobsen, P. B., Syrjala, K., 
& Cella, D. (2013). Development and initial validation of the NCCN/FACT symptom index 
for advanced kidney cancer. Value in Health, 16(5), 789-796.
53 EuroQol, G. (1990). EuroQol--a new facility for the measurement of health-related quality of 
life. Health policy (Amsterdam, Netherlands), 16(3), 199.
54 Rini B, Goddard A, Knezevic D, et al. A 16-gene assay to predict recurrence after surgery in 
localised renal cell carcinoma: development and validation studies. Lancet Oncol. 
2015;16(6):676-685. doi:10.1016/S1470-2045(15)70167-1.
55 Dolan P. Modeling valuations for EuroQol health states. Medical Care 1997;35: 1095-1108  
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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
AUC
area under the concentration-time curve
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
COVID-19
Coronavirus Disease 2019
CNS
central nervous system
CRF
Case Report Form, paper or electronic
ctDNA
circulating tumor DNA
DFS
disease-free survival
DMC
Data monitoring committee
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
EOI-PK
end of infusion-pharmacokinetics
ESR
Expedited Safety Report
FDA
Food and Drug Administration
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Term
Definition
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
HIPPA
Health Insurance Portability and Accountability Act of 1996
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IMAE
immune-mediated adverse event
IMP
investigational medicinal products
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K+
potassium
kg
kilogram
L
liter
LAM
Lactation amenorrhea method
LDH
lactate dehydrogenase
mg
milligram
min
minute
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Term
Definition
mL
milliliter
mmHg
millimeters of mercury
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
N/A
not applicable
NIMP
non-investigational medicinal products 
OS
overall survival
PD
pharmacodynamics
PK
pharmacokinetics
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
Tmax, TMAX
time of maximum observed concentration
WBC
white blood cell
WES
whole exome sequencing
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the 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:
•
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 (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (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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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 for
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects/participants currently enrolled in the study if they are affected by the amendment; and (3) 
the new form must be used to obtain consent from new subjects/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 
In situations where consent cannot be given to subjects/participants, their legally acceptable 
representatives (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the participant 
volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects'/participants’ signed 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. 
Subjects/participants unable to give their written consent (e.g., 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.
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SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments placebo infusions (whether supplied by BMS, its vendors, or the site) 
must substantiate study treatment
integrity and traceability from receipt, preparation, 
administration, and through destruction or return. Records must be made available for review at 
the request of BMS/designee or a Health Authority.
If
Then
Supplied by BMS (or 
its vendors):
Records or logs must comply with applicable regulations and guidelines and should 
include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each participant, including unique 
participant identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (e.g., lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence/biocomparability, if 
applicable 
•
dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
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If
Then
Sourced by site, and 
not supplied by BMS 
or its vendors 
(examples include IP 
sourced from the sites 
stock or commercial 
supply, or a specialty 
pharmacy)
The investigator or designee accepts responsibility for documenting traceability and 
study drug integrity in accordance with requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.   
These records should include:
•
label identification number or batch number 
•
amount dispensed to and returned by each participant, including unique 
participant identifiers
•
dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature are completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals.
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MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors)
Any unused study treatments supplied by BMS can only be 
destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study treatments containers 
must be immediately destroyed as required for safety, or to 
meet local regulations (e.g., cytotoxics or biologics).
If study treatments will be returned, the return will be arranged 
by the responsible Study Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the site’s stock 
or commercial supply, or a specialty pharmacy)
It is the investigator’s or designee’s responsibility to dispose of 
all containers according to the institutional guidelines and 
procedures.
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It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT 
A Signatory Investigator must be selected to sign the clinical study report. 
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (e.g., among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)
•
Other criteria (as determined by the study team)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
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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 resoved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work.
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
•
End of relevant systemic exposure is the time point where the IMP or any active major 
metabolites has decreased to a concentration that is no longer considered to be relevant for 
human teratogenicity or fetotoxicity. This should be evaluated in context of safety margins 
from the no-observed adverse effect level (NOAEL) or the time required for 5 half-lives of the 
IMP to pass.
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METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of < 1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol)b 
−
oral (birth control pills)
−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
transdermal
•
Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy
•
Progestogen-only hormonal contraception associated with inhibition of ovulation (This method of 
contraception can only be used by WOCBP participants in studies where hormonal contraception is 
permitted by the study protocol)b 
−
oral 
−
injectable
•
Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol)b
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS) (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
sudy protocol)b,c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.
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Continuous abstinence must begin at least 30 days prior to initiation of study therapy
•
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
•
Periodic abstinence (including but not limited to calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine hormone releasing systems are acceptable methods of contraception in the absence of definitive drug 
interaction studies when hormone exposures from intrauterine devices do not alter contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent
•
Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
Unaccetpatble Methods of Contraception 
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
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COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and Appendix 3, Adverse Events and Serious 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting.
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APPENDIX 5
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS a
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 6
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 4.0
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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6HS
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APPENDIX 7
COUNTRY-SPECIFIC REQUIREMENTS
Criterion to exclude HIV positive participants where country or local regulations require 
testing:
Country-specific language
Section 2 Flow Chart/Time and Events
Schedule, Table 2-1: Screening
Assessments- LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 1.a
“Known history of testing positive for human
immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS)”to be replaced with
“Positive test for HIV”.
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APPENDIX 8 
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 05, 13-Feb-2022
The purpose of Protocol Amendment 05 is to address the timing of interim and final disease-free 
survival (DFS) analyses in Part A, which were initially planned to occur within 6 months of each 
other. However, the earlier versions of the protocol did not capture the scenario where in which 
the interim and final analyses of DFS in Part A occurring in a shorter time interval that could occur 
in the following instances: 
• the number of DFS events needed for final analysis can be observed sooner after observing 
those needed for interim analysis.
• the total enrollment of both Part A and Part B is expected to be complete closer to the date 
of DFS final analysis and the criteria to conduct the DFS interim analysis (204 DFS events 
and enrollment close for the study) is not met.
The amendment is based on the need to address how the formal interim analysis of DFS in Part A 
would be handled for the above scenario.
