An Exploratory Study of the Biologic Effects and Biomarkers of Nivolumab in Combination With Ipilimumab in Subjects With Treatment-Naive Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
An Exploratory Study of the Biologic Effects and Biomarkers of Nivolumab in combination with 
Ipilimumab in Subjects with Treatment-Naive Stage IV or recurrent Non-Small Cell Lung 
Cancer (NSCLC) 
(CheckMate 592: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 592) 
 
Protocol: CA209-592 
NCT Number: NCT03001882 
Document Date (Date in which document was last revised): 18-Dec-2019 

Page: 1
Protocol Number: CA209592
IND Number: 125,872
EUDRACT Number 2018-000462-11
Date 28-Sep-2016
Revised Date 18-Dec-2019
CLINICAL PROTOCOL CA209592
An Exploratory Study of the Biologic Effects and Biomarkers of Nivolumab in combination with 
Ipilimumab in Subjects with Treatment-Naive Stage IV or recurrent Non-Small Cell Lung 
Cancer (NSCLC) 
(CheckMate 592: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 592)
Revised Protocol Number: 05
3401 Princeton Pike, Lawrence Township, NJ  08648
Telephone (office): 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrence Township, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (e.g., amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, e.g., a Contract Research 
Organization (CRO).
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Clinical Protocol
CA209592
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 18-Dec-2019
2
DOCUMENT HISTORY
Document 
Date of Issue
Summary of Change
Revised 
Protocol 05
18-Dec-2019
• Removed restriction of Part 1 enrollment from US sites only
• Allowed less frequent imaging for long-term responders
• Clarified laboratory collection for TSH and albumin
• Updated interim analyses
• Added myocarditis to Management Algorithms
Revised 
Protocol 04
03-May-2019
• Updated objectives, endpoints, and analyses for tissue and blood TMB 
• Updated and reorganized biomarker collection and removed receptor 
occupancy
• Allowed skipped dosing on D15 and D29 only
• Required brain imaging at screening and when clinically indicated
• Updated schemas, interim analyses, dosing details, and appendices
• Removed communication with medical monitor for insufficient tissue 
Revised 
Protocol 03
02-Mar-2018
Incorporates Amendment 05
Amendment 
05
02-Mar-2018
• Added Part 2 of protocol to include new participants for additional 
biomarker collection, objectives, endpoints, Procedural Outlines,   
• Updated to allow for archival tissue in Part 1 for PD-L1 screening 
assessment/group assignment only
• Added 2 year maximum duration of treatment
• Removed fine needle aspirate tissue collection
• Updated exclusion criteria, prohibited treatments, and discontinuation 
criteria to align with current nivolumab program standards
• Added EudraCT number 
• Added Appendix 8 Country Specific Amendment for HIV testing
Revised 
Protocol 02
29-Mar-2017
Incorporates Amendment 04
Amendment 
04
29-Mar-2017
Protocol amendment is being implemented to include a co-primary objective to 
evaluate tumor mutational burden (TMB) as a candidate biomarker of clinical 
efficacy of nivolumab and ipilimumab combination therapy. 
 
 
 Dosing for nivolumab was changed to a flat dose 
of 240mg every 2 weeks. Women of Childbearing Potential definitions and 
methods of contraception were updated to align with program level guidance
1) Synopsis Updated:
a) Objectives and Endpoints: Updated to include a co-primary
 
objective/endpoint to evaluate tumor mutational burden as a candidate 
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Clinical Protocol
CA209592
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 18-Dec-2019
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Document 
Date of Issue
Summary of Change
biomarker of clinical efficacy of nivolumab and ipilimumab 
combination therapy.
b) Overall Design, Study Schematic, and Study Treatment: Updated to 
reflect nivolumab flat dose of 240mg every 2 weeks. Treatment and 
follow-up period were added to Schematic.
2) Table 2-1, Screening Procedural Outline:
a) Timing of pregnancy test for WOCBP clarified.
b) Body Surface Area removed from Physical Measurements.
c) Laboratory Tests clarified. Phosphorus required at screening and TSH 
+ Free T3/T4 required within 72 hours of C1D1.
d) Paired Fine Needle Aspiration (FNA) added. 
3) Table 2-2, On Treatment Procedural Outline:
a) Physical Exam: Removed reference to nivolumab weight based dosing 
and added reference to nivolumab flat dosing.
b) Laboratory Tests clarified. Phosphorus added for consistency with 
Section 9.4.1.TSH + Free T3/T4 required within 72 hours of C1D1 and 
TSH with reflexive Free T3/T4 on Day 1 of each Cycle thereafter 
(every 6 weeks).
c) Paired FNA to be collected from biopsies at Cycle 1 Day 29 (Week 5) 
and upon documented progression.
g) Reference to RO added for Whole Blood Collection.
4) Table 2-3, Follow-Up and Survival Procedural Outline:
a) Laboratory Tests clarified. Phosphorus and Albumin added for 
consistency with Section 9.4.1.
b) Reference to Biomarker assessments/PD Sampling removed.
5) Section 3.1, Study Rationale: Added rationale for inclusion of tumor 
mutational burden as a study objective.
6) Section 3.2.2, Rationale for combination of nivolumab and ipilimumab: 
Updated to reflect nivolumab flat dose of 240mg every 2 weeks.
7) Section 3.2.2.1, Rationale for Nivolumab Flat Dosing: Section added.
8) Section 3.2.5, Research Hypothesis: Added reference to TMB.
9) Table 4-1, Objectives and Endpoints: Updated to include a co-primary
 
objective/enpoint to evaluate tumor mutational burden as a candidate 
biomarker of clinical efficacy of nivolumab and ipilimumab combination 
therapy.
10) Section 5.1, Overall Design: Updated to reflect nivolumab flat dosing.
11) Figure 5.1-1, Study Design Schematic: Updated to reflect nivolumab flat 
dose of 240mg every 2 weeks. Treatment and follow-up period were added 
to Schematic.
12) Section 5.5 , Justification for Dose: Updated to reflect nivolumab flat 
dose of 240mg every 2 weeks.
