Conditions: Renal Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 197
Healthy volunteers: no

Brief summary:
This study will generate safety data on Nivolumab given by itself in treatment of advanced Renal Cell Carcinoma (RCC). The primary objective of this study is to assess immune related side effects, also known as immune-mediated adverse events (IMAEs), in patients treated with Nivolumab.

Detailed description:

Arms:
arm 1: Nivolumab dose as specified

Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Page:
1
Protocol Number:
CA209374
IND Number:
113,463
EUDRACT Number
N/A
Date:
10-Apr-2015
Revised Date
31-Oct-2016
Clinical Protocol CA209374
A Phase 3b/4 Safety Trial of Nivolumab (BMS-936558) in Subjects with Advanced or 
Metastatic Renal Cell Carcinoma 
CheckMate 374: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 374
Revised Protocol Number: 03
Incorporates Amendment 03 and Administrative Letter 01
Study Director/Medical Monitor 
Yuanxin Rong MD
24-hr Emergency Telephone Number
USA: 1-866-470-2267
International: +1-248-844-7390
PPD Safety Hotlines: 1-888-483-7729; 1-800-201-8725
Bristol-Myers Squibb Research and Development
777 Scudders Mill Road
Plainsboro, NJ 08536
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use,
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
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who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
protocol 03
31-Oct-2016
Incorporates changes for Amendment 03 and Administrative Letter 01.
Global 
Amendment 03
31-Oct-2016

Clarification to specify that brain lesion(s) will only be assessed as 
non-target lesions

Appendix 6: Management Algorithms for Renal, Pulmonary, 
Hepatic, and Skin Adverse Events have been updated. 
Administrative 
Letter 01
17-May-2016
Study design schematics corrected to align with text changes made in 
Global Amendment 02. The study schematics will now specify that renal 
cell carcinoma patients enrolled with non-clear cell (preferred) or clear 
cell histology will be increased if the enrollment of 25 patients with brain 
metastases cannot be reached.
Revised 
protocol 02
30-Apr-2016
Incorporates changes in Amendment 02.
Global 
Amendment 02
30-Apr-2016

Eligibility changes:

Patients with previous treatment with mTOR inhibitor for 
clear-cell RCC histology are now eligible  

Patients with non-clear cell histology with up to 3 rather than 2 
prior systemic treatments are now eligible 

Patients with non-clear cell RCC histology will now include 
collecting duct and medullary RCC (Appendix 4 updated). 

New protocol section (Section 5.6.2) for additional research that may 
be conducted on specimens already collected from subjects added.
Revised 
protocol 01
02-Oct-2015
Incorporates changes in Amendment 01.
Global 
Amendment 01
02-Oct-2015
Major changes
The title of the study has been revised to reflect changes in the study 
population.
The term immune-mediated adverse events (IMAEs), replaces the term 
select adverse events for consistency with nivolumab program. Section 
6.2.2 has been added to specify these events. 
Total enrollment has been changed to 150 subjects from 250 subjects, 
with a maximum enrollment of 75 subjects with predominant clear cell 
histology and approximate enrollments of 50 subjects for non-clear cell 
and 25 subjects with brain metastases (either histology). 
Prior systemic treatments for subjects with non-clear cell histology 
may include treatment with mechanistic target of rapamycin (mTOR)
inhibitor. Subjects with non clear cell histology who otherwise qualify 
are eligible with no prior systemic treatment. 
Immune-related Response Criteria (irRC) has been removed from the 
protocol and is no longer an assessment of efficacy.  

 
Nivolumab will be administered to all enrolled subjects at a dose level 
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Document
Date of Issue
Summary of Change
of 240 mg IV every 2 weeks, replacing 3 mg/kg IV every 2 weeks as 
the dose for all enrolled subjects.
The steroid treatment and taper for brain edema is now specified in 
Section 3.4.3, Permitted Therapies.
The FACT-G assessment tool will not be administered in this study. 
Papillary Renal Cell Carcinoma subtype is specified in Appendix 4.
Appendices of the original protocol have been renumbered to reflect 
the deletion of irRC (Appendix 2 in original protocol) and the addition 
of Patient Reported Outcomes questionnaires: FKSI-19 (Appendix 2 in 
the revised protocol) and EQ-5D (Appendix 3 in the revised protocol).
Original 
Protocol
10-Apr-2015
Not applicable
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SYNOPSIS
Clinical Protocol CA209374
Protocol Title:  A Phase 3b/4 Safety Trial of Nivolumab (BMS-936558) in Subjects with Advanced or Metastatic 
Renal Cell Carcinoma 
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):  Nivolumab (BMS-936558), 240 mg every two weeks as a 30 minute (minutesIV infusion. 
Subjects may continue to receive treatment for a maximum of 24 months or until confirmed disease progression, 
unacceptable toxicity, withdrawal of informed consent or the study is discontinued by the Sponsor. Treatment can 
continue beyond initial assessment of progression as specified in Section 4.5.3.  
Study Phase:  3b/4
Research Hypothesis:  The frequency of high grade (CTCAE vs 4.0 Grade 3-5) immune-mediated adverse events 
(IMAEs) observed in patients with advanced or metastatic renal cell carcinoma who are treated with nivolumab
monotherapy will not differ from historical adverse event data in this patient population.
Objective:  
Primary Objective: 

To assess the incidence of high grade (CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs in subjects with advanced 
or metastatic renal cell carcinoma (RCC) who are treated with nivolumab monotherapy.
Secondary Objective: 

To characterize the outcome of all high grade (CTCAE v4.0 Grade 3 4 and Grade 5) IMAEs in subjects with 
advanced or metastatic RCC who are treated with nivolumab monotherapy. 
 
 
 
 
 
 
 
 
Study Design:  
This is a Phase 3b/4 safety study of nivolumab monotherapy for the treatment of patients with advanced or 
metastatic renal cell carcinoma. Approximately 180 subjects will undergo screening evaluations to determine 
eligibility within 28 days prior to first dose. Approximately 150 eligible subjects will be treated with 
240 mg nivolumab IV, over 30 minutes (minutesevery 2 weeks. Each 28-day dosing period will constitute a 
cycle.
Subjects will be enrolled into 1 of 3 treatment groups as follows:

Group 1: Subjects with predominant clear cell histology:  75 subjects (approximate)
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
Group 2: Subjects with non-clear cell histology:  50 subjects (approximate, with a minimum of 50 
subjects with non-clear cell histology).

Group 3: Subjects with brain metastases regardless of histology: 25 subjects (approximate).
Note:  If enrollment of 25 patients with brain metastases cannot be reached, the number of patients with non-clear 
cell (preferred) or clear cell histology group will be increased.
Subjects who are found on screening CT/MRI to have brain metastases will be enrolled to Group 3, if they do not 
require active treatment (radiation treatment/corticosteroids). Subjects who are found on screening CT/MRI to have 
brain metastases that require immediate treatment with radiation treatment/corticosteroids will be re-enrolled to 
Group 3 after completing active treatment. Subjects who develop brain metastases while on treatment with 
nivolumab will not be re-assigned to Group 3 but will remain in the group assigned at enrollment (See 
Section 3.4.3.2 for recommendations on palliative brain radiotherapy and resumption of treatment with nivolumab.) 
Brain lesions will be assessed only as non-target lesions.
After screening and enrollment, subjects will be treated for a maximum of 24 months on study, or until confirmed 
progression, unacceptable toxicity, withdrawal of consent, or the study is discontinued by the sponsor. Study 
treatment can continue beyond initial investigator assessed progression as specified in Section 4.5.3. The study will 
close after the last enrolled subject completes 5 years of follow up from the date of first treatment (LPFT).  
Subjects treated in the study who continue to derive benefit from the study treatment after 24 months of treatment or 
subjects who have not completed 24 months of treatment at discontinuation of the study by the Sponsor, should 
continue to be treated according to standard of care following completion of the study.
The study design schematic is presented in below.
Screening (N=180)
Study Population
Advanced or Metastatic RCC
Predominant clear cell 
histology
•At least 1but no more
than 2 prior systemic 
anti-VEGF treatments
•No more than 3 total prior 
systemic treatment 
regimens in the advanced 
or metastatic setting, may 
include mTOR inhibitor
Non-clear cell  histology
•0 – 3 prior systemic 
therapies and may include 
mTOR inhibitor
Brain metastases allowed 
if asymptomatic, without 
edema, and not receiving 
corticosteroids or radiation
PS: > or = 70% KPS
All MSKCC prognostic 
scores allowed
All MSKCC prognostic scores 
allowed
Intervention
(N=150)
Nivolumab 
240 mg IV q 2 weeks
Group 1
clear cell RCC
(n= 75 approximate)
Group 2
non-clear cell RCC
(n=50 approximate; 
minimum of 50 subjects 
with non-clear cell 
histology) 
Group 3
Subjects  with brain 
metastases
(n= 25 approximate)
If enrollment of 25 patients 
with brain metastases 
cannot be reached, the 
number of patients with 
non-clear cell (preferred) or 
clear cell histology group 
will be increased.
Treat for a maximum of
24 months
or until confirmed 
progression, unacceptable 
toxicity,  withdrawal of 
consent or discontinuation 
of the study by the 
Sponsor. 
Endpoints
Primary
• Safety: 
Immune-mediated 
adverse events 
(Grade 3-4 and 5) 
Secondary
• Characterize
Immune-mediated 
adverse events 
Grade 3-4 and 5) 
 
The study will continue until the last enrolled subject completes 
5 years of follow up from the date of first treatment (LPFT). 
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Study Population:  The study will enroll subjects with advanced (i.e., not amenable to curative surgery or radiation 
therapy) or metastatic (AJCC Stage IV) RCC with histological confirmation of predominant clear-cell or non-clear 
cell (papillary, chromophobe, translocation associated or unclassified) RCC as defined in Appendix 4.  Subjects with 
brain metastases are eligible if they are asymptomatic, without edema, and not on corticosteroids or receiving 
radiation treatment. Subjects with favorable, intermediate and poor risk categories per MSKCC Prognostic Score
(Appendix 5) are eligible for the enrollment.
Eligible subjects with clear cell histology must have received at least 1 but no more than 2 prior anti-VEGF 
therapies in the advanced metastatic setting, and no more than 3 prior systemic therapies, which may include an 
mTOR inhibitor per Amendment 02. Subjects with non-clear cell histology are eligible with up to 3 prior systemic 
therapies (including m-TOR inhibitor) or with no prior systemic therapy.
No prior neoadjuvant/adjuvant therapy is allowed for subjects with either RCC histology.  
 
 
 
 
Subjects with uncontrolled adrenal insufficiency, known history of testing positive for human immunodeficiency 
virus (HIV), known acquired immunodeficiency syndrome (AIDS), or any positive test for Hepatitis B or Hepatitis 
C virus indicating acute or chronic infection are not eligible for this study.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209374
Medication 
Potency 
IP/Non-IP 
Nivolumab (BMS-936558)
Solution for Injection
100 mg (10 mg/mL)
IP
Study Assessments:  
Assessments for safety include continuous monitoring for all adverse events using NCI CTCAE v. 4.0, including the 
IMAEs specified in Section 8.3.1.  Additional safety assessments include vital signs and oxygen saturation, physical 
measurements and target physical exam, performance status, laboratory evaluations (complete blood counts, serum 
chemistry, liver function, thyroid function) and pregnancy test as applicable and review of concomitant medications. 
To assess tumor response, CT/MRI will be performed at baseline and throughout the treatment and follow up 
periods as specified in Section 5. Additional study procedures include assessments for biomarkers, patient reported 
outcomes as evaluated by FKSI-19 and EQ-5D, and healthcare resource utilization.  
All study procedures/assessments performed during screening, during treatment with nivolumab and during follow 
up must be completed in accordance with Table 5.1-1, Table 5.1-2, and Table 5.1-3.
Statistical Considerations: 
Sample Size:  Approximately 150 subjects will be treated with nivolumab in this study. This sample size 
will allow for estimating an incidence rate of 0.67% (n=1 subject with events) with a 95% CI (confidence 
interval) of (0.02%, 3.7%), or an incidence rate of 2% (n=3 subjects with events) with a 95% CI of (0.4%, 
5.7%). Furthermore, the sample size will allow for enough events to compare incidence with historical 
adverse event data.
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Endpoints:  
Primary Endpoint: The primary objective of the study will be assessed by measuring the incidence for 
high grade (Grade 3-4 and Grade 5) IMAEs. 
The IMAEs are the following: skin, endocrinopathy, gastrointestinal, hepatic, renal, pulmonary, and 
neurologic adverse events.
Secondary Endpoints: The secondary objective of the study will be assessed by measuring the following:

median time to onset, median time to resolution (Grade 3-4) IMAEs.

percentage of subjects who received immune modulating medication (e.g. corticoidsteroids, 
infliximab, cyclophosphamide, IVIG, and  mycophenolate mofetil), or hormonal replacement 
therapy, the percentage of subjects who received ≥ 40 mg prednisone equivalents, total duration of 
all immune modulating medications given for the immune-mediated event.
 