With a milestone blinded data transfer received from the BICR vendor through the end of January 
2022, BMS observed 202 DFS events in Part A. Because the enrollment in Part B was ongoing 
(and still ongoing at the time of this amendment), the pre-specified criteria to perform the database 
lock was not met for conducting the interim analysis of DFS in Part A. Consequently, BMS could 
not proceed with a database lock for the interim analysis of DFS in Part A. The event projections 
have showed that the target number of events for final DFS analysis  
is expected approximately 
within 4 months from the time of observing the events needed for the interim DFS analysis. Due 
to these  
reasons,  BMS  believes  
that there  are operational  challenges  
to  perform  an  
interim  and 
final  analysis  close  
to one  another.  However, the  scenario  
to  proceed  directly  
to the  
final  DFS 
analysis in Part A was not pre-specified in the earlier versions of the protocol. As a result, BMS is 
issuing a protocol amendment to include this scenario with DFS final analysis only. Table 10.1.12 
gives details on the alpha, critical hazard ratio, target number of events for the newly added DFS 
final analysis only scenario in Part A. 
This amendment incorporates the changes from the approved Administrative Letters 09 and 10, 
which are detailed in the Document History but not listed in the Summary of Key Changes below. 
Additional  
revisions,  
including  sections  of  
the  protocol  synopsis,  have  been  made  
to  align  
the 
protocol with respect to these changes. Minor formatting and typographical corrections have been 
made, therefore have not been summarized.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title 
Description of Change
Brief Rationale
Section 10.1.1: Part A: 
Combination Comparison of 
DFS
Parameters and schedule of analysis 
for final DFS analysis alone in Part 
A were added. Also, summary 
Table 10.1.1-2 was added.
In the event that Part B enrollment is 
still ongoing at the time of observing 
the required number of events for the 
interim analysis and target number of 
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Table 10.1.1-2: Part A Summary 
of Sample Size Parameters and 
Schedule of Combination 
Analysis (without an Interim 
Analysis)
Section 10.3.4: Interim Analyses 
and Hierarchical Testing 
events needed for the final analysis is 
projected in a shorter time interval 
(approximately within 4 months), the 
interim analysis of DFS will not be 
performed and only one final analysis 
of DFS will be conducted.
Table 10.1.1-1: Part A Summary 
of Sample Size Parameters and 
Schedule of Combination 
Analyses (with an Interim 
Analysis) 
Table title has been updated and 
primary analysis population is 
clarified in the table.
Clarification is provided to reflect the 
population to be used.
Table 10.1.2-1: Part B Summary 
of Sample Size Parameters and 
Schedule of Monotherapy 
Analyses
Primary analysis population is 
clarified in the table.
Table 10.3.1-1: Censoring 
Scheme Used in Primary 
Definition of DFS 
Text in Situation column of the 
table was added to include tumor-
directed surgery.
To align with the Statistical Analysis 
Plan.
Overall Rationale for the Revised Protocol 04, 27-Oct-2020
This revised protocol removes Interim Analysis 1 for disease-free survival (DFS), which was 
scheduled to take place at 43 months for Part A and 68 months for Part B, and delays the remaining 
interim analysis for DFS from Part A (previously referred to as Interim Analysis 2) from 52 to 
56 months, which is the time when the total enrollment is expected to be complete. This will allow 
for improved follow-up and data maturity for the DFS analyses. For both Part A and Part B, overall 
survival (OS) will be hierarchically analyzed at the same time as the interim or final analysis for 
DFS in the same group of subjects. In addition, protocol clarifications and/or updates are provided 
to sections indicated.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number 
& Title
Description of Change
Brief Rationale
Title page, document 
history
Changed the original protocol date to 14-Feb-
2017.
This correction was made because 
Revision 03 had an incorrect original 
protocol date.
Section 1, Synopsis, 
Study Population
Added reference to Appendix 9.
Added “(a, b, c)” after pT3.
This update was made to better 
characterize the TNM staging for our 
study population.
Section 1, Synopsis, 
Objectives and 
Endpoints
Added clarification regarding the time periods 
which will be assessed for safety and 
tolerability in the objective and endpoint. 
These updates were made to clarify 
the time periods which will be 
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number 
& Title
Description of Change
Brief Rationale
assessed for safety and tolerability in 
the objective and endpoint.
Section 1, Synopsis, 
Overall Design
Added clarification surrounding the timing 
and window permitted for follow up visits.
This update was made to ensure 
consistency and alignment across the 
protocol regarding the timing and 
permitted window for follow up 
visits.
Section 1, Synopsis, 
Figure 1 and Figure 2
Updated figures to add “(a, b, c)” after pT3.
This update was made to better 
characterize the TNM staging for our 
study population.
Section 1, Synopsis
Added language to clarify the timing and 
permitted window for follow up visits. 
This update was made to ensure 
consistency and alignment across the 
protocol regarding the timing and 
permitted window for follow up 
visits.
Section 1, Synopsis
Removed list of references.
References were moved from this 
section of the protocol to the 
References section
Section 2 Schedule of 
Activities, Table 2-1
Added note about documentation of vaccine 
use.
This update was made to ensure 
appropriate documentation of vaccine 
use for study participants.
Section 2, Schedule 
of Activities, 
Table 2-1
Added a note to Serious Adverse Events 
Assessment row to include the collection of 
all AEs (SAEs and non-serious AEs) 
associated with suspected or confirmed to 
SARS-CoV-2 infection from time of consent.
Additional criteria for AE assessment 
was incorporated to include the 
collection all AEs (SAEs or 
non-serious AEs) associated with 
SARS-CoV-2 infection from time of 
consent.
Section 2, Schedule 
of Activities, 
Table 2-2
Added clarification to AE and SAE 
Assessment row to include the collection of 
AEs (SAEs and non-serious AEs) associated 
with SARS-CoV-2 infection during the 
treatment period.
All AEs (SAEs and non-serious AEs) 
associated with SARS-CoV-2 
infection should be collected 
continuously during the treatment 
period.
Section 2, Schedule 
of Activities, 
Table 2-2
Added a note in the laboratory results section 
regarding the review of laboratory test results 
that is required prior to each dose.
This note was added to emphasize 
protocol procedure and requirement 
outlined in the protocol Section 5.1.
Section 2, Schedule 
of Activities, 
Table 2-2
Added clarifying language to ctDNA notes 
column and removed the notation to collect 
samples in Cycles 4, 7, & 10 Day 1.