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Clinical Protocol
CA209592
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 18-Dec-2019
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Document 
Date of Issue
Summary of Change
13) Table 7.1-1, Selection and Timing of Dose: Updated to reflect nivolumab 
flat dose of 240mg every 2 weeks.
14) Section 7.1.1, Dosing Details: Updated to reflect nivolumab flat dose of 
240mg every 2 weeks.
16) Table 9.4.1-1 Laboratory Assessment Panels
a) TSH and Free T3/Free T4 testing clarified.
b) Testing for Drugs of Abuse Removed.
17) Table 9.6-1, Biomarker Assessment Schedule:
a) Paired FNA collection added.
19) Section 9.6.11, Paired FNA Collection: Section added.
21) Section 10.1, Sample Size Determination: Updated to reflect tumor 
mutational burden as a co-primary objective.
22) Section 10.2, Populations for Analysis: Defined tumor mutational burden 
evaluable patients.
23) Section 10.3, Statistical and Computational Analyses: Updated to reflect 
the association between ORR and tumor mutational burden will be explored 
using logistic regression model among treated patients evaluable for tumor 
mutational burden.
24) Section 10.3.1, Efficacy Analyses: Updated to reflect the association 
between ORR and TMB will be explored using logistic regression model.
25) Appendix 4, Women of Childbearing Potential definitions and methods of 
contraception: Appendix was updated to align with program level guidance.
Revised 
Protocol 01
03-Nov-2016 Incorporates Amendment 02
Amendment 
02
03-Nov-2016
Protocol amendment is being implemented to include a blood collection for 
Receptor Occupancy Measurements and language to align with program level 
standards for dosing administration.
1) Section 2, Screening Procedural Outline: Tumor tissue samples from 
biopsies will be divided into FFPE and a fresh sample in preservative, not 
frozen.
2) Section 7.4.5.1, Criteria to Resume nivolumab Dosing: Removed repeated 
criteria.
3) Section 8.1.1, Nivolumab or Ipilimumab Dose Discontinuation: Criteria 
updated to reflect program standards.
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Clinical Protocol
CA209592
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 18-Dec-2019
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Document 
Date of Issue
Summary of Change
4) Section 8.1.3, Post Treatment Study Follow-Up: Updated to reflect program 
language.
5) Section 9.6, Biomarkers: Tumor tissue samples from biopsies will be 
divided into FFPE and a fresh sample in preservative, not frozen.
6) Table 9.6-1, Biomarker Assessment Schedule: Receptor Occupancy Whole 
Blood Collection Added.
7) Section 9.6.10, Receptor Occupancy Measurements: Section added.
8) Various typographical errors corrected.
Original 
Protocol
28-Sep-2016 Not Applicable
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BMS-936558
nivolumab
OVERALL RATIONALE FOR REVISED PROTOCOL 05:
The CA209592 protocol was revised to allow addition enrollment at non-US sites for Part 1 and 
update the timing of the interim analyses. Additional updates provided internal consistency in the 
document.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Study Schema
Figure 5.1-1: Study Design Schematic 
Part 1 and Part 2
Removed restriction of Part 1 
enrollment from US sites only 
Rationale: 
Allows for additional enrollment 
for non-US sites for part 1. 
Table 2-2: On Treatment Procedural 
Outline (CA209592) for Part 1
Table 2-3: On Treatment Procedural 
Outline (CA209592) for Part 2
Table 2-4: Follow-Up and Survival 
Procedural Outline CA209592 (All 
Treatment Groups Part 1 and Part 2)
Clarified laboratory collection for 
TSH and albumin 
Updated document for internal 
consistency in document
Table 2-4: Follow-Up and Survival 
Procedural Outline CA209592 (All 
Treatment Groups Part 1 and Part 2)
Section 9.1.1.1 Efficacy Assessments 
using CT scan or MRI
Table 9.1.1.1-1: Imaging Assessment 
Schedule (Part 1 and Part 2)
After 3 years on study, tumor 
assessments for long-term survivors 
can be performed at a frequency per 
institutional guidelines or every 24 
weeks based on NCCN surveillance 
guidelines.
Aligns imaging assessments with
clinical practice for long-term 
responders.
Table 9.6-1: Biomarker Assessment 
Schedule for Part 1
Updated biomarker collection
Provides internal consistency in 
the document
Table 2-1 Screening Procedural 
Outline (CA209592) for Part 1 and 
Part 2 9.1.1.1 
Table 2.-2: On Treatment Procedural 
Outline (CA209592) for Part 1
Table 2.-3: On Treatment Procedural 
Outline (CA209592) for Part 2
Section 9.1.1.1 Efficacy Assessments 
using CT scan or MRI
Updated clinical laboratory 
collection
Provides internal consistency in 
the document
Section 5.1 Overall Design
Section 10.3.5 Interim Analyses
Updated language for Part 2 interim 
analysis sample size: 
Updates document with original 
planned analysis with sample 
size (~150 pts).
Appendix
Added myocarditis to Management 
Algorithms 
Aligns with program standards
Revised Protocol No.: 05
Date: 18-Dec-2019
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TABLE OF CONTENTS
TITLE PAGE 
................................................................................................................
DOCUMENT HISTORY..............................................................................................
OVERALL RATIONALE FOR REVISED PROTOCOL 05: 
.....................................
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05.........................
TABLE OF CONTENTS..............................................................................................
1 SYNOPSIS.................................................................................................................
2 SCHEDULE OF ACTIVITIES..................................................................................
3 INTRODUCTION .....................................................................................................
3.1 Study Rationale.................................................................................................
3.2 Background 
.......................................................................................................
3.2.1 Mechanism of Action................................................................................
3.2.1.1 Mechanism of Action of Nivolumab................................................
3.2.1.2 Mechanism of Action of Ipilimumab 
...............................................
3.2.2 Rationale for Combination of Nivolumab and Ipilimumab .....................
3.2.2.1 Rationale for Nivolumab Flat Dosing.............................................
3.2.3 Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab 
....
3.2.4 Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease....................................................................................
3.2.5 Rationale for Tumor Mutational Burden Testing ....................................
3.2.6 Research Hypothesis................................................................................
3.3 Benefit/Risk Assessment ..................................................................................
4 OBJECTIVES AND ENDPOINTS 
...........................................................................