 
 
 
 
 
 
 
 
Analyses:
Demographics, baseline disease characteristics and baseline laboratory results will be summarized using 
descriptive statistics for all treated subjects and all subjects in Groups 1, 2, and 3.
Primary Endpoint: The number and percentage of subjects who report high grade (Grade 3-4 and 
Grade 5) IMAEs will be summarized for all treated subjects. High grade (Grade 3-4 and Grade 5) IMAEs
will be tabulated using worst grade per NCI CTCAE v4.0 criteria by system organ class and Medical 
Dictionary for Regulatory Affairs (MedDRA) preferred term.
Second Endpoints:  Additional descriptive statistics for high grade (Grade 3 4 and Grade 5) IMAEs will 
include median values using the Kaplan-Meier (KM) product-limit method with 95% CI using Brookmeyer 
and Crowley of time to onset and time to resolution of IMAEs, and will be presented for all treated subjects 
in Groups 1, 2, and 3. Time to onset is calculated from first dosing date to the event onset date. If a subject 
never experienced the given AE, the subject will be censored at the last contact date. Time to resolution is 
calculated from the AE onset date to AE end date. If an AE is ongoing at the time of analysis, the time to 
resolution will be censored at the last contact date.
Management of high-grade (CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs will be characterized by 
measuring percentage of subjects who received immune modulating medication (or hormonal replacement 
therapy), percentage of subjects who received ≥ 40 mg prednisone equivalents, and total duration of all 
immune modulating medications given for the event, in all treated subjects who have experience high-grade 
(CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs and all subjects in Groups 1, 2, and 3.
 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 
. 
1.1
 
 
 
 
 
 
 
 
 
1.4 Research Hypothesis ......................................................................................... 
1.5 Objectives(s) ..................................................................................................... 
1.5.1 Primary Objectives .................................................................................. 
1.5.2 Secondary Objectives ............................................................................... 
 
1.6 
 
 
 
1.7 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.3 Permitted therapies .................................................................................. 
3.4.3.1 Focal Palliative Radiation .............................................................. 
3.4.3.2 Palliative brain radiation ............................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
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3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Management Algorithm for Nivolumab related adverse events .............. 
4.5.2 Dose Delay Criteria ................................................................................. 
4.5.2.1 Nivolumab Dose Delay Criteria ..................................................... 
4.5.3 Dose Escalations and Reductions ............................................................ 
4.5.3.1 Criteria to Resume Treatment with Nivolumab .............................. 
4.5.4 Treatment Beyond Disease Progression .................................................. 
4.5.4.1 Treatment Discontinuation Criteria for Nivolumab ....................... 
4.5.5 Treatment of Nivolumab-Related Infusion Reactions .............................. 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Screening Assessments ............................................................................. 
5.3.2 On-Study Safety Assessments and Procedures ........................................ 
5.3.3 Follow-up and Survival Procedures ........................................................ 
5.3.4 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Screening (Baseline visit) and On-Study Efficacy Assessments .............. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.6 
 
 
 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
5.9 Results of Central Assessments ........................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.2.2 Adverse Events of Interest ........................................................................ 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
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6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Primary Analyses ..................................................................................... 
8.4.3 Secondary Analyses ................................................................................. 
 
 
 
8.4.5 Pharmacokinetic Analyses ....................................................................... 
 
8.4.7 Outcomes Research Analyses .................................................................. 
8.4.8 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 RECIST 1.1 GUIDELINES .................................................................. 
 
 
 
 
 
 
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1.4
Research Hypothesis 
The frequency of high grade (CTCAE vs 4.0 Grade 3-5) IMAEs observed in patients with 
advanced or metastatic renal cell carcinoma who are treated with nivolumab monotherapy will not 
differ from historical adverse event data in this patient population.
1.5
Objectives(s)
1.5.1
Primary Objectives
To assess the incidence of high grade (CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs in subjects 
with advanced or metastatic renal cell carcinoma (RCC) who are treated with nivolumab 
monotherapy.
1.5.2
Secondary Objectives
To characterize the outcome of all high grade (CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs in 
subjects with advanced or metastatic RCC who are who are treated with nivolumab monotherapy.
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1.7
Overall Risk/Benefit Assessment
Subjects with advanced or metastatic renal cell carcinoma with clear cell histology who progress 
after prior anti-VEGF therapy and subjects with non-clear cell histology with prior treatment or no 
prior treatment represent a continued unmet medical need as progression free survival remains 
modest with subsequent or first-line therapies that may include everolimus or further anti-
angiogenic therapy.11 The clinical activity of nivolumab observed to date in RCC suggests the 
potential for improved clinical outcomes as monotherapy. Nivolumab does have the potential for 
clinically-relevant adverse events including liver toxicities, thyroiditis, pneumonitis, and diarrhea. 
However, the activity and manageable AEs profile observed with nivolumab supports the 
treatment of patients with advanced or metastatic renal cell carcinoma.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
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The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have obtained written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling
information to be provided to subjects and any updates. 
The investigator or BMS 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.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
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4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 3b/4 safety study of nivolumab monotherapy for the treatment of patients with 
advanced or metastatic renal cell carcinoma. Approximately 180 subjects will be screened to 
determine eligibility within 28 days prior to first dose. Approximately 150 eligible subjects will 
be treated every 2 weeks with 240 mg nivolumab, intravenously over 30 minutes (5 minutes). 
Each 28 day dosing period will constitute a cycle.
Subjects will be enrolled to 1 of 3 groups as follows:

Group 1: Subjects with predominant clear cell histology: 75 subjects (approximate)

Group 2: Subjects with non-clear cell histology: 50 subjects (approximate, with a minimum 
of 50 subjects with non-clear cell histology). 

Group 3: Subjects with brain metastases regardless of histology: 25 subjects (approximate).
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
Subjects who are found on screening CT/MRI to have brain metastases will be enrolled to 
Group 3 if they do not require active treatment (radiation treatment/corticosteroids)

Subjects who are found on screening CT/MRI to have brain metastases that require 
immediate treatment (radiation treatment/corticosteroids) will be re-enrolled to Group 3 
after completing active treatment

Subjects who while on treatment with nivolumab develop brain metastases will not be 
reassigned to Group 3 but will remain in the group assigned at enrollment. (See Section 
3.4.3.2 for recommendations on palliative brain radiotherapy and resumption of treatment 
with nivolumab.) 

Brain lesion(s) will only be assessed as non-target lesions.
Note:  If enrollment of 25 patients with brain metastases cannot be reached, the number of patients 
with non-clear cell (preferred) or clear cell histology group will be increased.
After screening and enrollment, subjects will be treated for a maximum of 24 months on study, or 
until confirmed progression, unacceptable toxicity, withdrawal of consent, or the study is 
discontinued by the sponsor. Study treatment can continue beyond initial investigator assessed 
progression as specified in Section 4.5.4. The study will close after the last enrolled subject 
completes 5 years of follow up from the date of first treatment (LPFT).
Subjects treated in the study who continue to derive benefit from the study treatment after 24 
months of treatment or subjects who have not completed 24 months of treatment at discontinuation 
of the study by the Sponsor, should continue to be treated according to standard of care following 
completion of the study.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
3.2
Post Study Access to Therapy
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate standard of care to treat the condition under study,
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol-related procedures that are not part of normal subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests and other requirements of the study.
2. Target Population
a) Histological confirmation of RCC subjects with:
Screening (N=180)
Study Population
Advanced or Metastatic RCC
Predominant clear cell 
histology
•At least 1but no more
than 2 prior systemic 
anti-VEGF treatments
•No more than 3 total prior 
systemic treatment 
regimens in the advanced 
or metastatic setting, may 
include mTOR inhibitor
Non-clear cell  histology
•0 – 3 prior systemic 
therapies and may include 
mTOR inhibitor
Brain metastases allowed 
if asymptomatic, without 
edema, and not receiving 
corticosteroids or radiation
PS: > or = 70% KPS
All MSKCC prognostic 
scores allowed
All MSKCC prognostic scores 
allowed
Intervention
(N=150)
Nivolumab 
240 mg IV q 2 weeks
Group 1
clear cell RCC
(n= 75 approximate)
Group 2
non-clear cell RCC
(n=50 approximate; 
minimum of 50 subjects 
with non-clear cell 
histology) 
Group 3
Subjects  with brain 
metastases
(n= 25 approximate)
If enrollment of 25 patients 
with brain metastases 
cannot be reached, the 
number of patients with 
non-clear cell (preferred) or 
clear cell histology group 
will be increased.
Treat for a maximum of
24 months
or until confirmed 
progression, unacceptable 
toxicity,  withdrawal of 
consent or discontinuation 
of the study by the 
Sponsor. 
Endpoints
Primary
• Safety: 
Immune-mediated 
adverse events 
(Grade 3-4 and 5) 
Secondary
• Characterize
Immune-mediated 
adverse events 
Grade 3-4 and 5) 
 
 
The study will continue until the last enrolled subject completes 
5 years of follow up from the date of first treatment (LPFT). 
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i)
Predominant clear-cell as defined in Appendix 4.
ii) Non-clear cell histology as defined in Appendix 4 including:
(1).papillary
(2).chromophobe 
(3).translocation associated.
(4).collecting duct
(5).medullary
(6).any pathology unclassified.
b) Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC 
Stage IV) RCC.
c) For subject with predominant clear cell histology:
i)
Must have received at least 1 but not more than 2 prior anti-VEGF therapy regimens 
(including, but not limited to sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and 
bevacizumab) in the advanced or metastatic setting
ii) Must have received no more than 3 total prior systemic treatment regimens in the 
advanced or metastatic setting, and must have evidence of progression on or after the 
last treatment regimen received and within 6 months prior to study enrollment.
iii) Subjects with prior treatment with mTOR are eligible per Amendment 02.
d) For subjects with non clear cell histology: 
i)
Must have received no more than 3 total prior systemic treatment regimens in the 
advanced or metastatic setting. Subjects with non clear cell histology and no prior 
systemic treatment are eligible for enrollment. 
e) Karnofsky Performance Status (PS) of at least 70% (Appendix 7).
f)
Measurable disease as per RECIST v1.1 (Appendix 1). Subject must have extracranial 
metastasis as measurable disease.
g) Subjects with favorable, intermediate and poor risk categories will be eligible for the study 
(MSKCC Prognostic Score, Appendix 5).
h) Subjects with brain metastases will be allowed if they are asymptomatic, without edema, 
and not on corticosteroids or receiving radiation treatment. Brain lesion(s) will only be 
assessed as non-target lesions.
Subject Re-enrollment:  This study permits the re-enrollment of a subject that has discontinued the 
study as a pre-treatment failure (ie, subjects who have not been treated). If re-enrolled, the subject 
must be re-consented and will receive a new patient identification number (PID).
3. Age and Reproductive Status
a) Males and Females, ages 18 years. 
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 drug.
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c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with nivolumab plus 5 half-lives of nivolumab (19 weeks) plus 30 days 
(duration of ovulation cycle) for a total of 23 weeks post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives
of the study drug (19 weeks) plus 90 days (duration of sperm turnover) for a total of 31 
weeks days post-treatment completion.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements.  However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
use of highly effective methods of contraception. Highly effective methods of contraception have 
a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as listed 
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Male condoms with spermicide

Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, 
injectables, implants and intrauterine devices (IUDs) such as Mirenaby WOCBP subject or 
male subject’s WOCBP partner. Female partners of male subjects participating in the study 
may use hormone based contraceptives as one of the acceptable methods of contraception since 
they will not be receiving study drug

Nonhormonal IUDs, such as ParaGard

Tubal ligation 

Vasectomy.

Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but female subjects must 
continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego complete 
abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION
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
Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge

Male Condom without spermicide 

Progestin only pills by WOCBP subject or male subject’s WOCBP partner 

Female Condom*.
* A male and female condom must not be used together
3.3.2
Exclusion Criteria
1. Medical History and Concurrent Diseases
a) Not applicable per Amendment 02: ie, subjects with predominant clear cell histology and 
prior treatment with an mTOR inhibitor (including, but not limited to, everolimus, 
temsirolimus, sirolimus, and ridaforolimus) are no longer excluded from this study.
b) Subjects with any active autoimmune disease or a history of known autoimmune disease. 
Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune 
condition only requiring hormone replacement, psoriasis not requiring systemic treatment, 
or conditions not expected to recur in the absence of an external trigger are permitted to 
enroll.
c) Any condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 14 days prior to first dose of 
study drug. Inhaled steroids and adrenal replacement steroid doses >10mg daily prednisone 
equivalents are permitted in the absence of active autoimmune disease.
d) Subjects with uncontrolled adrenal insufficiency.
e) 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.
f)
Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).
g) Any positive test for Hepatitis B or Hepatitis C virus indicating acute or chronic infection.
h) Known or underlying medical condition (eg, a condition associated with diarrhea or acute 
diverticulitis) that, in the investigator’s opinion, would make the administration of study 
drug hazardous to the subject or obscure the interpretation of toxicity determination or 
adverse events.
i)
Major surgery (eg nephrectomy) less than 28 days prior to first dose of study drug. Minor 
surgery less than 14 days prior to first dose of study drug.
j)
Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody (or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways); subjects who participated in CA209016 or were randomized in 
CA209214 are not eligible. 
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k) Anti-cancer therapies, including prior treatment with mTOR inhibitor must be discontinued 
at least 14 days prior to administration of study drug. If patient has received prior 
bevacizumab, then therapy must have been discontinued at least 21 days prior to 
administration of study drug. Palliative, focal or whole brain radiation therapy must be 
discontinued at least 2 weeks before administration of study drug.
l)
All toxicities attributed to prior anti-cancer therapy other than alopecia must have resolved 
to grade 1 (NCI CTCAE version 4) or baseline before administration of study drug.
2. Physical and Laboratory Test Findings
All baseline laboratory parameters should be obtained within 14 days (unless otherwise specified 
in Table 5.1-1) of first dose of study drug. 
i)
WBC < 2000/µL
ii)
Neutrophil < 1500/µL
iii)
Platelets < 100 x 103/µL
iv)
Hemoglobin < 9.0 g/dL
v)
AST > 3.0 x ULN
vi)
ALT > 3.0 x ULN
vii)
Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total
bilirubin < 3.0 mg/dL)
viii)
Serum 
creatinine 
of
> 2.0 X ULN 
(upper 
limit 
of 
normal) 
or 
creatinine clearance < 30 mL/minute (using Cockcroft/Gault formula)
Female CrCl  =
(140- age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CrCl      =
(140- age in years) x weight in kg x 1.00
72 x serum creatinine in mg/ dL
3. Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal antibodies.
4. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated.
b) Subjects 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 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
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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 > 
40mIU/mL to confirm menopause.
*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 judgment 
in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during the 
washout period, the woman can be considered postmenopausal:

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.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event):
 
 
Prior radiotherapy must have been completed at least 2 weeks prior to starting study treatment.
See Section 3.4.3 for guidance on concomitant palliative radiotherapy.
3.4.2
Other Restrictions and Precautions
Subjects with active, known or suspected autoimmune disease are excluded. Subjects 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.
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of starting 
treatment 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.
3.4.3
Permitted therapies
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
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prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted. Steroid treatment 
specified as ≤ 16 mg dexamethasone PO daily tapered in ≤ 4 weeks is allowed only for the 
treatment of brain edema. 
Concomitant palliative and supportive care for disease related symptoms (including 
bisphosphonates and RANK-L inhibitors) is allowed if initiated prior to first dose of study therapy.
3.4.3.1
Focal Palliative Radiation
The potential for overlapping toxicities with radiotherapy and nivolumab currently is not known. 
Therefore, palliative radiotherapy is not recommended while receiving nivolumab. If palliative 
radiotherapy is required for bone metastases then nivolumab should be withheld for at least 1 week 
before, during, and 1 week after radiation. Subjects should be closely monitored for any potential 
toxicity during and after receiving radiotherapy, and AEs should resolve to Grade 1 prior to 
resuming nivolumab.  Only bone lesions may receive palliative radiotherapy. Details of palliative 
radiotherapy should be documented in the source records and electronic case report form (eCRF). 
Details in the source records should include: dates of treatment, anatomical site, dose administered 
and fractionation schedule, and adverse events. Subjects receiving limited field palliative radiation 
therapy will be considered to have unequivocal progression of disease in the non-target lesion. 
Symptoms requiring palliative radiotherapy should be evaluated for objective evidence of disease 
progression. Administration of additional nivolumab to subjects who received limited field 
palliative radiation should follow guidelines specified in Section 4.5.4, Treatment beyond Disease 
Progression
3.4.3.2
Palliative brain radiation
The potential for overlapping toxicities with brain radiotherapy and nivolumab is not known. 
Therefore palliative brain radiotherapy is not recommended while receiving nivolumab.
Subjects receiving limited field palliative brain radiation therapy will be considered to have 
unequivocal progression of disease in the non-target lesion. Administration of additional 
nivolumab to subjects who received limited field palliative radiation should follow guidelines 
specified in Section 4.5.4, Treatment beyond Disease Progression.
If subjects require palliative brain radiation, nivolumab will be held for at least one week prior to 
brain radiation, during and 2 weeks following radiation. Subjects should be closely monitored for 
potential toxicity during and after receiving radiotherapy and AEs should resolve to Grade 1 prior 
to resuming treatment with nivolumab.
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3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the subject

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

Study specific criteria for discontinuation of treatment with nivolumab are presented in 
Section 4.5.4.1.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
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 drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
NOTE: A 4-week washout (minimum) of nivolumab is recommended for subjects who are 
discontinued from treatment with nivolumab for any reason and are being considered for 
treatment with mTOR inhibitor. 
3.6
Post Study Drug Study Follow up
In this study, safety is a key endpoint of the study. Post study follow-up is of critical importance 
and is essential to preserving subject safety and the integrity of the study. Subjects who discontinue 
study drug 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.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug 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 subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
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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 drug 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 subject 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.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the 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 subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’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 subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) see Table 4-1 and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)

Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
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CA209374
BMS-936558
nivolumab
4.1
Investigational Product
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.
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 subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
For this study the investigational product is BMS-936558 (nivolumab). 
4.2
Non-investigational Product
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. 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug 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 drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Study drug 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).
The product storage manager should ensure that the study drug 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 drug arise, the study drug should not be dispensed 
and contact BMS immediately.
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).
Infusion-related supplies (eg IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by
the sponsor and should be purchased locally if permitted by local regulations.
For non-investigational product, if marketed product is utilized, it should be stored in accordance
with the package insert, summary of product characteristics (SmPC), or similar.
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nivolumab
Please refer to the current version of the Investigator Brochure and/or pharmacy reference sheets
for complete storage, handling, dispensing, and infusion information for BMS-936558
(nivolumab).
Nivolumab (BMS-936558) vials must be stored at a temperature of 2°C to 8°C and should be
protected from light, freezing, and shaking. If stored in a glass front refrigerator, vials should be
stored in the carton. Recommended safety measures for preparation and handling of nivolumab
include laboratory coats and gloves.
For details on prepared drug storage and use time of nivolumab under room temperature/light and 
refrigeration, please refer to the BMS-936558 (nivolumab) Investigator Brochure section for
“Recommended Storage and Use Conditions” and/or pharmacy reference sheets. Care must be
taken to assure sterility of the prepared solution as the product does not contain any antimicrobial
preservative or bacteriostatic agent. No incompatibilities between nivolumab and polyolefin bags 
have been observed.
Please refer to the current BMS-936558 (nivolumab) Investigator Brochure: Preparation 
instructions for details on the administration of nivolumab.
4.4
Method of Assigning Subject Identification
After the subject’s eligibility is established and informed consent has been obtained, the subject 
will be enrolled and a number will be assigned through an interactive voice response system 
(IVRS). Also, the IVRS will be used to manage enrollment of subject subgroups. Specific 
instructions and procedures for using IVRS will be provided to the investigational site in a separate 
document/ manual.
The investigator (or designee) will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:

Date of informed consent

Date of birth

Gender at birth

Confirmed RCC histology

Confirmed presence or absence of brain metastases
4.5
Selection and Timing of Dose for Each Subject
Subjects will receive treatment every 2 weeks with 240 mg of nivolumab as a 30 minute 
(minutesIV infusion.
There will be no dose escalations or reductions of nivolumab allowed. Subjects may be dosed no 
less than 12 days from the previous dose. There are no premedications recommended for 
nivolumab on the first cycle. If an acute infusion reaction is noted, subjects should be managed 
according to Section 4.5.5.
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nivolumab
4.5.1
Management Algorithm for Nivolumab related adverse events
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
from 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 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
The above algorithms are found in the nivolumab Investigator Brochure, and can also be found in 
Appendix 6 of this protocol.
For subjects expected to require more than 4 weeks of corticosteroids or other immunosuppressants 
to manage and adverse event, consider recommendations provided in Adverse Event Management 
Algorithms in Appendix 6.
4.5.2
Dose Delay Criteria
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed.
4.5.2.1
Nivolumab Dose Delay Criteria
Nivolumab administration should be delayed for the following:

Any Grade 2 non-skin, drug-related adverse event, with the following exceptions:

Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay

Any Grade 3 skin, drug-related adverse event

Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, or total bilirubin:

Grade 3 lymphopenia or leukopenia does not require dose delay

If a subject has a baseline AST, ALT or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade 2 toxicity

If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade 3 toxicity

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
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nivolumab
4.5.3
Dose Escalations and Reductions
There will be no dose modification of nivolumab.
4.5.3.1
Criteria to Resume Treatment with Nivolumab
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to Grade 
1 or baseline, with the following exceptions:

Subjects with baseline AST/ALT or total bilirubin in the Grade 1 toxicity range who require 
dose delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin 

Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may resume treatment

If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Treatment Discontinuation criteria
4.5.4
Treatment Beyond Disease Progression
As described in Section 1.3.3, accumulating evidence indicates a minority of subjects treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD. Subjects treated with 
nivolumab will be permitted to continue treatment beyond initial RECIST 1.1 defined progressive 
disease (PD) as long as the following criteria are met:
1) Investigator-assessed clinical benefit
2) Tolerance of study drug
3) Stable performance status
4) Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
5) Subject provides written informed consent prior to receiving additional nivolumab treatment, 
using an ICF describing any reasonably foreseeable risks or discomforts, or other alternative 
treatment options.
The decision to continue treatment beyond initial progression should be discussed with the BMS 
medical Monitor and documented in the study records.
A radiographic assessment/ scan should be performed within 8 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the subject is clinically deteriorating 
and unlikely to receive any benefit from continued treatment with nivolumab.
If the investigator feels that the nivolumab subject continues to achieve clinical benefit by 
continuing treatment, the subject should remain on the trial and continue to receive monitoring 
according to the Time and Events Schedule on Table 5.1-2.
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nivolumab
For the subjects who continue nivolumab study therapy beyond progression, further progression 
is defined as an additional 20% increase in tumor burden volume from time of initial PD. This 
includes an increase in the sum of all target lesions and/ or the development of new measurable 
lesions. Treatment should be discontinued permanently upon documentation of further disease 
progression
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden volume if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes which must have a short axis of 
at least 15 mm).
Subjects with global deterioration of health status (as determined by the investigator) who require 
discontinuation of treatment without objective evidence of disease progression at the time of 
treatment discontinuation should be reported as ‘symptomatic deterioration’. Every effort should
be made to document objective progression (ie, radiographic confirmation) even after 
discontinuation of treatment.
4.5.4.1
Treatment Discontinuation Criteria for Nivolumab
Tumor assessments for all subjects should continue as per protocol even if dosing is discontinued.

Nivolumab treatment should be permanently discontinued for the following:
o
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 retreatment period 
OR requires systemic treatment
o
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration 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 requires discontinuation:

AST or ALT > 5-10x ULN for > 2 weeks

AST or ALT > 10x ULN

Total bilirubin > 5x ULN 

Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN
o
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events:
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nivolumab

Grade 4 neutropenia ≤7 days does not require discontinuation

Grade 4 lymphopenia or leukopenia does not require discontinuation

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 do not require discontinuation

Isolated Grade 4 amylase or lipase abnormalities those are not associated with 
symptoms or clinical manifestations of pancreatitis. The Sponsor Medical 
Monitor designee should be consulted for Grade 4 amylase or lipase 
abnormalities.
o
Any dosing interruption lasting > 6 weeks with the following exceptions:

Dosing interruptions to manage drug-related adverse events, such as prolonged 
steroid tapers, are allowed. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the Sponsor Medical Monitor designee 
must be consulted. Tumor assessments should continue as per protocol even if 
dosing is interrupted.

Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Sponsor Medical Monitor designee. Prior to re-
initiating treatment in a subject with a dosing interruption lasting > 6 weeks, the 
Sponsor Medical Monitor designee must be consulted. Tumor assessments 
should continue as per protocol even if dosing is interrupted.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing.
4.5.5
Treatment of Nivolumab-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and reported 
as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(Version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated).

Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
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nivolumab
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours).

Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
and/or bronchodilator therapy may also be administered as appropriate. If the infusion is 
interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% 
of the original infusion rate. Monitor subject closely. If symptoms recur, then no further 
nivolumab will be administered at that visit.

For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal 
impairment, pulmonary infiltrates]. Grade 4: Life-threatening; pressor or ventilatory 
support indicated).

Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the subject 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. Subject should be monitored until the Investigator is 
comfortable that the symptoms will not recur. Nivolumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor subject 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).
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
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nivolumab
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
Arrangements for the return of study drug will be made by the responsible Study Monitor.
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nivolumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209374)
Procedure
Screening 
(28 days prior to dosing 
unless otherwise specified)
Notes
Eligibility Assessments
Informed Consent
X
Obtain consent prior to performing any testing for eligibility
IVRS
X
An IVRS will be used to assign subject numbers 
Inclusion/Exclusion Criteria
X
Medical History
X
.
Safety Assessments
Physical measurements (including 
performance status)
X
Includes height, weight, performance status (Karnofsky); baseline EKG, and a 
focused physical exam is to be performed at screening.
Vital Signs
X
Temperature, BP, HR, RR. Obtain vital signs at screening and within 48 hours of 
first dose.
Assessment of Signs and Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 14 days 
of first dose, prior to study treatment initiation.
Concomitant medications
X
Within 14 days of first dose.
Laboratory Tests
X
Labs performed locally within 14 days prior to first dose (unless otherwise 
specified): CBC with differential, serum chemistry (BUN or serum urea level, 
serum creatinine, sodium, potassium, calcium, magnesium, phosphate, chloride, 
bicarbonate, and glucose), liver function tests (AST, ALT, total bilirubin, 
alkaline phosphatase, albumin, LDH).
The following labs can be performed locally within 28 days prior to first dose: 
TSH, free T3, free T4, hepatitis B surface antigen (HBV sAg) and Hepatitis C 
antibody (HCV Ab) or Hepatitis C RNA (HCV RNA).
Pregnancy Test
X
Within 24 hours prior to first dose for WOCBP only (serum or urine at the site).
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nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209374)
Procedure
Screening 
(28 days prior to dosing 
unless otherwise specified)
Notes
Radiographic Tumor Assessment 
(Chest, Abdomen, Head)
X
Within 28 days prior to first dose. CT/MRI of brain (with contrast, unless 
contraindicated) required for all subjects. Additional sites of known or suspected 
disease (including pelvis) should be imaged at screening.
Archived Tumor Tissue or Recent 
Tumor Biopsy 
X
One formalin-fixed paraffin embedded tumor tissue block, or 15 minimum FFPE 
unstained slides are to be submitted, if available. Submit a copy of the original 
pathology report along with the sample. Tissue samples from different biopsy 
procedures are to be submitted if available with each matching pathology report 
and biopsy date. Tissue sample from the metastatic tumor can be submitted if the 
primary tumor tissue is not available.
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nivolumab
Table 5.1-2:
On-Study Procedural Outline (CA209374)
Procedure
Each Cycle 
Day 1
2nd Dose of 
Cycle
Q 8 wks from 
Day 1 Cycle 1
Notes
Safety Assessments
Targeted assessments
X
Cycle 2 and beyond. 
Assessments within 48 hrs prior to dosing to include: 
Targeted physical exam, performance status and weight. 
Oxygen saturation by pulse oximetry at rest and after 
exertion for patients who complain of dyspnea or other 
respiratory symptoms
Adverse Events Assessment
Continuously assessed using NCI CTCAE v. 4.0.
Concomitant Medications
X
X
Laboratory Tests 
X
Cycle 2 and beyond: (within 72 hrs  prior to dosing)
CBC w/differential, LFTs, BUN or serum urea, creatinine. 
TSH (reflex to free T3 and free T4 if abnormal result). 
X
LFTS only (within 72 hours prior to dosing)
Pregnancy Test
X
Efficacy Assessments
Radiographic Tumor 
Assessments
X
At Week 8 (1 week) and every 8 weeks 1 week) 
thereafter,  regardless of dosing schedule for the first 13 
months then every 12 weeks+/-1 week until progression or 
treatment discontinuation whichever occurs later.
Subjects with a history of brain metastasis perform 
surveillance CT/MRI approximately every 12 weeks, or 
sooner if clinically indicated.
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nivolumab
Table 5.1-2:
On-Study Procedural Outline (CA209374)
Procedure
Each Cycle 
Day 1
2nd Dose of 
Cycle
Q 8 wks from 
Day 1 Cycle 1
Notes
Clinical Drug
Administer Study Treatment
X
X
All subjects start treatment on C1D1 and continue 
treatment every 2 weeks for a maximum of 24 months or 
until confirmed progression, unacceptable toxicity,
withdrawal of informed consent or discontinuation of the 
study by the Sponsor. Treatment for all subjects can 
continue beyond initial investigator-assessed progression.
Drug administration is +/- 2 days but no less than 12 days 
from previous dose. Study drug infusion start and stop 
times will be recorded.
Other
Patient-Reported Outcome 
Measurements
X
Prior to any study-related procedures: FKSI-19, and EQ-
5D
Health Resource Utilization
X
Prior to any study-related procedures
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Table 5.1-3:
Follow-up Procedural Outline (CA209374)
Procedure
Follow-up Visit 1 (X01) and Visit 2 
(X02).
Follow-up 
after
Visit 2 
(X02)
Notes
Follow up Visit (X01) = 30 days from last dose +/-5 days, or 
may be on date of discontinuation +/-5 days if the date of 
discontinuation is more than 35 days after last dose. Follow 
up Visit 2 (X02) = 100-114 days from last dose.
Vital Signs
X
Physical measurements
X
Includes performance status (Karnofsky)
Adverse Events Assessment
X
X*
*Beyond 100-114 days from the last dose of study therapy, 
subjects will be followed for ongoing drug-related AEs until 
resolved, return to baseline or deemed irreversible, or until lost to 
follow-up or withdrawal of study consent.
Laboratory Tests
X
CBC with differential, serum chemistry (BUN or serum urea 
level, serum creatinine, albumin, sodium, potassium, calcium, 
magnesium, phosphate, chloride, bicarbonate, glucose), liver 
function (AST, ALT, total bilirubin, alkaline phosphatase, LDH), 
thyroid function (TSH, reflex to free T3 and free T4 if abnormal 
result)
Review of concomitant 
medications
X
Pregnancy testing
X
Serum or urine
Collection of Survival 
Information
X
X
Every 3 months until death, lost to follow-up, or withdrawal of 
study consent for 5 years following start of therapy. May be
performed by phone contact or office visit.
Radiographic Tumor Assessment
X
X
For subjects who discontinue study treatment for reasons other 
than PD, follow up scans (or MRIs when appropriate) should be 
performed every 8 weeks (5 days) for the first 13 months then 
every 12 weeks+/-1 week until PD, death, lost to follow-up, or 
withdrawal of consent. Radiographic assessments should not be 
delayed until the X01 or X02.
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Table 5.1-3:
Follow-up Procedural Outline (CA209374)
Procedure
Follow-up Visit 1 (X01) and Visit 2 
(X02).
Follow-up 
after
Visit 2 
(X02)
Notes
Follow up Visit (X01) = 30 days from last dose +/-5 days, or 
may be on date of discontinuation +/-5 days if the date of 
discontinuation is more than 35 days after last dose. Follow 
up Visit 2 (X02) = 100-114 days from last dose.
Patient Reported Outcomes
FKSI-19 and EQ-5D
X
X
At X01 and X02 and then every 3 months for the first 12 months, 
then every 6 months thereafter, as permitted by local IRB. 
Assessments can be conducted by phone or mail.
Healthcare Resource Utilization
X
X
To be collected in alignment with PRO’s above (, FKSI-19 and 
EQ-5D). Assessments can be conducted by phone or mail.
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nivolumab
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or Lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (i.e., the most current result prior to first dose of 
study drug) and is the value by which study inclusion will be assessed, as it represents the subject’s 
most current, clinical state.
Retesting must be completed in accordance with Table 5.1-1.
5.2
Study Materials
The following materials will be provided at study start:

NCI CTCAE version 4.0

BMS-936558 (nivolumab) Investigational Brochure

Pharmacy Binder

Laboratory manuals for collection and handling of tissue specimens

Site manual for operation of interactive voice response system (for study enrollment)

Serious Adverse Event (or eSAE) case report forms

Pregnancy Surveillance Forms

PRO and HRU Training slides. 
Each site will be provided with PRO and HRU questionnaires. Subjects will complete these at the 
time of the scheduled visits, prior to any study procedures and study drug infusion. During the 
survival follow-up period PRO and HRU questionnaires will be collected at X01 and X02.  Beyond 
X02, the, FKSI-19, EQ-5D PRO as well as the HRU questionnaire will be administered at a 
frequency of every 3 months for the first 12 months, then every 6 months thereafter, as permitted 
by local IRB.
5.3
Safety Assessments
5.3.1
Screening Assessments
Screening assessments and procedures must be completed in accordance with Table 5.1-1. 
5.3.2
On-Study Safety Assessments and Procedures
The following assessments will be monitored as specified in Table 5.1-2 and Table 5.1-3 and will 
continue at the specified frequency until discontinuation from the study. 

Assessment within 48 hours prior to dosing to include: targeted physical exam, performance 
status and weight. Oxygen saturation by pulse oximetry at rest and after exertion for patients 
who complain of dyspnea or other respiratory symptoms.

Laboratory tests as indicated. 
Concomitant medications taken throughout the study duration should be recorded within the eCRF.
For subjects who discontinue study treatment due to toxicity, please follow the procedures for 
follow-up visits from Table 5.1-3.
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5.3.3
Follow-up and Survival Procedures
The Follow-Up Phase begins when the decision to discontinue a subject from study therapy is 
made (no further treatment with study therapy).

Subjects who discontinue treatment for reasons other than tumor progression will continue 
to have tumor assessments every 8 weeks (+1 week) for the first 13 months from 
randomization, and every 12 weeks (+1 week) thereafter until documented tumor 
progression, death, lost to follow-up, or withdrawal of consent.

Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a minimum 
of 100 days after last dose.

After completion of the first two follow-up visits, subjects will be followed every 3 months 
for survival.
5.3.4
Imaging Assessment for the Study
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.
5.4
Efficacy Assessments
5.4.1
Screening (Baseline visit) and On-Study Efficacy Assessments
Study evaluations will take place in accordance with Table 5.1-1 and Table 5.1-2, according to 
RECIST 1.1 criteria.35 High resolution CT with oral/intravenous contrast or contrast-enhanced 
MRI is the preferred imaging modalities for assessing radiographic tumor response. If a subject 
has a known allergy to contrast material, please use local prophylaxis standards to obtain the 
assessment with contrast if at all possible, or use the alternate modality. In cases where contrast is 
strictly contraindicated, a non-contrast scan will suffice. Screening assessments should be 
performed within 28 days of start of study treatment. Brain MRI is the preferred imaging method 
for evaluating CNS metastasis, and assessment is required during screening in all eligible subjects. 
All known or suspected sites of disease (including CNS) should be assessed at screening and at 
subsequent assessments using the same imaging method and technique. If more than one method 
is used at screening, then the most accurate method according to RECIST 1.1 should be used when 
recording data, and should again be used for all subsequent assessments. Bone scan, PET scan, or 
ultrasound imaging are not adequate for assessment of RECIST response. In selected 
circumstances where such modalities are the sole modality used to assess certain non-target organs, 
those non-target organs may be evaluated less frequently. For example, bone scans may need to 
be repeated only when complete response is identified in target disease or when progression in 
bone is suspected. Previously treated CNS metastases are not considered measurable lesions for 
purposes of RECIST determined response. Subjects with a history of brain metastasis should have 
surveillance MRI approximately every 12 weeks, or sooner if clinically indicated.
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Radiographic tumor assessments will be conducted at Week 8 (1 week) and every 8 weeks 
(1 week) for the first 13 months and then every 12 weeks (1 week) until disease progression or 
treatment discontinuation whichever occurs later. Tumor assessments for all subjects should 
continue as per protocol even if dosing is interrupted. Tumor measurements should be made by 
the same investigator or radiologist for each assessment whenever possible. Changes in tumor 
measurements and tumor responses to guide ongoing study treatment decisions will be assessed 
by the investigator using RECIST 1.1 (see Appendix 1 for details of RECIST 1.1). 
5.5
Pharmacokinetic Assessments
Not applicable.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.7
Outcomes Research Assessments
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 five dimension (EQ-5D) and visual analog scale (EQ-VAS).
The NCCN FKSI-19 is a 19-item scale that measures tumor specific HrQoL in kidney cancer 
patients. The FKSI-19 uses five Likert-type response categories that range from “not at all” to 
“very much”. Patients are asked to circle the response category that best characterizes their 
response over the last 7 days on 19 items that include symptoms such as lack of energy, fatigue, 
appetite, coughing, shortness of breath, pain, nausea and ability to work. 
General health status will be measured using the EQ-5D. The EQ-5D is a standardized instrument 
for use as a measure of self-reported general health status. The EQ-5D comprises 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety) and a visual analog rating scale 
(VAS). The utility data generated from the EQ-5D is recommended for and commonly used in 
health economics research analysis.
5.8
Other Assessments 
In addition, healthcare resource utilization (HRU) data (e.g., hospitalizations, non-protocol 
specified medical visits, etc) will be collected for all enrolled or treated subjects. Specifically, 
healthcare resource utilization is evaluated based on the number of medical care encounters such 
as hospital admissions and their duration, outpatient visits, diagnostic tests and procedures, 
concomitant medications and reasons for the encounters.
5.9
Results of Central Assessments
Not applicable.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
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does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject 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)