Clarifying language was added to 
address ctDNA collection alignment 
with the tumor assessment schedule. 
The incorrect notation to collect 
samples in Cycles 4, 7, & 10 Day 1 
was removed, as this was entered in 
error. 
Section 2, Schedule 
of Activities, 
Table 2-2
Added row for SARS-CoV-2 serology 
collection. Samples are to be collected at 
C1D1 and C12D1 for all participants, and 
SARS-CoV-2 serology will be 
collected to assess the impact of 
SARS-CoV-2 serologic status on 
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number 
& Title
Description of Change
Brief Rationale
approximately 4 weeks after a suspected or 
confirmed SARS-CoV-2 infection.
participants receiving the 
combination of nivolumab and 
ipilimumab or nivolumab 
monotherapy in the adjuvant setting 
for RCC 
 
Section 2, Schedule 
of Activities, 
Table 2-3
Outlined the required time period for 
collection and follow up for SAEs, non-
serious AEs of special interest, all AEs (SAEs 
and non-serious AEs) associated with 
suspected or confirmed SARS-CoV-2 
infection and study treatment-related 
non-serious AEs.
Additional clarification was provided 
regarding the follow up for 
designated AEs in the post-treatment 
period.
The time period for collection for 
study treatment-related AEs is being 
extended to better characterize and 
understand late-onset AEs considered 
related to study treatment
Section 2, Schedule 
of Activities, 
Table 2-3
Added row for ctDNA collection.
An additional ctDNA collection was 
added in order to align with tumor 
assessment schedule and to evaluate 
whether ctDNA is predictive of tumor 
burden.
Section 2, Schedule 
of Activities, 
Table 2-3
Added row for SARS-CoV-2 serology
collection. Samples are to be collected at 
follow-up visit 2 and approximately 4 weeks 
after a suspected or confirmed SARS-CoV-2 
infection.
SARS-CoV-2 serology will be 
collected to assess the impact of 
SARS-CoV-2 serologic status on 
participants receiving the 
combination of nivolumab and 
ipilimumab or nivolumab 
monotherapy in the adjuvant setting 
for RCC 
 
Section 2, Schedule 
of Activities, 
Table 2-3
Clarified that timing for scans should be based 
on date of first treatment, which is considered 
Week 1.
Language was added to provide 
clarification regarding tumor 
assessment schedule calculations to 
ensure alignment with the study 
protocol criteria.
Section 2, Schedule 
of Activities, 
Table 2-3
Clarified PRO assessment timing in notes 
column and within footnotes.
Language was added to clarify the 
timing of PRO assessments.
Section 2, Schedule 
of Activities, 
Table 2-3
Updated the footnote regarding timing for 
follow up visits.
This update was made to ensure 
consistency and alignment across the 
protocol regarding the timing and 
permitted window for follow up 
visits.
Section 3, 
Introduction
Updated the text and references within the 
section.
Text and references were updated to 
better capture and cite the information 
provided in the introduction.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number 
& Title
Description of Change
Brief Rationale
Section 3, 
Introduction, 
Table 3-1
Added 3 studies.
These 3 studies were included in 
version 2 of the protocol but were 
subsequently removed. For 
consistency purposes, we are 
including them again in this revision.
Section 4, Objectives 
and Endpoints, 
Table 4-1
Added clarification regarding the time periods 
which will be assessed for safety and 
tolerability in the secondary objective and 
endpoint. 
These updates were made to clarify 
the time periods which will be 
assessed for safety and tolerability in 
the secondary objective and endpoint.
Section 4, Objectives 
and Endpoints, 
Table 4-1
Added an exploratory objective and endpoint 
to assess the association between the 
recurrence score with efficacy outcomes.
Gene-signature based score will be 
assessed in relation to efficacy 
endpoints.
Section 4, Objectives 
and Endpoints, 
Table 4-1
Added an exploratory objective and endpoint 
regarding SARS-CoV-2 serologic status.
SARS-CoV-2 serology will be 
collected to assess the impact of 
SARS-CoV-2 serologic status on 
participants receiving the 
combination of nivolumab and 
ipilimumab or nivolumab 
monotherapy in the adjuvant setting 
for RCC 
 
Section 4, Objectives 
and Endpoints, 
Table 4-1
Added an exploratory objective and endpoint 
regarding safety of nivolumab combined with 
ipilimumab and nivolumab monotherapy 
beyond 100 days and up to 1 year of last dose 
of study therapy.
Safety information will be collected 
for study treatment-related AEs 
beyond 100 days and up to 1 year of 
last dose of study therapy.
Section 5.1, Overall 
Design, Figure 5.1-1 
and Figure 5.1-2
Updated figures to add “(a, b, c)” after pT3.
Removed “Original” from Figure 5.1-1 title.
This update was made to better 
characterize the TNM staging for our 
study population.
Section 5.1, Overall 
Design
Added language about BICR recurrence 
assessment process.
Language was added to provide 
guidance on requesting BICR 
assessment of recurrence and for 
when there is a discrepancy between 
the Investigator and the BICR 
recurrence interpretation.
Section 5.1, Overall 
Design
Added clarifying language regarding the 
timing and permitted window for follow up 
visits. 
This update was made to ensure 
consistency and alignment across the 
protocol regarding the timing and 
permitted window for follow up 
visits.
Section 5.4.1, 
Rationale for 
Selection of 
Participants at 
Moderate to High 
Risk of Relapse
Added a potential efficacy assessment using 
the SSIGN score.
SSIGN score assessments may be 
performed to identify SSIGN 
intermediate and high score 
subgroups.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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7.0
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Clinical Protocol
CA209914
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number 
& Title
Description of Change
Brief Rationale
Section 6.1, Inclusion 
Criteria
Added reference to Appendix 9.
Added “(a, b, c)” after pT3.
This update was made to better 
characterize and align the TNM 
staging for our study population.
Section 6.1, Inclusion 
Criteria
Added a note regarding the assessment of 
disease status for participants being 
considered to enter the study. 
This note was added to ensure the 
safety of the participants, as a 
participant should not be consented or 
enrolled into the study if the 
Investigator is not certain the 
participant is disease free. 