5 STUDY DESIGN.......................................................................................................
5.1 Overall Design 
..................................................................................................
5.1.1 Data Monitoring Committee and Other External Committees 
................
5.2 Number of Participants 
.....................................................................................
5.3 End of Study Definition 
....................................................................................
5.4 Scientific Rationale for Study Design...............................................................
5.5 Justification for Dose 
........................................................................................
5.6 Duration of Treatment with Nivolumab plus Ipilimumab 
................................
6 STUDY POPULATION 
............................................................................................
6.1 Inclusion Criteria ..............................................................................................
6.2 Exclusion Criteria .............................................................................................
6.3 Lifestyle Restrictions 
........................................................................................
6.4 Screen Failures..................................................................................................
6.4.1 Retesting During Screening or Lead-In Period 
.......................................
7 TREATMENT ...........................................................................................................
7.1 Treatments Administered..................................................................................
7.1.1 Dosing Details .........................................................................................
7.2 Method of Treatment Assignment 
....................................................................
7.3 Blinding.............................................................................................................
7.4 Dosage Modification.........................................................................................
7.4.1 Dose Delay Criteria.................................................................................
7.4.2 Dose Reductions.......................................................................................
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CA209592
nivolumab
Revised Protocol No.: 05
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7.4.3 Treatment of Infusion Reactions 
..............................................................
7.4.4 Management Algorithms for Immuno-Oncology Agents .........................
7.4.5 Criteria to resume dosing ........................................................................
7.4.5.1 Criteria to resume nivolumab dosing .............................................
7.4.5.2 Criteria to resume ipilimumab dosing 
............................................
7.5 Preparation/Handling/Storage/Accountability..................................................
7.6 Treatment Compliance......................................................................................
7.7 Concomitant Therapy........................................................................................
7.7.1 Prohibited and/or Restricted Treatments.................................................
7.7.2 Other Restrictions and Precautions.........................................................
7.7.2.1 Corticosteroids................................................................................
7.7.2.2 Palliative Radiotherapy 
..................................................................
7.7.2.3 Imaging Contraindications 
.............................................................
7.8 Treatment After the End of the Study...............................................................
8 DISCONTINUATION CRITERIA 
...........................................................................
8.1 Discontinuation from Study Treatment ............................................................
8.1.1 Nivolumab or Ipilimumab Dose Discontinuation 
....................................
8.1.2 Disease Progression ................................................................................
8.1.3 Post Treatment Study Follow-Up.............................................................
8.1.4 Discontinuation from the Study ...............................................................
8.2 Lost to Follow-Up.............................................................................................
9 STUDY ASSESSMENTS AND PROCEDURES.....................................................
9.1 Efficacy Assessments........................................................................................
9.1.1 Imaging Assessment for the Study............................................................
9.1.1.1 Efficacy Assessments using CT scan or MRI 
..................................
9.2 Adverse Events .................................................................................................
9.2.1 Time Period and Frequency for Collecting AE and SAE Information ....
9.2.2 Method of Detecting AEs and SAEs.........................................................
9.2.3 Follow-up of AEs and SAEs.....................................................................
9.2.4 Regulatory Reporting Requirements for SAEs.........................................
9.2.5 Pregnancy 
................................................................................................
9.2.6 Laboratory Test Result Abnormalities 
.....................................................
9.2.7 Potential Drug Induced Liver Injury (DILI)............................................
9.2.8 Other Safety Considerations 
....................................................................
9.2.8.1 Immune-mediated adverse events ...................................................
9.3 Overdose 
...........................................................................................................
9.4 Safety ................................................................................................................
9.4.1 Clinical Safety Laboratory Assessments..................................................
9.4.2 Imaging Safety Assessment 
......................................................................
9.6 Biomarkers........................................................................................................
Clinical Protocol
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CA209592
nivolumab
Revised Protocol No.: 05
Date: 18-Dec-2019
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9.6.10 Tumor Mutational Burden Evaluation in Tissue and Blood Part 2.......
9.6.11 Additional Research Collection 
.............................................................
9.7 Medical Resource Utilization and Health Economics ......................................
10 STATISTICAL CONSIDERATIONS ....................................................................
10.1 Sample Size Determination.............................................................................
10.2 Populations for Analyses ................................................................................
10.3 Statistical and Computational Analyses..........................................................
10.3.1 Efficacy Analyses 
...................................................................................
10.3.2 Safety Analyses.......................................................................................
10.3.4 Other Analyses 
.......................................................................................
11 REFERENCES ........................................................................................................
12 APPENDICES .........................................................................................................
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................
APPENDIX 2 STUDY GOVERANCE CONSIDERATIONS 
....................................
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING.........................................................................
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION.....................................................................
APPENDIX 5 ECOG PERFORMANCE STATUS 
.....................................................
APPENDIX 6 RECIST 1.1 GUIDELINES 
..................................................................
APPENDIX 7 MANAGEMENT ALGORITHMS.......................................................
APPENDIX 8 COUNTRY SPECIFIC REQUIREMENTS .........................................
APPENDIX 9 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY 
........
Clinical Protocol
BMS-936558
CA209592
nivolumab
Revised Protocol No.: 05
Date: 18-Dec-2019
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Clinical Protocol
CA209592
BMS-936558
nivolumab
1 
SYNOPSIS
Protocol Title:An Exploratory Study of the Biologic Effects and Biomarkers of Nivolumab in 
combination with Ipilimumab in Subjects with Treatment-Naive Stage IV or recurrent Non-
Small Cell Lung Cancer (NSCLC)
(CheckMate 592: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 592)
Study Phase:
Phase 2, exploratory
Rationale:
Immune checkpoint signaling through the programmed death 1 (PD-1) axis to its ligand (PD-L1) 
with or without CTLA-4 inhibition significantly dampens anti-tumor immune responses in 
different tumor types including NSCLC. Unfortunately, not all patients respond to immune 
checkpoint blockade, therefore there is a compelling need for a better understanding of factors that 
would predict response and progression.