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 subject or may require intervention [eg, 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 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
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 (eg, 
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 (eg, 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)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within 
100 days of discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies, must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the eCRF.  The paper SAE/pregnancy surveillance forms are only 
intended as a back-up option when the eCRF system is not functioning.  In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
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SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, the 
original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.2.2
Adverse Events of Interest
IMAEs are specific events occurring within 100 days of the last dose of study drug (which includes 
pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, and endocrine 
abnormalities [adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes 
mellitus, and hypophysitis]), regardless of causality, for which subjects received 
immunosuppressive medication for treatment of the event. The exception to the 
immunosuppressive 
medication 
criteria 
for 
IMAEs 
is 
endocrine 
events 
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(hypothyroidism/thyroiditis, 
hyperthyroidism, 
hypophysitis, 
diabetes 
mellitus, 
adrenal 
insufficiency), which are included regardless of treatment since these events are often managed 
without immunosuppression.
Per FDA guidance, IMAE analyses included events, regardless of causality, occurring within 100 
days of the last dose. These analyses are limited to subjects who received immunosuppressive 
medication for treatment of the event, with the exception of endocrine events 
(hypothyroidism/thyroiditis, 
hyperthyroidism, 
hypophysitis, 
diabetes 
mellitus, 
adrenal 
insufficiency), which were included in the analysis regardless of treatment since these events are 
often managed without immunosuppression.
Table 6.2.2-1 provides a summary of the IMAEs category and their respective PTs.
Table 6.2.2-1:
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
PTs included under IMAE Category
Pneumonitis
Pneumonitis, Interstitial lung disease
Diarrhea/Colitis
Diarrhea, Colitis, Enterocolitis
Hepatitis
Hepatotoxicity, Hepatitis, Hepatitis acute, Autoimmune 
hepatitis, AST increased, ALT increased, Bilirubin 
increased, ALP increased
Adrenal insufficiency
Adrenal insufficiency
Hypothyroidism/Thyroiditis
Hypothyroidism, Thyroiditis
Thyroiditis acute (collapsed with thyroiditis for 
frequency), Autoimmune thyroiditis (collapsed with 
thyroiditis for frequency)
Hyperthyroidism
Hyperthyroidism
Hypophysitis
Hypophysitis
Diabetes mellitus
Diabetes mellitus, Diabetic ketoacidosis
Nephritis and renal dysfunction
Nephritis, Nephritis allergic, Tubulointerstitial 
nephritis, Acute renal failure, Renal failure, Increased 
creatinine
Rash
Rash, Rash maculopapular
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
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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).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject 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 and in accordance with SAE reporting procedures described in Section 
6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
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 6.1.1 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
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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.
6.7
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 nonserious or serious AE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
In general, for nivolumab monotherapy, the safety profile to date is similar across tumor types, 
while IMAEs of high grade (Grade 3-4) are rather uncommon. Their overall incidence was 6% in 
a previous Phase 1 trial that tested nivolumab at doses between 0.1 mg/kg to 10 mg/kg in 306 
subjects with different recurrent or refractory malignancies (MDX-03).36,37
In order to further characterize the frequency and outcome of such apparently infrequent safety 
events, the current study will treat approximately 150 subjects with nivolumab. This sample size 
will allow for estimating an incidence rate of 0.67% (n=1 subject with events) with a 95% CI 
(confidence interval) of (0.02%, 3.7%), or an incidence rate of 2% (n=3 subjects with events) with 
a 95% CI of (0.4%, 5.7%). Furthermore, the sample size will allow for enough events to compare 
incidence in large community practice with historical adverse event data.
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Table 8.1-1:
Estimated Incidence Rates and 95% CIs
Sample Size
Incidence Rate (%)
Lower 95% CI 
(%)
Upper 95% CI 
(%)
150
0.67
0.02
3.66
150
1.0
0.16
4.73
150
2.0
0.41
5.73
150
5.0
2.33
10.24
150
10.0
5.71
15.96
150
11.0
6.74
17.52
150
12.0
7.27
18.30
150
13.0
8.34
19.84
150
14.0
8.88
20.60
150
15.0
9.98
22.11
150
16.0
10.53
22.86
150
17.0
11.65
24.36
150
18.0
12.21
25.10
150
19.0
13.35
26.57
150
20.0
13.92
27.30
150
21.0
15.07
28.76
150
22.0
15.65
29.49
150
23.0
16.82
30.93
150
24.0
17.41
31.65
150
25.0
18.59
33.07
The number of subjects who are evaluable for AEs in the study will be 150. We make the 
conservative assumption based on Motzer29 that the rate of IMAEs of grades 3-5 is 13%. The 
primary goal of the present study is to address whether the rate is consistent with the rate reported 
in the Motzer study in the sense that the final 95% confidence interval is wholly less than 20%. As 
indicated in Table 8.1-1, this would happen if the observed rate is less than 13.3% or less (20/150 
or fewer grade 3-5 IMAEs). The trial has 61% power to demonstrate consistency of rates in the 
sense that the probability is 61% of showing the upper bound of the 95% confidence interval is 
less than 20% when the true rate is 13%.  The trial has 80% power to demonstrate the consistency 
of rates when then true rate is 11.5%
The observed rate may be somewhat larger than 13.3% and will still be consistent with 
expectations regarding safety, although it may raise concerns that the present population may be 
different from that of the Motzer study or that the assessment of AEs is different in the two studies. 
Only if the 95% confidence interval extends beyond 25% would the results of the study raise 
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serious safety concerns. This would happen if the observed rate is at least 18% (27/150 or more 
grade 3-5 STRAEs), see Table 8.1-1. Again assuming that the true rate is 13%, the power of the 
study, the probability that the 95% confidence interval is wholly less than 25% (and so the 
observed rate is less or equal to18%) is 95%. Also, if the true rate in the present study is actually
15%, the probability of showing that the 95% confidence interval is wholly less than 25% is 82%.
8.2
Populations for Analyses

All enrolled subjects: all subjects who signed an informed consent form and were registered 
into the IVRS. 

All treated subjects: all subjects who received any nivolumab. This is the primary population 
for safety and efficacy analyses. Subpopulation analyses will be conducted for subjects in 
Groups 1-3.

All response evaluable subjects: all treated subjects who have baseline and at least one on-
study evaluable tumor measurement.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective of the study will be assessed by measuring the incidence for high grade 
(Grade 3-4 and Grade 5) IMAEs.
The IMAEs of interest are the following: skin, endocrinopathy, gastrointestinal, hepatic, renal, 
pulmonary, and neurologic adverse events.
8.3.2
Secondary Endpoint(s)
The secondary objective of the study will be assessed by measuring the following:

median time to onset, median time to resolution of high grade (Grade 3-4) IMAEs

percentage of subjects who received immune modulating medication (e.g. corticoidsteroids, 
infliximab, cyclophosphamide, IVIG, and  mycophenolate mofetil), or hormonal replacement 
therapy, the percentage of subjects who received ≥40 mg prednisone equivalents, total 
duration of all immune modulating medications given for the IMAE and summary of subjects 
with resolution of AES after initiating these therapies.
 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographics, baseline disease characteristics and baseline laboratory results will be summarized 
using descriptive statistics for all treated subjects and all subjects in Groups 1, 2, and 3.
8.4.2
Primary Analyses
The number and percentage of subjects who report high grade (Grade 3-4 and Grade 5) IMAEs 
will be summarized for all treated subjects. High grade (Grade 3-4 and Grade 5) IMAEs will be 
tabulated using worst grade per NCI CTCAE v4.0 criteria by system organ class and Medical 
Dictionary for Regulatory Affairs (MedDRA) preferred term.
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8.4.3
Secondary Analyses
Additional descriptive statistics of high grade (Grade 3-4 and Grade 5) IMAEs will include median 
values using the Kaplan-Meier (KM) product-limit method with 95% CI using Brookmeyer and 
Crowley method of time to onset and time to resolution, and will be presented for all treated 
subjects in Groups 1, 2, and 3. Time to onset is calculated from first dosing date to the event onset 
date. The IMAEs of interest are the following: skin, endocrinopathy, gastrointestinal, hepatic, 
renal, pulmonary, and neurological adverse events. If a subject never experienced the given AE, 
the subject will be censored at the last contact date. Time to resolution is calculated from the AE 
onset date to AE end date. If an AE is ongoing at the time of analysis, the time to resolution will 
be censored at the last contact date.
Management of high-grade (CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs will be characterized 
by measuring percentage of subjects who received immune modulating medication (or hormonal 
replacement therapy), percentage of subjects who received ≥ 40 mg prednisone equivalents, and 
total duration of all immune modulating medications given for the event, in all treated subjects 
who have experience high-grade (CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs and all subjects in 
Groups 1, 2, and 3.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4.7
Outcomes Research Analyses
Descriptive summary statistics of Patient Reported Outcomes will be presented at baseline and 
each on-study time point, unless otherwise specified. Mean changes from baseline for each of the 
2 scales will be calculated for each subject at each on-study time point. In addition, subject 
compliance will be described per time point by the proportion of subjects who filled out the QoL 
assessments over the numbers of subject known to be alive and eligible for assessment at these 
time points.
8.4.8
Other Analyses 
Descriptive summary statistics of Health Care Utilization data will be presented at baseline and 
each on-study time point, unless otherwise specified.
8.5
Interim Analyses
Not applicable.
Data cuts for publication purposes will be performed until all subjects have completed the study, 
which is defined as the time point when the last enrolled subject has had the opportunity for five 
year for overall survival (OS) follow-up. 
The final analysis will be performed when all subjects have completed the study,
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STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS 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 BMS 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 BMS. 
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9.1.2.1
Source Documentation
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. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator 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, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study, (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product and 
the following non-investigational product(s). 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 subject, including unique subject identifiers
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amount transferred to another area/site for dispensing or storage

non-study disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
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 BMS 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 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic 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. For electronic CRFs, review and 
approval/signature is completed electronically through the BMS electronic data capture tool. The
investigator must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
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For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation and 
must adhere to BMS’s publication requirements as set forth in the approved clinical trial agreement 
(CTA). All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to BMS at the earliest practicable time for review, but at any 
event not less than 30 days before submission or presentation unless otherwise set forth in the 
CTA. BMS shall have the right to delete any confidential or proprietary information contained in 
any proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests.  Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence
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LIST OF ABBREVIATIONS
Term
Definition
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AT
aminotransaminases
-HCG
beta-human chorionic gonadotrophin
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLR
renal clearance
CLT
total body clearance
cm
centimeter
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CYP
cytochrome p-450
D/C
discontinue
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
ECG
electrocardiogram
eCRF
Electronic Case Report Form
eg
exempli gratia (for example)
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Term
Definition
ESR
Expedited Safety Report
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMAE
immune-mediated adverse event
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
K+
potassium
kg
kilogram
L
liter
LC
liquid chromatography
LDH
lactate dehydrogenase
MDSC
myeloid-derived suppressor cell
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Term
Definition
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
mTOR
mechanistic target of rapamycin
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
PBMC
peripheral blood mononuclear cell
PO
per os (by mouth route of administration)
PRO
patient reported outcomes
QD, qd
quaque die, once daily
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TID, tid
ter in die, three times a day
UV
ultraviolet
VEGF
vascular endothelial growth factor
VHL
Von Hippel–Lindau (tumor suppressor gene)
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Term
Definition
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
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SAP_001.pdf: 
Official Title of Study: 
A PHASE 3B/4 SAFETY TRIAL OF NIVOLUMAB (BMS-936558) IN SUBJECTS WITH 
ADVANCED OR METASTATIC RENAL CELL CARCINOMA 
CHECKMATE 374: CHECKPOINT PATHWAY AND NIVOLUMAB CLINICAL TRIAL 
EVALUATION 374 
 
NCT Number:  NCT02596035 
Document Date (Date in which document was last revised): September 9, 2016 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 3B/4 SAFETY TRIAL OF NIVOLUMAB (BMS-936558) IN SUBJECTS WITH 
ADVANCED OR METASTATIC RENAL CELL CARCINOMA
CHECKMATE 374: CHECKPOINT PATHWAY AND NIVOLUMAB CLINICAL TRIAL 
EVALUATION 374
PROTOCOL CA209-374
VERSION 2.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
1
2
STUDY DESCRIPTION ..........................................................................................6
2.1
Study Design ............................................................................................................6
2.2
Treatment Assignment..............................................................................................8
2.3
Blinding and Unblinding...........................................................................................8
2.4
Protocol Amendments...............................................................................................8
3
OBJECTIVES ..........................................................................................................9
3.1
Primary.....................................................................................................................9
3.2
Secondary.................................................................................................................9
3.3
4
ENDPOINTS..........................................................................................................10
4.1
Primary Endpoint(s) ...............................................................................................10
4.2
Secondary Endpoint(s)............................................................................................10
4.3
5
SAMPLE SIZE AND POWER...............................................................................11
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................12
6.1
Study Periods..........................................................................................................12
6.1.1
Baseline Period ......................................................................................................12
6.1.2
Post-baseline period ...............................................................................................12
6.2
Treatment Regimens...............................................................................................12
6.3
Populations for Analyses ........................................................................................12
7
STATISTICAL ANALYSES..................................................................................13
7.1
General Methods ....................................................................................................13
7.2
Study Conduct........................................................................................................13
7.2.1
Accrual...................................................................................................................13
7.2.2
Relevant Protocol Deviations..................................................................................13
7.3
Study Population ....................................................................................................14
7.3.1
Subject Disposition.................................................................................................14
7.3.2
Demographics and Other Baseline Characteristics.................................................14
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7.3.3
Medical History and Pretreatment Events...............................................................14
7.3.4
Prior Therapy Agents .............................................................................................14
7.3.5
Baseline Examinations............................................................................................15
7.4
Extent of Exposure .................................................................................................15
7.4.1
Administration of Study Therapy.............................................................................15
7.4.2
Modifications of Study Therapy ..............................................................................16
7.4.2.1
Dose Delays ...........................................................................................................16
7.4.2.2
Dose Reductions/Escalations and Infusion Interruption..........................................16
7.4.3
Concomitant Medications.......................................................................................16
7.5
Efficacy..................................................................................................................16
7.5.1
OS ..........................................................................................................................16
7.5.1.1
Survival Analysis ....................................................................................................16
7.5.1.2
Subject Follow-up...................................................................................................17
7.5.1.3
Follow-up Therapy .................................................................................................17
7.5.1.4
Analysis of Survival by Tumor Response.................................................................17
7.6
Safety.....................................................................................................................18
7.6.1
Primary Analyses....................................................................................................18
7.6.2
Secondary Analyses ................................................................................................19
7.6.3
Deaths ....................................................................................................................19
7.6.4
Serious Adverse Events...........................................................................................19
7.6.5
Adverse Events Leading to Discontinuation of Study Therapy.................................19
7.6.6
Adverse Events Leading to Dose Delay of Study Therapy........................................19
7.6.7
Adverse Events .......................................................................................................19
7.6.8
Immune Mediated Adverse Events...........................................................................19
7.6.8.1
Incidence of IMAE..................................................................................................20
7.6.8.2
Time-to onset of IMAE............................................................................................20
7.6.8.3
Time-to resolution of IMAE ....................................................................................21
7.6.8.4
Immune modulating medication for IMAE ..............................................................21
7.6.9
Multiple Events.......................................................................................................21
7.6.10
Select Adverse Events .............................................................................................21
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7.6.10.1
Incidence of select AE.............................................................................................21
7.6.10.2
Time-to onset of select AE.......................................................................................22
7.6.10.3
Time-to resolution of select AE...............................................................................22
7.6.10.4
Immune Modulating Medication for Select AE........................................................23
7.6.11
Other Events of Special Interest..............................................................................23
7.6.11.1
Incidence of other events of special interest ............................................................23
7.6.11.2
Time-to onset of other events of special interest......................................................24
7.6.11.3
Time-to resolution of other events of special interest...............................................24
7.6.11.4
Immune Modulating Medication for other events of special interest........................25
7.6.12
Laboratory Parameters...........................................................................................25
7.6.12.1
Hematology ............................................................................................................25
7.6.12.2
Serum Chemistry ....................................................................................................25
7.6.12.3
Electrolytes.............................................................................................................25
7.6.12.4
Additional Analyses ................................................................................................25
7.6.13
Vital Signs and Pulse Oximetry...............................................................................25
7.6.14
Immunogenicity Analyses........................................................................................26
7.6.15
Pregnancy ..............................................................................................................26
7.6.16
Clinical Safety Program (CSP)...............................................................................26
7.6.17
Adverse Events By Subgroup ..................................................................................26
7.8
Outcomes Research Analyses .................................................................................27
7.9
Health Care Resource Utilization............................................................................29
8
CONVENTIONS....................................................................................................29
9
CONTENT OF REPORTS .....................................................................................30
APPENDIX 1
ADVERSE EVENTS OF INTEREST DEFINITION AND 
CONVENTIONS....................................................................................32
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LIST OF TABLES
Table 2:
Protocol Amendments ..............................................................................8
Table 3:
Administration of study therapy: definition of parameters.......................15
Table 4:
Derivation of clustered AE of interest.....................................................33
LIST OF FIGURES
Figure 1:
Study Design Schematic...........................................................................7
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6
 