Section 6.1, Inclusion 
Criteria
The following updates were made:
•
Added sub criteria (i,ii, and iii) to 
Criterion 3b)
•
Added clarification to Criterion 3c
•
Added clarification to Criterion 3d) and 
added sub criteria (i,ii, iii, and iv) to 
Criteria 3d)
•
Criterion 3e) is no longer applicable
•
The first sentence in Criterion 3f) is no 
longer applicable (the second sentence 
pertaining to WOCBP is still applicable)
•
Removed text related to male 
contraception in the last paragraph and 
added a statement regarding transmission 
of study drug to a developing fetus
These changes were made to: 
•
Provide clarification and 
additional details regarding 
inclusion and contraception 
requirements for both WOCBP
and for women who are not of 
childbearing potential
•
Remove contraceptive 
requirements for male 
participants based on current 
safety information
Section 6.2, 
Exclusion Criteria
Added a note about enrollment of patients 
with past nephrectomy or other surgical 
procedure.
This note was added to better clarify 
the exclusion of patients with a 
history of RCC and who have been 
considered cured after a nephrectomy 
or other surgical procedure in the past 
and now present with a new RCC.
Section 6.2, 
Exclusion Criteria
Added a note regarding the use of inactivated 
vaccines. 
Clarification was added regarding the 
use of inactivated vaccines.  
Section 6.2, 
Exclusion Criteria
Added a criterion regarding SARS-CoV-2 
infection.
This exclusion criterion was added to 
exclude participants with 
SARS-CoV-2 infection (either 
suspected or confirmed) within 
4 weeks prior to screening.
Section 6.2, 
Exclusion Criteria
Revised the criterion regarding the use of 
botanical preparations. 
This exclusion criterion was revised 
to provide clarification regarding the 
complementary medications that are 
not permitted within 2 weeks prior to 
first study treatment.
Section 6.2, 
Exclusion Criteria
Added a criterion regarding participation in 
other interventional trials, including those for 
COVID-19, and receipt of an investigational 
This exclusion criterion was added 
regarding participation in 
interventional trials, including those 
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number 
& Title
Description of Change
Brief Rationale
COVID-19 vaccine or other investigational 
product designed to treat or prevent 
COVID-19. 
for COVID-19, and receipt of an 
investigational SARS-CoV-2 vaccine 
or other investigational product 
designed to treat or prevent 
COVID-19.
Section 6.4.1, 
Retesting During 
Screening or Lead-In 
Period
Added statement regarding re-enrollment, 
specifically that this study permits the 
reenrollment of a participant that has 
discontinued the study as a pre-treatment 
failure (ie, participant has not been 
randomized/has not been treated). 
This statement was re-introduced in 
the protocol as it was inadvertently 
removed in Revised Protocol 02. 
Section 6.4.1, 
Retesting During 
Screening or Lead-In 
Period
Added criteria regarding SARS-CoV-2 
infection.
Language was added to provide 
guidance for SARS-CoV-2 testing 
and for when participants develop 
suspected or confirmed SARS-CoV-2 
infection during the screening period.
Section 7.1.1, 
Administration and 
Table 7.1.1-2
Added clarifying language regarding the 
duration of infusion and time between 
infusions within the section and in the 
footnote of the table. A statement was also 
added indicating that simultaneous infusions 
of nivolumab and ipilimumab will not be 
permitted.
Language was added to clarify and 
emphasize study drug administration 
requirements and expectations.
Section 7.1.1.1, 
Nivolumab
Added clarifying language regarding the 
duration of infusion.
Language was added to clarify study 
drug administration requirements and 
expectations.
Section 7.1.1.2, 
Ipilimumab
Added clarifying language regarding the 
duration of infusion.
Language was added to clarify study 
drug administration requirements and 
expectations.
Section 7.2, Method 
of Treatment 
Assignment
Added reference to Appendix 9.
This update was made to better align 
the TNM staging for our study 
population.
Section 7.3.1 
Unblinding at the 
Time of Disease 
Recurrence
Added guidance regarding the timing of the 
request for unblinding if a tumor biopsy 
collection at the time of suspected recurrence 
is planned.  
This statement was added to provide 
additional guidance surrounding the 
unblinding process. 
Section 7.4.1, Dose 
Delay Criteria for 
Study Treatment
Added Arm C to list of study arms.
Update was made to align with study 
design.
Section 7.4.1, Dose 
Delay Criteria for 
Study Treatment
Added a criterion for dose delay regarding 
SARS-CoV-2 infection.
SARS-CoV-2 infection (either 
suspected or confirmed) will meet 
criteria for dose delay.
Section 7.4.2, 
Criteria to Resume 
Treatment
Added criteria required to resume treatment 
following SARS-CoV-2 infection.
All criteria indicated regarding the 
SARS-CoV-2 infection must be met 
to resume treatment.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number 
& Title
Description of Change
Brief Rationale
Section 7.7.1, 
Prohibited and/or 
Restricted 
Treatments
Revised the statement regarding the use of 
botanical preparations.
This language was revised to provide 
clarification regarding the 
complementary medications that are 
not permitted during the study.
Section 7.7.1, 
Prohibited and/or 
Restricted 
Treatments
Added a statement regarding live/attenuated 
vaccines and inactivated vaccines during the 
treatment period.
This text was added to better clarify 
the prohibited and/or restricted 
treatments for participants enrolled in 
the study.
Section 9.1.3.2, 
Investigator 
Assessment of 
Recurrence
Clarified that timing for scans should be based 
on date of first treatment, which is considered 
Week 1.
Language was added to provide 
clarification regarding tumor 
assessment schedule calculations to 
ensure alignment with the study 
protocol criteria.
Section 9.1.3.3, 
BICR Assessment of 
Recurrence
Updated language regarding the 
de-identification of relevant 
cytology/pathology results that support a 
diagnosis of recurrence.
Language was added to provide 
guidance on the BICR recurrence 
assessment process.
Section 9.1.5, 
Outcomes Research 
Assessments
Added a statement to indicate that 
patient-reported outcome assessments should 
be completed prior to study-related 
procedures. 
Clarification was provided regarding 
the timing of patient-reported 
outcome assessments in regards to 
other study-related procedures. 
Section 9.2.1, Time 
Period and Frequency 
for Collecting AE 
and SAE Information
Outlined the required time period for 
collection for AEs associated with 
SARS-CoV-2 and those non-serious AEs 
considered related to study therapy.