Emerging science and evidence from multiple studies, including exploratory analyses from the 
phase 2 study CA209568 (nivolumab + ipilimumab) and phase 3 study CA209026 (nivolumab 
monotherapy), tumor mutational burden (TMB) was identified as an important potential biomarker
(independent of PD-L1) to help identify patients most likely to benefit from immunotherapy.
CA209592 is a two-part, exploratory, phase 2 open-label study aiming to explore potential 
biomarkers of response, including tumor mutational burden, and their association with clinical 
benefit when nivolumab + ipilimumab combination is given as primary therapy for advanced or 
metastatic NSCLC, regardless of PD-L1 expression (Part 1). Part 2 of the study explores the 
association between TMB (blood and tissue) and clinical efficacy.
In Part 1, changes occurring in candidate biomarkers within the tumor or within the peripheral 
blood during treatment, or at the time of disease progression, may provide an understanding of the 
mechanism of action, and the biology of underlying response (efficacy/safety) and/or underlying 
acquired resistance, which may help inform future combination strategies.
Based on the Part 2 expansion cohort in this study, tumor TMB and blood TMB will be collected 
at baseline. The association of tissue and blood TMB analyses with clinical outcomes will be 
assessed independently.
Study Population:
Participants with Stage IV or recurrent NSCLC, with no prior systemic anticancer therapy given 
as primary therapy for advanced or metastatic disease.
Revised Protocol No.: 05
Date: 18-Dec-2019
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Clinical Protocol
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Part 1 Objectives and Endpoints:
Objectives
Endpoints
Primary
• To evaluate baseline tumor mutational burden as a 
candidate biomarker of clinical efficacy of 
nivolumab and ipilimumab combination therapy.
• To investigate the potential association between 
candidate biomarkers in peripheral blood and tumor 
tissue at baseline and on-treatment with clinical 
efficacy measures. 
• The clinical efficacy will be measured by the 
analysis endpoint of objective response rate 
(ORR). The association of ORR with candidate 
biomarkers in peripheral blood and tumor tissue at 
baseline and on-treatment will be assessed. 
Candidate biomarkers may include:
o Baseline tissue TMB and blood TMB
o Potential biomarkers/signatures (including 
PD-L1 expression) both at baseline and on 
treatment
o Immunomodulatory and pharmacodynamic 
activity
Secondary
• To evaluate efficacy in patient subgroups defined by 
baseline discovery biomarkers.
• ORR, disease control rate (DCR)
• Duration of response (DOR) and time to response 
(TTR)
• Progression free survival (PFS) 
• Overall survival (OS) 
Revised Protocol No.: 05
Date: 18-Dec-2019
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Clinical Protocol
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nivolumab
Part 2 Objectives and Endpoints:
Objectives
Endpoints
Primary
• To evaluate the association between baseline 
tissue TMB/blood TMB and clinical efficacy 
(ORR) for participants in Part 2
• The clinical efficacy will be measured by the 
analysis endpoint of objective response rate 
(ORR). The association of ORR with
baseline tissue TMB and blood TMB will be 
assessed.
Secondary
• To investigate bacterially-generated and human 
components enteric biomarkers and identify 
potential associations with clinical outcomes, 
including safety and efficacy, for subjects in 
Part 2.
• ORR, PFS, OS
• Incidence of AES, SAEs, and select AEs
Overall Design:
Protocol CA209592 is an open-label, exploratory trial evaluating nivolumab in combination with 
ipilimumab in participants ≥18 years old with histologically confirmed advanced or metastatic 
NSCLC, with no prior systemic anticancer therapy given as primary therapy for advanced disease. 
In Part 1, participants will undergo screening evaluations to determine eligibility within 28 days 
prior to cohort assignment, and approximately 100 patients will be treated. Tumor sample for 
PD-L1 status assessment is required at screening for group assignment.
Upon determination of PD-L1 status (cut-off of 1%), 2 cohorts will be defined: PD-L1 positive 
and negative, and patients in each cohort (n= 50 ea.) will receive nivolumab + ipilimumab.
In Part 2, approximately 150 participants will be assigned to a single cohort and treated with 
nivolumab + ipilimumab regardless of their PD-L1 status.
All participants will be treated with the following:
• nivolumab 240mg IV every 2 weeks + ipilimumab 1 mg/kg IV every 6 weeks until disease 
progression, unacceptable toxicity, withdrawal of consent, the study ends, or maximum 
treatment duration of 2 years, whichever occurs first. Participants will be permitted to continue 
on nivolumab +/- ipilimumab beyond initial RECIST 1.1 defined progression, as long as they 
meet the criteria described in Section 8.1.2.
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Number of Participants: 
Part 1: Approximately 150 participants are expected to be enrolled to achieve approximately 100 
treated participants in the trial. 
Part 2: Approximately 200 participants are expected to be enrolled to achieve 150 treated 
participants. Sites in US and Europe may participate in Part 2. 
Study Schematic Part 1 and Part 2:
Study treatment:
Study Drug for CA209592
Medication 
Dosage level(s)
Frequency of Administration
Route of Administration
nivolumab
240mg
Every 2 weeks
IV
ipilimumab
1 mg/kg
Every 6 weeks
IV
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Date: 18-Dec-2019
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Clinical Protocol
CA209592
BMS-936558
nivolumab
2 
SCHEDULE OF ACTIVITIES
Table 2-1: 
Screening Procedural Outline (CA209592) for Part 1 and Part 2
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X
ICF signed during screening for protocol participation prior to any study specific 
procedures. Study allows for re-enrollment of a participant that has discontinued the study as 
a pre-treatment failure. If re-enrolled, the participant must be re-consented and assigned a 
new patient ID number from IWRS.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to 
dosing.Section 6.
Medical History
X
Body Imaging
X
Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known 
and/or suspected sites of disease, within 28 days prior to the first dose 
 
Brain Imaging
X
MRI of the brain without and with contrast is required for ALL participants during screening 
to rule out brain metastases. CT of the brain (without and with contrast) can be performed if 
MRI is contraindicated. See Section 9.1.1 and Appendix 6 for further details.
Prior Systemic Therapy
X 
Any prior medications received to treat cancer.