 
 
 
 
 
 
Research Hypothesis:  
The frequency of high grade (CTCAE v4.0 Grade 3-5) IMAEs observed in patients with 
advanced or metastatic RCC who are treated with nivolumab monotherapy will not differ from 
historical adverse event data in this patient population. 
Schedule of Analyses:
Data cuts for publication purposes will be performed until all subjects have completed the study, 
which is defined as the time point when the last enrolled subject has had the opportunity for five 
year for overall survival (OS) follow-up.
The final analysis will be performed when all subjects have completed the study.
2
STUDY DESCRIPTION
2.1
Study Design
This is a Phase 3b/4 safety study of nivolumab monotherapy for the treatment of patients with 
advanced or metastatic RCC. Approximately 180 subjects will be screened to determine 
eligibility within 28 days prior to first dose. Approximately 150 eligible subjects will be treated 
every 2 weeks with 240 mg nivolumab, intravenously over 30 minutes (±5 minutes). Each 28 
day dosing period will constitute a cycle.
Subjects will be enrolled into 1 of 3 treatment groups as follows:
•
Group 1: Subjects with predominant clear cell histology: 75 subjects (approximate)
•
Group 2: Subjects with non-clear cell histology: 50 subjects (approximate, with a 
minimum of 50 subjects with non-clear cell histology)
•
Group 3: Subjects with brain metastases regardless of histology: 25 subjects 
(approximate).
Note: If enrollment of 25 patients with brain metastases cannot be reached, the number of 
patients with non-clear cell (preferred) or clear cell histology group will be increased.
Subjects who are found on screening computed tomography (CT)/ magnetic resonance imaging 
(MRI) to have brain metastases will be enrolled to Group 3, if they do not require active 
treatment (radiation treatment/corticosteroids). Subjects who are found on screening CT/MRI to 
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have brain metastases that require immediate treatment with radiation treatment/corticosteroids 
will be re-enrolled to Group 3 after completing active treatment. Subjects who develop brain 
metastases while on treatment with nivolumab will not be re-assigned to Group 3 but will remain 
in the group assigned at enrollment
After screening and enrollment, subjects will be treated for a maximum of 24 months or until 
confirmed progression, unacceptable toxicity, withdrawal of consent, or the study is discontinued 
by the sponsor. Study treatment can continue beyond initial investigator assessed progression. 
The study will close after the last enrolled subject completes 5 years of follow up from the date 
of first treatment.
Subjects treated in the study who continue to derive benefit from the study treatment after 24 
months of treatment or subjects who have not completed 24 months of treatment at 
discontinuation of the study by the Sponsor, should continue to be treated according to standard 
of care following completion of the study.
The study design schematic is presented in Figure 1.
Figure 1:
Study Design Schematic
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2.2
Treatment Assignment
After the subject’s eligibility is established and informed consent has been obtained, the subject 
will be enrolled and a number will be assigned through an interactive voice response system 
(IVRS). Since this is a single arm study, all enrolled subjects who meet eligibility criteria will be 
treated with nivolumab at 240 mg IV every 2 weeks.
2.3
Blinding and Unblinding
Not applicable.
2.4
Protocol Amendments
This SAP incorporates the following protocol amendments.
Table 2:
Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
Global Amendment 02 
30-Apr-2016

Eligibility changes:

Patients with previous treatment with mTOR
inhibitor for clear-cell RCC histology are now 
eligible

Patients with non-clear cell histology with up 
to 3 rather than 2 prior systemic treatments are 
now eligible

Patients with non-clear cell RCC histology will 
now include collecting duct and medullary 
RCC (Appendix 4 updated).

New protocol section (Section 5.6.2) for additional 
research that may be conducted on specimens 
already collected from subjects added.
Global Amendment 01
02-Oct-2015

The title of the study has been revised to reflect 
changes in the study population.

The term immune-mediated adverse events 
(IMAEs), replaces the term select adverse events 
for consistency with nivolumab program. 

Total enrollment has been changed to 150 subjects 
from 250 subjects, with a maximum enrollment of 
75 subjects with predominant clear cell histology 
and approximate enrollments of 50 subjects for 
non-clear cell and 25 subjects with brain metastases 
(either histology).

Prior systemic treatments for subjects with non-
clear cell histology may include treatment with 
mechanistic target of rapamycin (mTOR) inhibitor. 
Subjects with non-clear cell histology who 
otherwise qualify are eligible with no prior 
systemic treatment.

Immune-related Response Criteria (irRC) has been 
removed from the protocol and is no longer an 
assessment of efficacy.

 

Nivolumab will be administered to all enrolled 
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Table 2:
Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
subjects at a dose level of 240 mg IV every 2 
weeks, replacing 3 mg/kg IV every 2 weeks as the 
dose for all enrolled subjects.

The steroid treatment and taper for brain edema is 
now specified in protocol Section 3.4.3, Permitted 
Therapies.

The FACT-G assessment tool will not be 
administered in this study.

Papillary Renal Cell Carcinoma subtype is 
specified in protocol Appendix 4.

Appendices of the original protocol have been 
renumbered to reflect the deletion of irRC 
(Appendix 2 in original protocol) and the addition 
 
 
3
OBJECTIVES
3.1
Primary
To assess the incidence of high grade (CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs in subjects 
with advanced or metastatic RCC who are treated with nivolumab monotherapy.
3.2
Secondary
To characterize the outcome of all high grade (CTCAE v4.0 Grade 3 4 and Grade 5) IMAEs in 
subjects with advanced or metastatic RCC who are treated with nivolumab monotherapy.
 
 
 
 
 
 
 
 
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4
ENDPOINTS
4.1
Primary Endpoint(s)
The primary objective of the study will be assessed by measuring the incidence for high grade 
(Grade 3-4 and Grade 5) IMAEs.
The IMAEs are the following: skin, endocrinopathy, gastrointestinal, hepatic, renal, pulmonary, 
and neurologic adverse events.
4.2
Secondary Endpoint(s)
The secondary objective of the study will be assessed by measuring the following:

median time to onset, median time to resolution of high grade (Grade 3-4 and Grade 5) 
IMAEs

percentage of subjects who received immune modulating medication (e.g. corticosteroids, 
infliximab, 
cyclophosphamide, 
Intravenous 
Immune 
Globulin 
[IVIG], 
and 
mycophenolate mofetil), or hormonal replacement therapy, the percentage of subjects 
who received ≥ 40 mg prednisone equivalents, total duration of all immune modulating 
medications given for the IMAE and summary of subjects with resolution of AEs after 
initiating these therapies.
 
 
 
 
 
 
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
Approximately 150 subjects will be treated with nivolumab in this study. This sample size will 
allow for estimating an incidence rate of 0.67% (n=1 subject with events) with a 95% CI 
(confidence interval) of (0.02%, 3.7%), or an incidence rate of 2% (n=3 subjects with events) 
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with a 95% CI of (0.4%, 5.7%). Furthermore, the sample size will allow for enough events to 
compare incidence with historical adverse event data.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Baseline Period
Baseline evaluations or events will be defined as evaluations or events that occur before the date 
and time of the first dose of study treatment.
In cases where the time (onset time of event or evaluation time and dosing time) is missing or not 
collected, the following definitions will apply:

Pre-treatment AEs will be defined as AEs with an onset date prior to but not 
including the day of the first dose of study treatment

Baseline evaluations (laboratory tests, pulse oximetry and vital signs) will be 
defined as evaluations with a date on or prior to the day of first dose of study 
treatment
If there are multiple valid assessments, the last assessment prior to the first dose of study 
treatment will be used as the baseline in the analyses. If multiple assessments are collected at the 
same date (and time if collected), the assessment with the latest database entry date (and time if 
collected) will considered as baseline. 
6.1.2
Post-baseline period
On-treatment AEs will be defined as AEs with an onset date-time on or after the date-time of the 
first dose of study treatment (or with an onset date on or after the day of first dose of study 
treatment if time is not collected or is missing). For subjects who are off study treatment, AEs 
will be counted as on-treatment if the event occurred within 30 days (or 100 days depending on 
the analysis) of the last dose of study treatment. No “subtracting rule” will be applied when an 
AE occurs both pre-treatment and post-treatment with the same preferred term and grade.
On-treatment evaluations (laboratory tests, pulse oximetry, and vital signs) will be defined as 
evaluations taken after the day (and time, if collected and not missing) of first dose of study 
treatment. For subjects who are off study treatment, evaluations should be within 30 days (or 100 
days depending on the analysis) of the last dose of study treatment.
Late emergent drug-related AEs will be defined as drug-related AEs with an onset date greater 
than 100 days after the last dose of study treatment in subjects off study treatment.
6.2
Treatment Regimens
All subjects will be treated with nivolumab.
6.3
Populations for Analyses

All enrolled subjects: all subjects who signed an informed consent form and were 
registered into the interactive voice response system (IVRS).
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
All treated subjects: all subjects who received any dose of nivolumab. This is the 
primary population for safety and efficacy analyses. Subpopulation analyses will be 
conducted for subjects in Groups 1-3.

All response evaluable subjects: all treated subjects who have baseline and at least one 
on-study evaluable tumor measurement.

All PD-L1 tested subjects: all subjects who had a tumor biopsy specimen available for 
assessment of PD-L1 expression.
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, the bulleted titles in the following subsections describe tabulations of 
discrete variables, by the frequency and proportion of subjects falling into each category. 
Percentages given in these tables will be rounded and, therefore, may not always sum to 100%. 
Continuous variables will be summarized using the mean, standard deviation, median, minimum 
and maximum values.
Time to event distribution will be estimated using Kaplan Meier techniques. This will be done 
for endpoints PFS-l, OS and DOR. Median survival time along with 95% CI will be constructed 
based on a log-log transformed CI for the survivor function S(t)4,5. Rates at fixed time points will 
be derived from the Kaplan Meier estimate and corresponding confidence interval will be 
derived based on Greenwood formula6 for variance derivation and on log-log transformation 
applied on the survivor function S(t)7.
7.2
Study Conduct
7.2.1
Accrual
The following will be presented on the enrolled population: 

Number of subjects accrued by country and investigational site

Number of subjects accrued by month.
A by-subject listing of accrual and a by-subject listing of eligibility criteria will be produced.
7.2.2
Relevant Protocol Deviations
The following programmable deviations will be considered as relevant protocol deviations. A 
table summarize the relevant protocol deviations will be present. 
Eligibility:
•
Subject having a baseline Karnofsky Performance Status less than 70%.
On-Study:
•
Subject not discontinuing study therapy upon evidence of further progression, defined as 
an additional 20% or greater increase in tumor burden from time of initial progression 
(including all target lesions and new measurable lesions).
A by subject listing will be produced.
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7.3
Study Population
7.3.1
Subject Disposition
The total number of subjects enrolled (treated or not) will be presented along with the reason for 
not being treated.
Number of subjects who discontinued treatment along with corresponding reason will also be 
tabulated.
A by-subject listing of pre-treatment subject status and a by-subject listing of end of treatment 
subject status will be produced.
7.3.2
Demographics and Other Baseline Characteristics
Descriptive statistics will be summarized the following baseline characteristics for all treated 
subjects.

Age (descriptive statistics) ; Age (<65, ≥65 and <75, ≥ 75, ≥ 65)

Gender, Race/Ethnicity, Region

Karnofsky Performance Status (<70, 70, 80, 90, 100%)

Height, weight, baseline ECG

Enrollment Group (1, 2, 3)

Histology (Clear Cell RCC, Non-Clear Cell RCC)

Brian metastases (yes/no)

All lesions: sites of diseases, number of disease sites per subject

Presence of target lesions, measurement of largest target lesion, sum of reference diameter, 
site of target lesion, procedures for evaluating target lesion

Baseline PD-L1 expression 

Baseline MSKCC risk group (Favorable, Intermediate, Poor)
By-subject listings of demographics, ECG, physical measurements, baseline disease 
characteristics will be provided.
7.3.3
Medical History and Pretreatment Events
Pretreatment events will be summarized by worst CTC grade (grade 1, 2, 3, 4, 5, unknown) by 
system organ class (SOC)/ preferred term (PT) for all treated subjects.
General medical history will be listed by subject. 
7.3.4
Prior Therapy Agents
The following will be summarized:

Number of prior systemic regimens received in advanced/metastatic setting (0, 1, 2, 3, >3)

Number 
of 
prior 
systemic 
regimens 
with 
anti-angiogenic 
agent 
received 
in 
advanced/metastatic setting (0, 1, 2, > 2)

Prior systemic regimen with cytokine agent in advanced/metastatic setting (yes or no)
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
Prior systemic regimen with FDA approved VEGF TKI agent in advanced/metastatic setting 
(yes or no)

Prior adjuvant or neo-adjuvant therapy (yes/no)

Prior surgery related to cancer (yes or no)

Prior radiotherapy (yes or no)

Prior systemic therapy classified by therapeutic class and generic name.