Time period for collection of 
SARS-CoV-2 infection-related events 
has been added. The time period to 
collect information regarding AEs 
considered related to study therapy 
has been extended to better 
characterize and understand late-onset 
AEs considered related to study 
treatment. This will provide important 
safety data in the adjuvant setting and 
better understand the safety profile.
Section 9.2.3, 
Follow-up of AEs 
and SAEs
Outlined the required time period for 
collection for AEs associated with 
SARS-CoV-2 and those non-serious AEs 
considered related to study therapy.
Follow up expectations for 
SARS-CoV-2 infection-related events 
for those considered related to study 
therapy have been added.
Section 9.5, 
Pharmacokinetics; 
Table 9.5-1
Revised the language regarding the timing for 
follow-up samples.
This revision was made to ensure 
consistency and alignment across the 
protocol regarding the timing and 
permitted window for follow up 
visits.
Section 9.5, 
Pharmacokinetics; 
Table 9.5-1
Updated the footnote regarding the end of 
infusion-PK sampling timing.
This footnote was updated to better 
clarify the timing on end of 
infusionPK sampling.
Protocol Amendment No.: 06
Date: 08-Dec-2022
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Clinical Protocol
CA209914
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number 
& Title
Description of Change
Brief Rationale
Section 9.8, 
Biomarkers
Added a description and Table 9.8.1 to 
summarize the biomarker sampling schedule 
and requirements for the study. 
Description and Table 9.8.1 were 
added to add clarification regarding 
the biomarker sampling schedule and 
requirements for the study.
Section 9.8.1, 
Additional Research 
Collection
Added and updaed information about sample 
collection and storage.
Updated information regarding 
sample collection and storage was 
provided. 
Section 9.8.1, 
Additional Research 
Collection, 
Table 9.8.1-1
Revised the information in table regarding 
tumor biopsy sample.
This revision was made to add 
clarification regarding the additional 
research sampling schedule the study.
Section 9.8.2, Tissue 
Specimens
Added a statement indicating that tumor 
samples will be used for assessment of tumor 
recurrence score based on gene signature 
analysis.
Gene signature analysis will be 
performed on tumor samples to 
predict the risk of recurrence of the 
tumor.
Section 9.8.7, Whole 
Blood for 
Genotyping
Added language to support whole exome 
sequencing assessment on whole blood 
samples.
Statement was added to allow a 
whole exome sequencing assessment 
to be performed on whole blood 
samples.
Section 9.8.8 
Immunogenicity 
Assessments
Added reference to Table 9.5-1.
This reference was added because the 
immunogenicity sampling schedule is 
provided in Table 9.5-1.
Section 9.8.9, Other 
Assessments
Added language on samples collected to 
assess SARS-CoV-2 serologic status.
Serum will be collected for potential 
future measurements of anti-
SARSCoV-2 antibodies by serology 
(anti SARS CoV-2 total and 
immunoglobulin G [IgG]) to explore 
potential association with safety, 
efficacy, and/or immune biomarkers.
Section 10.1.1, 
Part A: Combination 
Comparison of DFS
Removed 1 interim analysis for DFS.
Updated Table 10.1.1-1.
Interim Analysis 1 for the 
combination comparison of DFS was 
removed and the remaining interim 
analysis for DFS from Part A was 
delayed to allow for improved 
follow-up and data maturity for the 
DFS analyses and to align with the 
timing when enrollment is expected 
to be complete. OS hierarchical 
combination analyses aligned with 
DFS combination analyses. Table was 
updated to reflect the removal of 
Interim Analysis 1.
Section 10.1.2, Part 
B: Monotherapy 
Comparison of DFS
Removed 1 interim analysis for DFS.
Updated Table 10.1.2-1.
Interim Analysis 1 for the 
monotherapy comparison of DFS was 
removed from Part B to allow for 
improved follow-up and data maturity 
Protocol Amendment No.: 06
Date: 08-Dec-2022
155
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930108721
7.0
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Approved
1.0
v

Clinical Protocol
CA209914
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number 
& Title
Description of Change
Brief Rationale
for the DFS analyses. OS hierarchical 
monotherapy analyses aligned with 
DFS monotherapy analyses. Table 
was updated to reflect the removal of 
Interim Analysis 1.
Section 10.3.4, 
Interim Analyses and 
Hierarchical Testing
Added details surrounding the hierarchical 
overall survival (OS) analysis, for both Part A 
and Part B, at the same time as the interim or 
final analysis for DFS in the same group of 
subjects.
Details were added regarding the 
alignment of the OS hierarchical 
monotherapy analyses with DFS 
monotherapy analyses.
Appendix 2, Study 
Governance 
Considerations
Updated appendix.
This appendix was updated to align 
with the most recent Protocol Model 
Document.
Appendix 4, Women 
of Childbearing 
Potential Definitions 
and Methods of 
Contraception
Updated appendix.
This appendix was updated to align 
with the most recent Protocol Model 
Document.
Appendix 9, 
Correlations of 
Classifications in 
Cancer Staging 
Systems
Added appendix.
This appendix was added to address 
correlations of classifications across 
cancer staging systems used in this 
study. 
Throughout 
Document
Updated “patient” terminology to 
“participant” throughout the document, where 
applicable.
This update was made to ensure 
alignment and consistency regarding 
terminology throughout the 
document. 
Overall Rationale for the Revised Protocol 03, 01-Nov-2019
As the treatment of RCC landscape continues to evolve, accumulative evidence showed a single-
agent activity for anti-PD-1 or anti-PD-L1 monotherapy in the 1L treatment of advanced RCC. 
Single-agent activity of anti-PD1 in the 1L metastatic setting supports the evaluation of nivolumab 
as monotherapy. 
The original study design of the study will remain unchanged and will be designated as Part A of 
the study. The addition of a monotherapy arm in Part B of the study allows for assessment of the 
clinical benefit, as measured by disease free survival (DFS) with OS as a key secondary endpoint, 
provided by nivolumab monotherapy and the contribution of ipilimumab to the benefit observed 
with combination therapy. If the safety profile is acceptable and nivolumab monotherapy or 
nivolumab combined with ipilimumab is shown to improve DFS, this study would support the 
approval of nivolumab or nivolumab combined with ipilimumab in treatment-naive advanced RCC 
participants post-surgery.