ECOG Performance Status
X 
ECOG Status of 0 or 1 required for treatment assignment.Appendix 5.
Safety Assessments
Physical Measurements
X 
Includes height and weight
Full Physical Examination
X 
Within 14 days prior to first dose.
Vital Signs
X 
Including seated blood pressure, heart rate, and temperature. 
Assessment of Signs and Symptoms
X 
Within 14 days prior to first dose.
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Table 2-1: 
Screening Procedural Outline (CA209592) for Part 1 and Part 2
Procedure
Screening
Visita
Notes
Concomitant Medication Collection
X 
Within 14 days prior to first dose.
Laboratory Tests
X
Section 9.4.1, Within 14 days prior to first dose.
CBC w/differential, Chemistry panel including: Albumin, LDH, AST, ALT, ALP, T.Bili, 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, Phosphorus, Glucose, amylase, 
lipase.
TSH and Free T4/Free T3 required within 72 hours of C1D1.
Hepatitis B surface antigen (HBV sAg), and hepatitis C antibody (HCV Ab) or Hepatitis C 
RNA (HCV RNA).
Participants who test positive for hepatitis C but test negative for ribonucleic acid are 
allowed to enroll.
Pregnancy Test (WOCBP Only) 
X
Section 9.2.5.Negative pregnancy test required within 24 hours prior to first dose.
Biomarker Assessments
Tumor Tissue Sample(Part 1)
Archived Tumor Tissue or Recent Tumor Biopsy
X
Part 1 only: Fresh biopsy required.  Archival sample obtained within 3 months of 
enrollment acceptable for PD-L1 assessment only. See Section 9.6.
One (1) formalin-fixed paraffin embedded tumor tissue block or a minimum of 15unstained 
tumor tissue sections are acceptable.
Specimens must be tested by third party lab to determine PD-L1 status prior to group 
assignment.
Tumor Tissue Sample (Part 2)
Archived Tumor Tissue or Recent Tumor Biopsy
Part 2 only: Recent sample/fresh biopsy or archival, obtained within 3 months of 
enrollment.
One (1) formalin-fixed paraffin embedded tumor tissue block or a minimum of 15 unstained 
tumor tissue sections are acceptable. Fresh biopsy tissue is preferred.
Specimen collection and shipment to central vendor must be verified prior to treatment 
assignment. See Section 9.6
EGFR Mutation Status/ ALK Translocation 
Status (Part 1 and Part 2)
X
Part 1 and Part 2: To be performed by the local lab prior to first dose in all non-squamous 
participants.
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Table 2-1: 
Screening Procedural Outline (CA209592) for Part 1 and Part 2
Procedure
Screening
Visita
Notes
Study Treatment
Enrollment in IWRS
X
Section 7.2. For participant number assignment at the time informed consent is obtained.
a All screening assessments must be completed and participant should be registered for treatment assignment in IWRS within 28 days, unless otherwise noted.
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Table 2-2: 
On Treatment Procedural Outline (CA209592) for Part 1
Procedure
On
Treatment
Visits
Notes
1 Cycle = 6 weeks
Visits occur every 2 weeks (±3days) to align with nivolumab dose administration.
Safety Assessments
Physical Examination/Physical
Measurements (including 
performance status)
X
Appendix 5.
Weight and ECOG status. Dosing calculations for ipilimumab should be based on the body weight. If the 
participant’s weight on the day of dosing differs by > 10% from the weight used to calculate the dose, the 
dose must be recalculated. All doses should be rounded to the nearest milligram. Note: nivolumab dosing is 
240 mg flat dosing.
Vital Signs
X 
Obtain BP, HR, and temperature just prior to dosing.
Adverse Events Assessment
X
Section 9.2.
Review of Concomitant 
Medications
X
Laboratory Tests
X
Section 9.4.1.
On-study local laboratory assessments should be done within 72 hours prior to each dose.
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum urea level, 
creatinine, Ca, Mg, Na, K, Cl, Phosphorus, LDH, glucose, amylase, lipase.
Thyroid Function Testing
X
TSH + Free T3/T4 required within 72 hours of C1D1,
If TSH is abnormal, then TSH with reflexive Free T4, Free T3 is to be performed on Day 1 of each Cycle 
(every 6 weeks). 
Pregnancy Test (WOCBP Only)  
X
Serum or urine within 24 hours prior to first dose (C1D1) and then every 4 weeks (±1 week) regardless of 
dosing schedule.
Biomarker Assessments
On Treatment Tumor Biopsy
X
See Note.
Section 9.6.
To be performed at Cycle 1 Day 29 (Week 5 ±1 Week) AND upon documented progression.
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Table 2-2: 
On Treatment Procedural Outline (CA209592) for Part 1
Procedure
On
Treatment
Visits
Notes
1 Cycle = 6 weeks
Visits occur every 2 weeks (±3days) to align with nivolumab dose administration.
Efficacy Assessments
Body Imaging
See note.
Section 9.1.1.
Tumor assessments should occur every 8 weeks (± 1 week) for the first 12 months on treatment, then every 
12 weeks (± 1 week) until documented radiographic disease progression. 
An additional and optional CT scan is planned at W5, to guide tumor biopsy as needed and to support 
predicting tumor response based on early tumor growth characteristics using a mathematical tumor growth 
model.
CT chest and CT/MRI abdomen and pelvis (with contrast, unless contraindicated), plus any area that is 
being monitored. Use same imaging method as was used at screening.
For participants who discontinue study treatment for reasons other than radiographic PD, follow-up scans 
should continue to be performed according to the on-study assessment schedule until PD, withdrawal of 
consent, start of subsequent therapy, death, or lost to follow-up.
Participants who remain on therapy beyond initial progression, will have an assessment performed within 6 
weeks to confirm progression (see section 8.1.2)
All PET/CT scans should be before any scheduled biopsy at the same time point, if possible.
Brain Imaging
X
Participants with a history of brain metastasis or symptoms should have a surveillance MRI study per 
standard of care (approximately every 12 weeks), or sooner if clinically indicated. CT of the brain without 
and with contrast can be performed if MRI is contraindicated. See Section 9.1.1.1 for further details.