Prior/current other medication classified by anatomic and therapeutic classes.
Medication will be reported using the generic name. Listings of prior systemic cancer therapy, 
prior radiotherapy and prior surgery related to cancer, prior/current medications by subject will 
also be provided.
7.3.5
Baseline Examinations
Subjects with abnormal baseline physical examination will be tabulated by examination criteria.
A listing of physical examination abnormal findings by subject will also be provided.
7.4
Extent of Exposure
Analyses in this section will be performed in all treated subjects.
7.4.1
Administration of Study Therapy
The following parameters will be summarized (descriptive statistics) by treatment arm:

Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 
90 - < 110%;  ≥ 110%. 

Number of doses received (summary statistics)

Cumulative dose 

Duration of treatment: duration of treatment will be presented using a Kaplan-Meier curve 
whereby the last dose date will be the event date for subjects who discontinued study therapy.  
Subjects who are still on study therapy will be censored on their last dose date.  
A by-subject listing of extent of exposure: weight, number of doses, date of first and last dose, 
cumulative dose, relative dose intensity, duration of treatment, and reason for discontinuation
Table 3:
Administration of study therapy: definition of parameters
nivolumab
Dosing schedule per protocol
240 mg every 2 weeks 
Dose
Dose (mg) is defined as Total Dose administered (mg) at each dosing date is
collected on the CRF.
Cumulative Dose
Cum dose (mg) is sum of the doses (mg) administered to a subject during 
the treatment period.
Relative dose intensity (%)
Cum dose (mg) /[ (Last dose date - Start dose date + 14) x 240 /14 ] x 100
Duration of treatment 
Last dose date - Start dose date +1
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7.4.2
Modifications of Study Therapy  
7.4.2.1
Dose Delays
A dose will be considered as actually delayed if the delay is exceeding 2 days (i.e., greater than 
or equal to 3 days from scheduled dosing date). It is defined as (duration of previous cycle in 
days - 14). Dose delays will be divided into following categories: 3-7 days, 8-14 days, 15-42 
days, >42 days. Reason for dose delay will be retrieved from CRF dosing pages.
The following parameters will be summarized:

Number of dose delays per subject, Length of Delay and Reason for Dose Delay

Number of subjects with at least one dose delay along with reason for dose delay.
7.4.2.2
Dose Reductions/Escalations and Infusion Interruption
There will be no dose escalations or reductions of nivolumab allowed. Subjects may be dosed no 
less than 12 days from the previous dose.
Nivolumab infusion can be interrupted and/or the IV infusion rate can be reduced. This 
information will be retrieved from CRF dosing pages.
The following will be summarized:

Number of subjects with at least one infusion with iv rate reduced along with the reason of 
the rate reduction and number of infusions with IV rate reduction per subject

Number of subjects with at least one dose infusion interrupted along with the reason for the 
interruptions and number of infusions interrupted per subject 
A by subject listing of study drug administered will be provided. A batch listing number will be 
also provided.
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken 
at any time on-treatment (i.e. on or after the first day of study therapy and within 100 days 
following the last dose of study therapy), will be coded using the WHO Drug Dictionary.
The following summary tables will be provided: 

Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term) 

Immune modulating concomitant medication
A by-subject listing will accompany the tables.
7.5
Efficacy
7.5.1
OS
7.5.1.1
Survival Analysis
The OS curve will be estimated using the Kaplan-Meier (KM) product-limit method, along with 
the median and its 95% CI using Brookmeyer and Crowley method. Survival rates at different 
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time points (at 6, 12, 18, 24, and 36 months) will also be estimated using KM estimates from the 
OS curve. Associated two-sided 95% CIs will be calculated using the Greenwood formula. This 
analysis will be performed for all treated subjects and all subjects in Groups 1, 2, and 3.
The status of subjects who are censored in the OS Kaplan-Meier analysis will be tabulated for 
Group 1, 2, and 3, using following categories:

on-study (on-treatment and not progressed, on-treatment progressed, in follow-up);

off-study: (lost to follow-up, withdraw consent, etc.).
A by subject listing of overall survival will be produced.
7.5.1.2
Subject Follow-up
The currentness of follow-up for survival will be explored with the following K-M curve. The 
time between “the last known alive date” and the “Last Patient Last Visit Date” for alive subjects 
will be presented. Medians along with 95% CI using Brookmeyer and Crowley method will also 
be provided. The currentness of follow-up will be categorized into the following categories: 0 days, 
1-3 months, 3-6 months, 6-9 months, 9-12 months and ≥ 12 months.
7.5.1.3
Follow-up Therapy
Subsequent therapies will be summarized and listed.

Subsequent Therapy

Any subsequent therapy

Surgery

Radiotherapy

Subsequent systemic therapy classified by therapeutic class and generic name

By Subject Listing of Subsequent Therapy
7.5.1.4
Analysis of Survival by Tumor Response
Survival by response category will be analyzed by treatment group using the landmark method.
In the landmark method, a fixed time after the initiation of therapy is selected as a landmark for 
conducting the analysis of survival by response. Subjects still on study at the landmark time will 
be separated into two response categories according to whether they have responded before that 
time. This will assess whether survival from the landmark depends on the subject's response 
status at the landmark. Subjects who go off protocol (e.g. subjects who die) before the time of 
landmark will be excluded from the analysis.
The survival curves from Week 8, Month 4, Month 6, Month 8, Month 12, by response status, 
will be produced using the KM product-limit method for all treated subjects who are still at risk 
and all subjects in Groups 1, 2, and 3. Two-sided, 95% CIs for median OS will be computed.
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7.6
Safety
7.6.1
Primary Analyses
The number and percentage of subjects who report high grade (Grade 3-4 and Grade 5) IMAEs 
will be summarized for all treated subjects. High grade (Grade 3-4 and Grade 5) IMAEs will be 
tabulated using worst grade per NCI CTCAE v4.0 criteria by system organ class and Medical 
Dictionary for Regulatory Affairs (MedDRA) preferred term.
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7.6.2
Secondary Analyses
Additional descriptive statistics will include median values using the Kaplan-Meier (KM) 
product-limit method with 95% CI using Brookmeyer and Crowley of time to onset and time to 
resolution of IMAEs, and will be presented for all treated subjects in Groups 1, 2, and 3. Time to 
onset is calculated from first dosing date to the event onset date. If a subject never experienced 
the given AE, the subject will be censored at the last contact date. Time to resolution is 
calculated from the AE onset date to AE end date. If an AE is ongoing at the time of analysis, the 
time to resolution will be censored at the last contact date.
Management of high-grade (CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs will be characterized 
by measuring percentage of subjects who received immune modulating medication (or hormonal 
replacement therapy), percentage of subjects who received ≥ 40 mg prednisone equivalents, and 
total duration of all immune modulating medications given for the event, in all treated subjects 
who have experience high-grade (CTCAE v4.0 Grade 3-4 and Grade 5) IMAEs and all subjects 
in Groups 1, 2, and 3.
7.6.3
Deaths
See Section 7.6.1 of Core Safety SAP
7.6.4
Serious Adverse Events
See Section 7.6.2 of Core Safety SAP
7.6.5
Adverse Events Leading to Discontinuation of Study Therapy
See Section 7.6.3 of Core Safety SAP
7.6.6
Adverse Events Leading to Dose Delay of Study Therapy
See Section 7.6.4 of Core Safety SAP
7.6.7
Adverse Events
See Section 7.6.5 of Core Safety SAP
7.6.8
Immune Mediated Adverse Events
IMAEs are specific events occurring within 100 days of the last dose of study drug (which 
includes pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, and endocrine 
abnormalities [adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes 
mellitus, and hypophysitis]), regardless of causality, for which subjects received 
immunosuppressive medication for
treatment of the event. The exception to the 
immunosuppressive 
medication 
criteria 
for 
IMAEs 
is 
endocrine 
events 
(hypothyroidism/thyroiditis, 
hyperthyroidism, 
hypophysitis, 
diabetes 
mellitus, 
adrenal 
insufficiency), which are included regardless of treatment since these events are often managed 
without immunosuppression.
Unless otherwise specified, analyses will be performed by IMAE category on events where 
immune modulating medication was initiated. Analyses may also be repeated by categories of 
endocrine events.
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7.6.8.1
Incidence of IMAE
IMAEs will be summarized for each category:

Overall summary of any IMAEs by worst CTC grade presented by Category/PT (any grade, 
grade 3-4, grade 5)

Overall summary of any serious IMAEs by worst CTC grade presented by Category /PT (any 
grade, grade 3-4, grade 5)

Overall summary of any IMAEs leading to discontinuation by worst CTC grade presented by 
Category/PT (any grade, grade 3-4, grade 5)

Overall summary of any IMAEs leading to drug delay by worst CTC grade presented by 
Category/PT (any grade, grade 3-4, grade 5)

Overall summary of drug-related IMAEs by worst CTC grade presented by Category/PT (any 
grade, grade 3-4, grade 5)

Overall summary of drug-related IMAEs leading to discontinuation by worst CTC grade 
presented by Category/PT (any grade, grade 3-4, grade 5)

Overall summary of any IMAEs by worst CTC grade presented by Category/PT (grade 1, 2, 
3, 4, 5, unknown)

Overall summary of any serious IMAEs by worst CTC grade presented by Category/PT 
(grade 1, 2, 3, 4, 5, unknown)

Overall summary of any IMAEs leading to discontinuation by worst CTC grade presented by 
Category/PT (grade 1, 2, 3, 4, 5, unknown)

Overall summary of any IMAEs leading to drug delay by worst CTC grade presented by 
Category/PT (grade 1, 2, 3, 4, 5, unknown)
The analyses will be conducted using the 100-day safety window.
By-subject IMAE listing will be provided.
7.6.8.2
Time-to onset of IMAE
Time-to onset of the following specific events will be summarized for each category of IMAEs:

Time-to onset of any grade IMAE

Time-to onset of grade 3 to 5 IMAE

Time-to onset of any grade IMAE where immune modulating medication was initiated

Time-to onset of grade 3 to 5 IMAE where immune modulating medication was initiated
The following summary statistics will be reported for treated subjects who experienced at least 
one immune-mediated adverse event from the category: median, min and max. Median time to 
onset along with 95% confidence interval using the Kaplan-Meier technique is also reported for 
all treated subjects. If the subject did not experience a IMAE in the category, time-to onset will 
be censored at the maximum follow-up time of all subjects in their respective treatment group 
(i.e. for subjects without an event, follow-up time is defined from first dosing date up to last 
dosing date +100 days if subjects are off treatment and followed for at least 100 days, otherwise 
it is defined up to the last known alive date).
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See time-to onset definition subsection of Appendix 1 for additional details. The analyses will be 
conducted using the 100-day safety window.
7.6.8.3
Time-to resolution of IMAE
Time to resolution of the following specific events will be summarized separately for each 
category/subcategory.

Time-to resolution of  any grade IMAE

Time-to resolution of grade 3 to 5 IMAE
Time-to resolution analyses are restricted to treated subjects who experienced the specific events. 
Time-to resolution where immune modulating medication was initiated analyses is restricted to 
treated subjects who experienced the specific events and who received immune modulating 
medication during the longest IMAE.
The following summary statistics will be reported: percentage of subjects who experienced the 
specific events, percentage of subjects with resolution of the longest IMAE, median time-to 
resolution along with 95% CI (derived from Kaplan-Meier estimation) and ranges.
See time-to resolution definition subsection of Appendix 1 for additional details.
The analyses will be conducted using the 100-day safety window.
7.6.8.4
Immune modulating medication for IMAE
For each category of IMAE, the following will be reported for each treatment group:

Percentage of subjects who received immune modulating concomitant medication for 
management of other events of special interest in the category among subjects who 
experienced at least one other events of special interest in the category. 