Protocol Amendment No.: 06
Date: 08-Dec-2022
156
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930108721
7.0
v
Approved
1.0
v

Clinical Protocol
CA209914
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number 
& Title
Description of Change
Brief Rationale
Section 2, Table 2-2 
On-Treatment 
Procedural Outline
ctDNA collection added
To explore utility as a biomarker 
associated with clinical efficacy (less 
invasive than tumor biopsy) 
Section 2, Table 2-3
Clarified that anti-tumor therapies are to be 
collected in survival follow up. 
Clarification added on timing of PRO 
collection during follow-up and survival
To clarify language
To clarify language and to collect 
long-term PRO assessments
Section 3, Table 3-1
Updated with most recent listing, and data 
from clinical trials
Update was done to provide the most 
recent data and keep the protocol 
current
Section 3.1, Study 
Rationale
Updated to provide rationale for inclusion of 
the Part B treatment into the study design. 
To elucidate on the rationale for 
including a Part B into the study
Section 3.1.1 
Research Hypothesis 
Updated to reflect in the addition of Part B 
into the study. 
Incorporation of Part B provides 
Section 3.2.1.1 
Updated background information on 
nivolumab in RCC was added. 
Incorporate recent data on 
monotherapy in the RCC setting and 
also combination therapy with 
ipilimumab. 
Section 3.3 
Benefit/Risk 
Assessment
Updated to include discussion of nivolumab 
monotherapy
To elucidate on the benefit/risk 
assessment for including a Part B into 
the study
Section 4 Objectives
Revised to include the objectives for Part B of 
the study. 
Primary and secondary objectives 
were updated to incorporation Part B 
of the study. 
Section 5.1 Overall 
Design 
Updated to reflect incorporation Part B in the 
study design: updated number of participants, 
randomization arms, and schema
Updated with the details of Part B.  
Section 5.2, Number 
of Participants
Updated the number of participants to account 
for Part A and Part B of the new study design.  
The sample size was increased for 
incorporation of Part B.
Section 5.4.4, 
Rationale for 
Nivolumab 
Monotherapy
Rationale for the addition of the Part B study 
added. 
To elucidate on the rationale for the 
addition of the new monotherapy arm 
in Part B.
Section 5.5.2, 
Justification for Dose 
of Nivolumab 
Monotherapy 
Treatment Added.  
Updated to incorporate justification for 
nivolumab 240 mg as monotherapy. 
To elucidate on the dosing 
justification on the new monotherapy 
arm
Section 6.2, 
Exclusion Criteria
Added exclusion criteria for participants that 
have received a live vaccine within 30 days of 
first dose. 
Update was made to reflect the 
current program-level exclusion 
criteria
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number 
& Title
Description of Change
Brief Rationale
Section 7.1.1, Table 
7.1.1-2 Dosing 
Schedule 
Added treatment for each cycle for Arm C in 
Part B. 
To provide dosing details on the new 
monotherapy arm, Arm C in Part B.
Section 7.7.3
Permitted therapy
Added a statement to indicate that 
concomitant medications are also to be 
recorded in the appropriate section of the CRF 
within 100 days of the last dose date of study 
drug 
To clarify when concomitant 
medications are to be recorded during 
the study
Section 9.1.5 
Outcomes Research 
Assessment 
Clarified description of FKSI-19. 
To add more granularity on the 
FKSI-19 description
Section 9.2.9 
Management 
Algorithms
Added myocarditis algorithm
Update was made to reflect the 
current program-level myocarditis 
algorithm
Section 9.8.6 
Peripheral Blood 
DNA Mutation 
Research 
Added for collection of ctDNA
To explore utility as a biomarker 
associated with clinical efficacy (less 
invasive than tumor biopsy)
Section 10.1 Sample 
Size Determination; 
Section 10.1.2 
Monotherapy 
Comparison of DFS
Sample Size section was updated to reflect 
sample size determinations for Part A and B. 
Part A remains intact as the original 
design, Part B determinations were 
added (Section 10.1.2) to reflect 
determination of sample size for 
monotherapy comparison of DFS. 
Section 10.1.3 
Contribution of 
Components 
Analysis of DFS
CoC description added. 
CoC description and timing added to 
the protocol. 
Section 10.2, 
Populations for 
Analyses 
Populations for Part B analyses have been 
added. 
To reflect the additional populations 
for analyses in Part B. 
Section 10.3.3.3 
Outcomes Research 
Analyses 
Updated to include clarification of analyses 
Updated to include nivolumab vs placebo 
comparisons. 
To clarify intended outcome research 
analyses
Section 10.3.4 
Interim Analyses and 
Hierarchical Testing
Updated to include interim analyses for Part A 
and B, and to include description of 
hierarchical testing 
To clarify intended interim analyses, 
and hierarchal testing that will occur 
for the OS interim analysis. 
Overall Rationale for the Revised Protocol 02, 06-Apr-2018
The purpose of this revised protocol is to reduce frequency of patient questionnaires, update 
exclusion criteria 3f for serum creatinine, and provide additional information and/or clarification 
to sections indicated. Typographical and grammatical errors were also corrected.
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This applies to all sites and all patients. The changes in this amendment do not impact the safety 
of participants and should be implemented after Institutional Review Board or Ethics Committee 
review.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
Title Page
Medical Monitor info updated. 
As per Administrative Letter
Synopsis Key Inclusion Criteria 
(Item a);
6.1 (Item 2a)
Wording updated to indicate clean surgical 
margins are required for all patients and 
clarified timing of nephrectomy.
Clarification of criteria
Synopsis Key Inclusion Criteria 
(Item d);
6.1 (Item 2d)
“(post-operative)” was added in NOTE:  
“...on the baseline (post-operative) tumor 
assessment...”
To clarify that this refers to the 
post-operative baseline 
assessment.
Synopsis Overall Design;
5.1 Overall Design
Changed wording regarding duration of 
time between nephrectomy and 
randomization (greater than 4 weeks and 
less than or equal to 12 weeks).
Clarification
Figures 1-1 and 5.1-1
Updated study schema was inserted.
Ease of viewing
Table 2-1
42-day screening window removed.