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Table 2-2: 
On Treatment Procedural Outline (CA209592) for Part 1
Procedure
On
Treatment
Visits
Notes
1 Cycle = 6 weeks
Visits occur every 2 weeks (±3days) to align with nivolumab dose administration.
Study Treatment
Day 1
Day 15
Day 29
Dispense Study Treatment 
X X X
Within 3 days of the treatment assignment in IWRS, the participant must receive the first dose of study 
medication. Participants may be dosed no less than 19 days between doses during administration of ipi/nivo 
in combination and no less than 12 days between doses nivo if is administered alone.
Nivolumab Administration 
X X X Treatment is administered every 2 weeks (+/- 3 days). Refer to Section 7.1.1.
Ipilimumab Administration 
X
Treatment is administered every 6 weeks (+/- 5 days). Refer to Section 7.1.1.
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Table 2-3: 
On Treatment Procedural Outline (CA209592) for Part 2
Procedure
On Treatment
Visits
Notes
1 Cycle = 6 weeks 
Visits occur every 2 weeks (±3days) to align with nivolumab dose administration.
Safety Assessments
Physical Examination/Physical
Measurements (including 
performance status)
X
Appendix 5.
Weight and ECOG status. Dosing calculations for ipilimumab should be based on the body weight. 
If the participant’s weight on the day of dosing differs by > 10% from the weight used to calculate 
the dose, the dose must be recalculated. All doses should be rounded to the nearest milligram.
Note: nivolumab dosing is 240mg flat dosing.
Vital Signs
X 
Obtain BP, HR, and temperature just prior to dosing.
Adverse Events Assessment
X
Section 9.2.
Review of Concomitant 
Medications
X
Laboratory Tests
X
Section 9.4.1.
On-study local laboratory assessments should be done within 72 hours prior to each dose.
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum urea 
level, creatinine, Ca, Mg, Na, K, Cl, Phosphorus, LDH, glucose, amylase, lipase.
Thyroid Function Testing
X
TSH + Free T3/T4 required within 72 hours of C1D1,  
If TSH is abnormal, then TSH with reflexive Free T4, Free T3 is to be performed on Day 1 of each 
Cycle (every 6 weeks). 
Pregnancy Test (WOCBP Only) 
X
Serum or urine within 24 hours prior to first dose (C1D1) and then every 4 weeks (±1 week) 
regardless of dosing schedule.
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Table 2-3: 
On Treatment Procedural Outline (CA209592) for Part 2
Procedure
On Treatment
Visits
Notes
1 Cycle = 6 weeks 
Visits occur every 2 weeks (±3days) to align with nivolumab dose administration.
Efficacy Assessments
Body Imaging
See note.
Section 9.1.1.
Tumor assessments should occur every 8 weeks (± 1 week) for the first 12 months on treatment, 
then every 12 weeks (± 1 week) until documented radiographic disease progression.
CT chest and CT/MRI abdomen and pelvis (with contrast, unless contraindicated), plus any area 
that is being monitored. Use same imaging method as was used at screening.
For participants who discontinue study treatment for reasons other than radiographic PD, follow-up 
scans should continue to be performed according to the on-study assessment schedule until PD, 
withdrawal of consent, start of subsequent therapy, death, or lost to follow-up.
Participants who remain on therapy beyond initial progression, will have an assessment performed 
within 6 weeks to confirm progression (see Section 8.1.2) 
Brain Imaging
See note.
Participants with a history of brain metastasis or symptoms should have surveillance MRIs per 
standard of care (approximately every 12 weeks) or sooner if clinically indicated. CT of the brain 
without and with contrast can be performed if MRI is contraindicated. See Section 9.1.1.1 for 
further details.
Study Treatment
Day 
1
Day 
15
Day 
29
Dispense Study Treatment
X 
X 
X
Within 3 days of the treatment assignment in IWRS, the participant must receive the first dose of 
study medication. Participants may be dosed no less than 19 days between doses during 
administration of ipi/nivo in combination and no less than 12 days between doses nivo if is 
administered alone.
Nivolumab Administration
X 
X 
X Treatment is administered every 2 weeks (+/- 3 days). Refer to Section 7.1.1.
Ipilimumab Administration
X
Treatment is administered every 6 weeks (+/- 5 days). Refer to Section 7.1.1.
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Table 2-4: 
Follow-Up and Survival Procedural Outline CA209592 (All Treatment Groups Part 1 and Part 2)
Procedure
Follow-Up
Visits 1a& 2b
Survival
Follow-up Visitsc
Notes
Safety Assessments
Targeted Physical Examination 
X
To assess for potential late emergent study drug related issues.
Vital Signs
X
Adverse Events Assessment
X
Beyond 100 days from the last dose of study drug, participants will be followed for 
ongoing drug-related adverse events until resolved, return to baseline or deemed 
irreversible, or until lost to follow-up, withdrawal of study consent, or start of 
subsequent therapy.
Laboratory Tests
X
To be done at FU1, to be repeated at FU2, if study related toxicity persists. 
CBC w/ differential, LFTs, BUN or serum urea level, creatinine, Ca, Mg, Na, K, 
Cl, Phosphorus, LDH, Glucose, amylase, lipase. 
If TSH is abnormal, then TSH with reflexive Free T4, Free T3 is to be performed
Pregnancy Test (WOCBP Only)  
X
Section 9.2.5.
Efficacy Assessments
Radiographic Tumor 
Assessments
X
For participants who discontinue study treatment for reasons other than 
radiographic PD, follow-up scans should continue to be performed according to the 
on-study assessment schedule (Table 2-2and Table 2-3) until PD, withdrawal of 
consent, or start of subsequent therapy, death, or lost to follow-up
After 3 years on study, tumor assessments for long-term survivors can be 
performed at a frequency per institutional guidelines or every 24 weeks based on 
NCCN surveillance guidelines.