The total medication treatment duration, duration of high dose of corticosteroid and tapering 
duration (summary statistics)
These analyses will be performed on any IMAE, grade 3-5 IMAE.
The analysis will be conducted using the 100-day safety window.
7.6.9
Multiple Events
See Section 7.6.8 of Core Safety SAP
7.6.10
Select Adverse Events
Unless otherwise specified, analyses will be performed by select AE category.  Some analyses 
may also be repeated by subcategory of endocrine events.
7.6.10.1
Incidence of select AE
Select AEs will be summarized by treatment group for each category/subcategory:

Overall summary of any select AEs by worst CTC grade presented by Category or 
Subcategory/PT (grade 1, 2, 3, 4, 5, unknown)
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
Overall summary of any select AEs by worst CTC grade presented by Category or 
Subcategory/PT (any grade, grade 3-4, grade 5)

Overall summary of drug-related select AEs by worst CTC grade presented by Category or 
Subcategory / PT (grade 1, 2, 3, 4, 5, unknown)

Overall summary of drug-related select AEs by worst CTC grade presented by Category or 
Subcategory / PT (any grade, grade 3-4, grade 5)

Overall summary of any serious select AEs by worst CTC grade presented by Category or 
Subcategory /PT (any grade, grade 3-4, grade 5)

Overall summary of drug-related serious select AEs by worst CTC grade presented by 
Category or Subcategory /PT (any grade, grade 3-4, grade 5)

Overall summary of any select AEs leading to discontinuation by worst CTC grade presented 
by Category or Subcategory /PT (any grade, grade 3-4, grade 5)

Overall summary of drug-related select AEs leading to discontinuation by worst CTC grade 
presented by Category or Subcategory /PT (any grade, grade 3-4, grade 5).
The analyses will be conducted using the 30-day safety window, and some will be repeated using 
the 100-day safety window.
Summary of frequency of unique select AE by Category will also be reported for each treatment 
group.
By-subject select AE listing and a select AE definition listing will be provided.
7.6.10.2
Time-to onset of select AE
Time-to onset of the following specific events will be summarized for each category/subcategory 
of select AEs for treated subjects who experienced at least one select adverse event from the 
category/subcategory, reporting median, min, and max:

Time-to onset of any grade select AE by treatment group

Time-to onset of grade 3 to 5 select AE by treatment group

Time-to onset of any grade drug-related select AE by treatment group

Time-to onset of grade 3 to 5 drug-related select AE by treatment group
See time-to onset definition subsection of Appendix 1 for additional details. The analyses will be 
conducted using the 30-day safety window.
7.6.10.3
Time-to resolution of select AE
Time to resolution of the following specific events will be summarized separately for each 
category/subcategory.

Time-to resolution of  any grade select  AE by treatment group

Time-to resolution of grade 3 to 5 select AE by treatment group

Time-to resolution of any grade drug-related select AE by treatment group

Time-to resolution of grade 3 to 5 drug-related select AE by treatment group
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
Time-to resolution of any grade select AE where immune modulating medication was 
initiated, by treatment group.

Time-to resolution of grade 3 to 5 select AE where immune modulating medication was 
initiated, by treatment group.

Time-to resolution of any grade  drug-related select AE where immune modulating 
medication was initiated, by treatment group

Time-to resolution of grade 3 to 5 drug-related select AE where immune modulating 
medication was initiated, by treatment group
Time-to resolution analyses are restricted to treated subjects who experienced the specific events. 
Time-to resolution where immune modulating medication was initiated analyses are restricted to 
treated subjects who experienced the specific events and who received immune modulating 
medication during the longest select AE.
See time-to resolution definition subsection of Appendix 1 for additional details. The analyses 
will be conducted using the 30-day safety window.
7.6.10.4
Immune Modulating Medication for Select AE
For each category/subcategory of select AEs, the following will be reported for each treatment 
group:

Percentage of subjects who received immune modulating concomitant medication for 
management of any select AE in the category among subjects who experienced at least one 
select adverse event in the category/subcategory. 

The total medication treatment duration, duration of high dose of corticosteroid and tapering 
duration (summary statistics)
These analyses will be performed on any select AEs, drug-related select AEs, grade 3-5 select 
AEs and drug-related select AEs.
The analysis will be conducted using the 30-day safety window.
7.6.11
Other Events of Special Interest
Unless otherwise specified, analyses will be performed by other events of special interest
category.  
7.6.11.1
Incidence of other events of special interest
Other events of special interest will be summarized by treatment group for each category:

Overall summary of other events of special interest by worst CTC grade presented by 
Category/PT (grade 1, 2, 3, 4, 5, unknown)

Overall summary of other events of special interest by worst CTC grade presented by 
Category or Subcategory/PT (any grade, grade 3-4, grade 5)

Overall summary of drug-related other events of special interest by worst CTC grade 
presented by Category or Subcategory / PT (grade 1, 2, 3, 4, 5, unknown)
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
Overall summary of drug-related other events of special interest by worst CTC grade 
presented by Category or Subcategory / PT (any grade, grade 3-4, grade 5)

Overall summary of serious other events of special interest by worst CTC grade presented by 
Category/PT (grade 1, 2, 3, 4, 5, unknown)

Overall summary of other events of special interest leading to discontinuation by worst CTC 
grade presented by Category/PT (grade 1, 2, 3, 4, 5, unknown)

Overall summary of other events of special interest where immune modulating medication 
was initiated by worst CTC grade presented by Category/PT (grade 1, 2, 3, 4, 5, unknown)

Overall summary of other events of special interest where immune modulating medication 
was initiated by worst CTC grade presented by Category/PT (any grade, grade 3-4, grade 5)

Overall summary of drug-related other events of special interest where immune modulating 
medication was initiated by worst CTC grade presented by Category/PT (grade 1, 2, 3, 4, 5, 
unknown)
The analyses will be conducted using the 30-day safety window, and repeated using the 100-day 
safety window.
7.6.11.2
Time-to onset of other events of special interest
Time-to onset of the following specific events will be summarized for each category of other 
events of special interest for treated subjects who experienced at least one event from the 
category, reporting median, min, and max:

Time-to onset of any grade other events of special interest by treatment group

Time-to onset of grade 3 to 5 other events of special interest by treatment group

Time-to onset of any grade drug-related other events of special interest by treatment group

Time-to onset of grade 3 to 5 drug-related other events of special interest by treatment group

Time-to onset of any grade other events of special interest where immune modulating 
medication was initiated, by treatment group.

Time-to onset of grade 3 to 5 other events of special interest where immune modulating 
medication was initiated, by treatment group.
See time-to onset definition subsection of Appendix 1 for additional details. The analyses will be 
conducted using the 30-day safety window, and some will be repeated using the 100-day safety 
window.
7.6.11.3
Time-to resolution of other events of special interest 
Time to resolution of the following specific events will be summarized separately for each 
category.

Time-to resolution of  any grade other events of special interest by treatment group

Time-to resolution of grade 3 to 5 other events of special interest by treatment group

Time-to resolution of any grade drug-related other events of special interest by treatment 
group
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
Time-to resolution of grade 3 to 5 drug-related other events of special interest by treatment 
group

Time-to resolution of any grade other events of special interest where immune modulating 
medication was initiated, by treatment group.

Time-to resolution of grade 3 to 5 other events of special interest where immune modulating 
medication was initiated, by treatment group.
Time-to resolution analyses are restricted to treated subjects who experienced the specific events. 
The analyses will be conducted using the 30-day safety window, and some will be repeated using 
the 100-day safety window.
See time-to resolution definition subsection of Appendix 1 for additional details.
7.6.11.4
Immune Modulating Medication for other events of special interest
For each category of other events of special interest, the following will be reported for each 
treatment group:

Percentage of subjects who received immune modulating concomitant medication for 
management of other events of special interest in the category among subjects who 
experienced at least one other events of special interest in the category. 

The total medication treatment duration, duration of high dose of corticosteroid and tapering 
duration (summary statistics)
These analyses will be performed on any other events of special interest, grade 3-5 other events 
of special interest.
The analysis will be conducted using the 100-day safety window.
7.6.12
Laboratory Parameters
7.6.12.1
Hematology
See Section 7.6.9.1 of Core Safety SAP
7.6.12.2
Serum Chemistry
See Section 7.6.9.2 of Core Safety SAP
7.6.12.3
Electrolytes
See Section 7.6.9.3 of Core Safety SAP
7.6.12.4
Additional Analyses
See Section 7.6.9.4 of Core Safety SAP
7.6.13
Vital Signs and Pulse Oximetry
See Section 7.6.10 of Core Safety SAP
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7.6.14
Immunogenicity Analyses
Not applicable
7.6.15
Pregnancy
See Section 7.6.12 of Core Safety SAP
7.6.16
Clinical Safety Program (CSP)
Not applicable
7.6.17
Adverse Events By Subgroup
See Section 7.6.14 of Core Safety SAP
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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•
 
 
.
7.8
Outcomes Research Analyses
Descriptive summary statistics of Patient Reported Outcomes will be presented at baseline and 
each on-study time point, unless otherwise specified. Mean changes from baseline for each of the 
2 scales will be calculated for each subject at each on-study time point. In addition, subject 
compliance will be described per time point by the proportion of subjects who filled out the QoL 
assessments over the numbers of subject known to be alive and eligible for assessment at these 
time points. The analysis will be performed for all treated subjects and in Groups 1, 2, and 3.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.9
Health Care Resource Utilization
Hospitalization rate based on person year will be summarized in table. Descriptive summary 
statistics of length of stay will be presented at baseline and each on-study time point, unless 
otherwise specified. The analysis will be performed for all treated subjects and in Groups 1, 2, 
and 3.
All hospitalization will be presented in a listing.
8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates:
For missing and partial adverse event onset dates, imputation will be performed using the 
Adverse Event Domain Requirements Specification1. Missing and partial Non-Study Medication 
Domain dates will be imputed using the derivation algorithm described in BMS Non-Study 
Medication Domain Requirements Specification2.
For death dates, the following conventions will be used for imputing partial dates:

If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known alive date +1 day and the 
maximum will be considered as the death date.

If the month or the year is missing, the death date will be imputed as the last known alive 
date + 1 day

If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known alive date + 1 day
For date of progression, the following conventions will be used for imputing partial dates:

If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day.
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
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
* In case, the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of death 
will be considered as the date of progression.
The following conversion factors will be used to convert days to months or years: 1 month = 
30.4375 days and 1 year = 365.25 days.
Duration (e.g. time from first diagnosis of NSCLC to first dosing date, duration response, and 
time to response) will be calculated as follows:
Duration = (Last date - first date + 1)
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
9
CONTENT OF REPORTS
The complete list of analyses contributing to the clinical study report is given in the Data 
Presentation 
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APPENDIX 1
ADVERSE EVENTS OF INTEREST DEFINITION AND 
CONVENTIONS
The adverse events of interest including IMAE, select AE, and other event of special interest 
consist of a list of preferred terms grouped by specific category and by subcategory. These 
categories and subcategories are defined by the Sponsor and the list that is most current at the 
time of analysis will be used. Also changes may be made to this list with each new version of 
MedDRA.
Time-to onset definition
Time-to onset of AE (any grade) for a specific category (e.g. pulmonary events, gastrointestinal
events, ...) is defined as the time between the day of the first dose of study treatment  and the 
onset date of the earliest AE (of any grade) in this category.
If the subject did not experience an AE (of any grade) in the category, time-to onset will be 
censored at the maximum follow-up time of all subjects in their respective treatment group (i.e 
for subjects without an event, follow-up time is defined from first dosing date up to last dosing 
date +30 days (or 100 days depending on the analysis) if subjects are off treatment and followed 
for at least  30 days (or 100 days depending on the analysis) , otherwise it is defined up to the last 
known alive date). The resulting Kaplan-Meier plot will represent the cumulative rate of the 
select AE (any grade) in the category over time.
Time-to onset of AE (grade 3-5) for a specific category is defined similarly but restricted to 
grade 3-5 AEs.
Time-to onset of drug-related (grade 3-5 or any grade) AE for a specific category is defined 
similarly but restricted to drug-related AEs.
Time-to onset for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Time-to resolution definition
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific 
category will be collapsed into what will be termed “clustered” AEs. For example, if a subject 
(without pre-treatment AE) experienced an AE from 1st to 5th January, another AE (with 
different PT but within same category) from 6th to 11th January and same AE from 10th to 12th 
January, these will be collapsed into one clustered AE from 1st to 12th January. Table 4 is 
summarizing key derivation steps for each type of clustered AEs.
Time-to resolution of AE (any grade) for a specific category is defined as the longest time from 
onset to complete resolution or improvement to the grade at baseline among all clustered select 
AEs in this category experienced by the subject. Events which worsened into grade 5 events 
(death) or have a resolution date equal to the date of death are considered unresolved. If a 
clustered AE is considered as unresolved, the resolution date will be censored to the last known 
date alive. Improvement to the grade at baseline implies that all different adverse events in the 
clustered adverse event should at least have improved to the corresponding (i.e. with same 
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preferred term) baseline grade. This measure is defined only for subjects who experienced at 
least one AE in the specific category.
The time-to resolution of AE (grade 3-5) for a specific category is defined similarly with an 
onset date corresponding to a grade 3-5 AE.
Time-to resolution of drug-related AE (any grade or grade 3-5) is defined similarly but restricted 
to drug-related AE.
The time-to resolution of AE (any grade or grade 3-5, drug-related or all) where immune 
modulating medication was initiated is defined similarly with the additional condition that the 
subject started an immune modulating medication during the longest AE resolution period.
Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Table 4:
Derivation of clustered AE of interest
Type of clustered AE of interest
Derivation
Any grade
Collapse any on-treatment AE from the same category
Drug-related of any grade
Collapse any on-treatment drug-related
AE from the same category
Grade 3-5
Collapse any on-treatment AE from the same category.
Resolution will be based on the onset date of the earliest grade 3-
5 records  (if no grade 3-5 record, clustered AE is excluded)
Drug-related of Grade 3-5
Collapse any on-treatment drug-related AE from the same 
category
Resolution will be based on the onset date of  the earliest grade 3-
5 record (if no Grade 3-5 record, clustered AE is excluded)
The algorithm for collapsing adverse event of interest (IMAE, select AE, other event of special 
interest) records is using the following conventions:
For each subject and specified category, the corresponding adverse event records will be 
collapsed when:
1) Multiple adverse event records have the same onset date.
2) The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).
The onset date of an event record is after the onset date and prior to or on the resolution date of a 
preceding event record (overlapping events).
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DOCUMENT HISTORY
Version 
Number
Date
Author(s)
Description
1.0
13JAN2016
Initial version
2.0
09SEP2016
Modify IMAE section; add select AE and other 
events of special interest sections; add 
Appendix 1.
Update SAP v1.0 to add more details of the 
analysis.
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