Randomization must occur 
within 12 weeks of surgery 
which provides for an end of 
screening timepoint. 
Table 2-1  Lab test;
Appendix 7 Country-Specific 
Requirements
Replaced Germany with “country or local 
regulations” where HIV testing required.
Appendix provides information 
regarding screening and 
exclusion criteria related to HIV 
testing.
Table 2.2 Patient Reported 
Outcomes
•
Decreased frequency of 
questionnaires.
•
Added footnote c indicating that 
Question GP5 on FSKI-19 can be left 
blank at baseline.
•
Decrease need for patient to 
complete and will provide 
sufficient timepoints for 
evaluation.
•
Participant has not received 
treatment yet and question 
asks if patient is bothered by 
side effects of treatment.
Table 2.3 Tumor Assessments
Updated allowable windows for scans.
Provide more flexibility in 
scheduling Q6 month and yearly 
scans.
Table 2.3 Tumor Assessments;
9.1.3.2 Investigator Assessment 
of Recurrence
Added bullet that tumor assessments can 
be discontinued when recurrence has been 
confirmed by BICR.
Clarification to avoid confusion.
Table 2.3 Patient Reported 
Outcomes
•
Updated information for collection.
•
Added footnotes c and d to clarify that 
PROs can be performed via telephone 
and timing for recurred patients to 
obtain questionnaires.
Clarify timing in survival 
follow-up.
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
3 Introduction;
11 References
Second to last paragraph added 
information regarding sunitinib approval in 
adjuvant in US, including a reference to 
updated NCCN guidelines.
Provide data regarding US 
approval.
Table 3-1, PROTECT
Updated outcome measure for PROTECT 
study.
Provided update since study 
completed.
3.2.1.3 Nivolumab plus 
Ipilimumab in RCC;
Tables 3.2.1.3-1, 3.2.1.3-3, 
3.2.1.3-4
Added information regarding results of 
CA209-214 - nivolumab plus ipilimumab 
in first line RCC
Provide information regarding 
combination studies and results.
5.1 Overall Design
•
Changed wording regarding duration 
of time between nephrectomy and 
randomization (greater than 4 weeks 
and less than or equal to 12 weeks).
•
Removed info related to 42-day 
screening period and re-enrollment. 
•
Added clarifications on repeat labs 
during screening.
Clarification
6.1 Inclusion Criteria
•
Item 2a wording updated to indicate 
clean surgical margins are required for 
all patients and clarified timing of 
nephrectomy. 
•
Item 2c related to N1 status added 
further language indicating one or 
more regional lymph nodes having 
positive results. 
•
Item 2d (post-operative) was added in 
NOTE:   ....on the baseline (post-
operative) tumor assessment ...
•
Clarification of criteria
•
Clarification of criteria
•
To clarify that this refers to 
the post-operative baseline 
assessment
6.2 Exclusion Criteria
•
Item 1a Germany removed and 
language updated to include all 
countries and locals where testing is 
mandated
•
Item 2c added regarding the exclusion 
of treatment with botanical 
preparations
•
Item 3f changed to exclude for serum 
creatinine of >1.5 x ULN unless 
creatinine clearance is ≥ 40 ml/min
•
Clarify exclusion of HIV 
positive participants in areas 
where testing is mandated. 
•
Nivolumab program 
language
•
Updated to reflect standard 
used in program allowing 
participants with adequate 
clearance to participate
6.4.1 Retesting During 
Screening 
Removed first paragraph regarding re-
enrollment
Paragraph did not apply to 
retesting 
7 Treatment;
7.1.1 Administration;
7.1.1.2 Ipilimumab
Added percentages to IMP injection 
solution
Clarification and consistency
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
7.1.1 Administration
Updated language in last two full 
paragraphs
Clarification
Table 7.1.1-1
Revised table title to better reflect contents
Clarification
Table 7.1.1-2 
Added note indicating approximately 30 
minutes between nivolumab and 
ipilimumab infusions
Reminder/clarification
7.1.1.1 Nivolumab
Referred reader to IB for additional 
instructions on preparation.
Additional instruction
7.1.1.2 Ipilimumab
Added language regarding approximate 30 
minute between nivolumab and 
ipilimumab 
Reminder/clarification
7.2 Method of Treatment 
Assignment
Added date of nephrectomy to bulleted list 
of information required for randomization
Clarification
7.4.1 Dose Delay Criteria for 
Study Treatment
Added Grade 3 asymptomatic amylase and 
lipase as not requiring dose delay.
Nivolumab program language
7.4.2 Criteria to Resume 
Treatment
Added information on allowable systemic 
corticosteroid doses 
Clarification
7.6 Treatment Compliance
Added that source data will be verified by 
the BMS unblinded site monitor.
Clarification
7.7.1 Prohibited and/or 
Restricted Treatments
Added bullet that any botanical 
preparations are prohibited.
Nivolumab program language
7.7.3 Permitted Therapy
Changed wording slightly from 
“Physiologic replacement doses of 
systemic corticosteroids... for participants 
with adrenal insufficiency” to “Adrenal 
replacement steroid doses...”
Nivolumab program language
8.1.1 Study Treatment 
Discontinuation Criteria
Re-organized bulleted criteria into events 
that do require discontinuation and events 
that do not require discontinuation.
Clarification to avoid confusion.
9.1.2 Methods of Measurement
Revised and expanded CT/MRI text, 
including details regarding 
contraindications.
Clarification
9.1.2 Methods of Measurement
Removed references to RECIST
No lesion measurements at 
baseline so criteria not 
applicable.
9.1.3.1 Assessment of Baseline 
Disease-free Status
Changed timing of imaging performed 
post-nephrectomy from “at least” to 
“greater than” 4 weeks.
Correction
9.1.3.2 Investigator Assessment 
of Recurrence
•
Removed phrase “for the duration of 
the disease-free follow-up” from text 
regarding tumor assessments.
•
Updated General Considerations and 
replaced Table 9.1.3.2-1.
•
Avoid confusion regarding 
follow-up assessments.
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number & Title
Description of Change
Brief Rationale
•
Provide clarifications to 
criteria used to assess 
recurrence.
9.1.3.3 BICR Assessment of 
Recurrence
Additional instruction added.