Collection of Survival Status and
Subsequent Therapy Information
X
X
Every 3 months after FU2; May be completed by office visit, phone contact or 
email, to assess subsequent anti-cancer therapy.
a Follow-up visit 1 (FU1) = 30 days from the last dose +/- 7 days or coincides with the date of discontinuation (+/- 7 days) if date of discontinuation is greater 
than 35 days after last dose.
b Follow-up visit 2 (FU2) = 100 days (+/- 7 days) from follow-up visit 1
c Every 3 months (+/- 7 days) from FU2
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3 
INTRODUCTION
CA209592 is an open-label, exploratory Phase 2 trial aiming to investigate the biologic effects and 
biomarkers of
 nivolumab in combination ipilimumab in subjects, with no prior systemic anticancer 
therapy given as primary therapy for advanced or metastatic non-small cell lung cancer (NSCLC).
3.1 
Study Rationale
Immune checkpoint signaling through the programmed death 1 (PD-1) axis to its ligand (PD-L1) 
with or without CTLA-4 inhibition significantly dampens anti-tumor immune responses in 
different tumor types including NSCLC. 
Clinical activity of nivolumab and ipilimumab combination was evaluated in patients with 
advanced NSCLC as first line treatment in CA209012. Dual inhibition (PD-1 and CTLA-4) was 
associated with higher response rate over nivolumab monotherapy with very acceptable safety 
profile. Data from the same study are also showing better outcome in patients with tumors 
expressing PD-L1 versus those with no expression. ORR was higher with increasing PD-L1 
expression, with response rates of the combination exceeding response rates with monotherapy at 
each expression level.
Unfortunately, not all patients respond to immune checkpoint blockade, therefore there is a 
compelling need for a better understanding of factors that would predict response and progression. 
CA209592 is an exploratory Phase 2, open-label, trial aiming to evaluate response in patients with 
no prior systemic anticancer therapy given as primary therapy for advanced or metastatic NSCLC, 
with or without PD-L1 expression and addresses the following objectives in Part 1:
• To evaluate tumor mutational burden as a candidate biomarker of clinical efficacy of 
nivolumab and ipilimumab combination therapy;
• Characterize the immunomodulatory and pharmacodynamic activity of nivolumab in 
combination with ipilimumab, within the tumor microenvironment and in the periphery; 
• Evaluate/identify potential biomarkers/signatures within pre-treatment and within 
on-treatment samples that are correlated with primary response/non-response and/or safety;
Part 2 will address the following primary objectives: 
• Evaluate the association between baseline tissue TMB/blood TMB with clinical efficacy 
(ORR) for participants
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Tumor mutational burden (TMB) refers to the total number of nonsynonymous somatic mutations 
that exist within a tumor’s genome. A subset of these mutations, termed neo-antigens, may result 
in an expressed protein that is not recognized by the host’s immune system as self, and therefore 
has the potential to be immunogenic, leading to an anti-tumor immune-mediated response. Tumors 
with a high mutation burden may have a higher rate of neo-antigens which, in principle, would be 
expected to be more immunogenic than tumors with comparatively low mutation burden.1
Therefore, high TMB has been hypothesized to correlate with improved efficacy in patients
 treated 
with I-O therapies. This hypothesis has been supported in multiple publications across IO 
therapies, tumor types, and lines of treatment. The first published study of TMB as a biomarker of 
clinical outcomes
 was
 reported
 by
 Snyder et al (2014), where high TMB was found to be associated 
with efficacy in metastatic melanoma patients treated with anti-CTLA-4 therapy. Further studies 
by Rizvi et al (2015) reported TMB as a biomarker of pembrolizumab efficacy in second-line 
NSCLC patients. Additional studies of pembrolizumab and atezolizumab in NSCLC have been 
generally consistent with these results.2
In 2017, TMB was evaluated in an exploratory post hoc analysis in the BMS-sponsored first line 
NSCLC study, CheckMate 026, which represents the first Phase III study to retrospectively 
demonstrate the impact of TMB on efficacy of a PD-1/L1 inhibitor.
3This analysis demonstrated 
that in patients with high TMB, ORR was numerically higher in the nivolumab arm versus the 
chemotherapy arm (47% vs. 28%) and median PFS was longer in the nivolumab arm compared to 
the chemotherapy arm (9.7 vs. 5.8 mo., HR 0.62; 95% CI 0.38, 1.00). OS was notable, though 
similar (18.3 vs. 18.8 mo. and 1 year OS rates of 64% vs 60%, respectively), between the arms in 
patients with high TMB, although of note, 68% of patients in the chemotherapy arm received 
subsequent nivolumab.3Interestingly, the ORR and mPFS rates observed in the high TMB 
subgroup within CheckMate 026 were similar to those reported in the first line NSCLC study of 
pembrolizumab (Keynote-024), where ORR and mPFS were 45% and 10.3 months, respectively, 
in patients with 50% PD-L1 expression treated with pembrolizumab monotherapy.4
Recent data released in the ongoing phase 3 CA209227 study had met its co-primary endpoint of 
PFS with the nivolumab plus ipilimumab combination versus chemotherapy in first-line advanced 
NSCLC patients whose tumors have high TMB ( 10 mutations/megabase), regardless of PD-L1 
expression. In the study, TMB was evaluated using Foundation Medicine’s analytically validated 
assay FoundationOne CDx. Additionally, based on an interim analysis for overall survival (OS), 
the Data Monitoring Committee recommended that the study continue. The safety profile was 
consistent with previously reported findings in first-line NSCLC for the combination schedule of 
nivolumab 3 mg/kg every two weeks and low-dose ipilimumab (1 mg/kg) every six weeks. 
CA209568 (CheckMate 568) is a two-part, phase 2 open-label study evaluating efficacy and safety 
of first-line treatment with nivolumab and ipilimumab in Stage IV NSCLC (Part 1), as well as the 
safety of combining nivolumab and ipilimumab plus platinum doublet chemotherapy (Part 2). The 
objective of Part 1 is to determine if the administration of nivolumab in combination with 
ipilimumab as first line treatment will lead to clinical benefit as demonstrated by a clinically 
meaningful ORR in PD-L1 positive (membranous staining in 1% tumor cells) and PD-L1 
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negative (< 1% tumor cells) Stage IV NSCLC. An unpublished interim analysis in 2017 
demonstrated that TMB is predictive of clinical response in such population.