Clarification
Table 9.1.4-1, Acceptable 
Imaging Assessment Methods
Added a third alternative method for 
abdomen and pelvis.
Consistency
9.2.2 Method of Detecting AEs 
and SAEs
Added text regarding collection and 
assessment of AEs.
Nivolumab program language
Table 9.5-1 PK and 
Immunogenicity Sampling 
Schedule
Added to footnote b regarding the timing 
of collecting predose samples.
Clarification
Appendix 4 WOCBP and 
Contraception
Acceptable contraception methods updated 
to include hormonal methods.
Nivolumab program language
Appendix 7 Response Criteria 
(RECIST 1.1)
Appendix removed.
RECIST criteria not used in this 
study.
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APPENDIX 9
CORRELATIONS OF CLASSIFICATIONS IN CANCER STAGING 
SYSTEMS
The CA209-914 study stratification criteria is based on the 2010, 7th edition American Joint 
Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM classification 
and Fuhrman grading and therefore, only information on these classification systems should be 
entered into the database.
The AJCC/UICC TNM (tumor, node, and metastasis) classification on cancer staging systems are 
regularly updated. The AJCC/UICC 8th edition1 was implemented in 2018 and it introduces some 
(minor) staging changes and refines some definitions, but retains most of the 7th edition 
parameters.2 Thus, in the new edition, the word “grossly” to describe renal vein and segmental 
branch invasion has been removed from the T3a, because the 7th edition had over-reliance on the 
pathologist gross inspection of the hilar vessels. However, tumor involvement of renal vessels can 
be missed grossly. In addition, for the T3a staging, the statement “Muscle containing” was changed 
to “segmental branches” and the “Invasion of pelvicalyceal system” was added as this part of the 
collecting system is within the hilum.
For the purposes of our CA209-914 study conduct, we are maintaining the Tumor staging 
equivalent between the 2010, 7th edition AJCC/UICC and the 2017, 8th edition AJCC/UICC.3
2010, 7th edition AJCC TNM 
classification
2017, 8th edition AJCC/ UICC 
TNM classification
Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor ≤7 cm in greatest dimension, limited to the kidney
T1a
Tumor ≤4 cm in greatest dimension, limited to the kidney
T1b
Tumor > 4 but ≤7 cm in greatest dimension, limited to the kidney
T2
Tumor > 7 cm in greatest dimension, limited to the kidney
T2a
Tumor >7 cm but ≤10 cm in greatest dimension, limited to the 
kidney
T2b
Tumor > 10 cm, limited to the kidney
T3
Tumor extends into major veins or perinephric tissues, but not into 
the ipsilateral adrenal gland and not beyond Gerota’s fascia
T3a
Tumor grossly extends into the 
renal vein or its segmental 
(muscle containing) branches, or 
tumor invades perirenal and/or 
renal sinus fat but not beyond 
Gerota’s fascia
Tumor extends into the renal 
vein or its segmental branches, 
or invades the pelvicalyceal 
system, or invades perirenal 
and/or renal sinus fat but not 
beyond Gerota’s fascia
T3b
Tumor grossly extends into the 
vena cava below the diaphragm
Tumor extends into the vena 
cava below the diaphragm
T3c
Tumor grossly extends into vena 
cava above diaphragm or 
invades the wall of the vena 
cava
Tumor extends into the vena 
cava above the diaphragm or 
invades the wall of the vena 
cava
T4
Tumor invades beyond Gerota’s fascia (includes contiguous 
extension into ipsilateral adrenal gland)
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Tumor grade — The AJCC 8th edition adopted the histologic grade (G1–G4) WHO/ISUP 
nucleolar grading, replacing the traditional Fuhrman nuclear grade.
However, UICC 8E has retained the use of Fuhrman for clear cell RCC and has not adopted the 
WHO/ISUP nucleolar grade-adopted 8E AJCC.
In the WHO/ISUP histologic grade, the nucleolar grade alone is sufficient to define grades 1 to 3 
for clear cell and papillary RCC.4 Aggressive histologies such as sarcomatoid and rhabdoid 
differentiation are incorporated into WHO/ISUP grade 4.
Therefore, for the purposes of our CA209-914 study conduct, we are maintaining the histologic-
grading equivalent between the Fuhrman and the WHO/ISUP systems.
Comparison of Conventional Four-Tiered Fuhrman Grading and WHO/ISUP Grading System is 
below5:
Grade
Fuhrman Grade System
WHO/ISUP Grading 
System
Nuclear Diameter 
(μm)
Nuclear 
Shape
Nucleoli
Nucleoli
1
Small (≈10)
Round/
uniform
Absent/
inconspicuous
Absent or inconspicuous 
and basophilic at ×400 
magnification
2
Large (≈15)
Irregular 
outline
Visible at ×400 
magnification
Conspicuous and 
eosinophilic at ×400 
magnification and visible 
but not prominent at ×100 
magnification
3
Larger (≈20)
Obvious 
irregular 
outline
Visible and 
prominent at ×100 
magnification
Conspicuous and 
eosinophilic at ×100 
magnification
4
Grade 3 plus bizarre 
multilobed nuclei ± 
spindle cells
Extremely unclear 
pleomorphism, 
multinucleate giant cells, 
and/or rhabdoid and/or 
sarcomatoid differentiation
References
1 American Joint Comittee on Cancer. Cancer Staging Manual, 8th Edition Updates and 
Corrections; 
2018. 
Available 
from 
URL: 
https://cancerstaging.org/references-
tools/deskreferences/pages/8eupdates.aspx
2 Paner GP, Stadler WM, Hansel DE, et al. Updates in the eighth edition of the 
tumor-node-metastasis staging classification for urologic cancers. Eur Urol 2018;73(4):560-9. 
3 Cornejo KM, Rice-Stitt T, Wu CL. Updates in staging and reporting of genitourinary 
malignancies. Arch Pathol Lab Med 2020;144(3):305-19.
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4 Delahunt B, Sika-Paotonu D, Bethwaite PB, et al. Grading of clear cell renal cell carcinoma 
should be based on nucleolar prominence. Am J Surg Pathol 2011;35(8):1134-9.
5 Samaratunga H, Gianduzzo T, Delahunt B. The ISUP system of staging, grading and 
classification of renal cell neoplasia. J Kidney Cancer VHL 2014;1(3):26-39.
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