Recently the phase 2 POPLAR and phase 3 OAK studies, from Roche/Genentech confirmed 
retrospective data analysis reported analytic and clinical validation for the blood TMB (bTMB) 
assay.5Using the Foundation Medicine
's assay, these studies indicated that high bTMB associated 
with response to atezolizumab in individuals with previously-treated non-small cell lung cancer.
These results indicate that TMB may be an important, predictive independent biomarker that can 
identify a population of first-line NSCLC patients who can potentially benefit from I-O therapy.
Changes
 occurring
 in
 candidate biomarkers
 within
 the
 tumor and peripheral
 blood
 during
 treatment 
or at the time of disease progression may provide an understanding of the mechanism of action 
underlying response (efficacy/safety) and/or underlying acquired resistance. This may help to 
inform on the biology of response to nivolumab + ipilimumab therapy and may inform future 
combination strategies.
3.2 
Background
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality 
worldwide, accounting for approximately 18% of all cancer deaths.6Despite treatment with 
platinum-based chemotherapy, the standard of care for first-line therapy, patients with metastatic 
NSCLC have a median survival of approximately 10 months, and a 5-year survival rate of less 
than 5%.
7
Immunotherapeutic approaches recently have demonstrated clinical efficacy in several cancer 
types, including melanoma and hormone-refractory prostate cancer.
8Tumors may modulate and 
evade the host immune response through a number of mechanisms, including down regulation of 
tumor-specific antigen expression and presentation, secretion of anti-inflammatory cytokines, and 
upregulation of inhibitory ligands. T cell checkpoint regulators such as CTLA-4 and programmed 
death-1 (PD-1, CD279) are cell surface molecules that, when engaged by their cognate ligands, 
induce signaling cascades down-regulating T cell activation and proliferation. One proposed 
model by which therapeutic T cell checkpoint inhibitors derive antitumor activity is through 
disruption of immune tolerance to tumor cell antigens. Nivolumab (BMS-936558) is a fully 
human, IgG4 (kappa) isotype mAb that binds PD-1 on activated immune cells and prevents 
engagement of the receptor with its ligands PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273), 
thereby abrogating inhibitory signals and augmenting the host antitumor response. In early clinical 
trials, nivolumab has demonstrated activity in several tumor types, including melanoma, renal cell 
cancer (RCC), and NSCLC.9In particular, substantial activity has been noted in previously treated 
NSCLC subjects, where objective response rates approached 25%, and the progression-free 
survival (PFS) rate at 24 weeks approached 45%, with no clear differences between squamous and 
non-squamous histology.10In general, nivolumab also has been well tolerated to date, with a 
favorable safety profile relative to anticipated toxicities based on an immunostimulatory 
mechanism of action.11
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Similar
 clinical
 activity
 and
 safety
 have
 also been observed
 among
 a
 cohort
 of
 chemotherapy-naive 
NSCLC subjects treated with nivolumab monotherapy in another trial, and preliminary data 
suggest that PD-L1 tumor expression may be predictive for response to nivolumab.12
Immunotherapies with or without chemotherapy have been recently reported to show clinical 
benefit as first-line therapy for the following patient populations. In metastatic NSCLC with 50% 
PD-L1 expression, first-line PD-1 checkpoint inhibition as monotherapy has been associated with 
clinical benefit (KEYNOTE-024 pembrolizumab vs chemotherapy). However, first-line PD-1 
checkpoint inhibition as monotherapy did not prove to be superior to chemotherapy in a broader, 
PD-L1 selected population in CA209026 (CheckMate-026). These results together show the 
limitations of first-line chemotherapy-free immunotherapy regimen to a relatively small group of 
patients with high (± 50%) PD-L1 expression.
Other drug combination studies evaluated immunotherapy + chemotherapy (± bevacizumab) 
combinations have shown PFS benefit in metastatic nonsquamous NSCLC patients. In the phase 
2 KEYNOTE-021 study, randomized patients with stage IIIB/IV, chemotherapy-naive, 
nonsquamous NSCLC received chemotherapy with or without 24 months treatment with 
pembrolizumab. After a median follow-up of 10.6 months, a significantly greater objective
response rate (55% vs. 29%, P = 0.0016) was observed in the patients who received 
pembrolizumab as well as chemotherapy, compared to those treated with chemotherapy alone. 
While patients were not selected by the amount of PD-L1 expression in their tumor, researchers 
did note a higher response rate (around 80%) for the pembrolizumab and chemotherapy 
combination in tumors with PD-L1 expression greater than or equal to 50%.13
The IMpower150, a controlled phase 3 study evaluated the efficacy and safety of tezolizumab in 
combination with chemotherapy with or without bevacizumab in people with stage IV non-
squamous NSCLC who had not been treated with chemotherapy for their advanced disease. The 
study met its co-primary endpoint of PFS and demonstrated that the combination of atezolizumab 
and bevacizumab plus chemotherapy provided a statistically significant and clinically meaningful 
reduction in the risk of disease worsening or death (PFS) compared to bevacizumab plus 
chemotherapy in the first-line treatment of people with advanced non-squamous non-small cell 
lung cancer (NSCLC).
14
3.2.1 
Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death.
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.
15,16,17
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system.
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T-cell stimulation is a complex process involving the integration of numerous positive as well as 
negative co-stimulatory signals in addition to antigen recognition by the T-cell receptor (TCR).18
Collectively, these signals govern the balance between T-cell activation and tolerance.
3.2.1.1 
Mechanism of Action of Nivolumab
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA-4, ICOS, and BTLA.19 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon- (IFN-) and Bcl-xL. PD-1 expression also been 
noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.20These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
21
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ≤1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-
4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN- release in the mixed lymphocyte reaction (MLR). Using a CMV 
re stimulation assay with human PBMC, the effect
 of
 nivolumab
 on antigen
 specific
 recall
 response 
indicates
 that nivolumab
 augmented
 IFN- secretion
 from
 CMV
 specific
 memory
 T cells
 in
 a
 dose-
dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine analog 
of nivolumab enhances the anti-tumor immune response and result in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).
21
Single dose pharmacokinetics (PK) of nivolumab was evaluated in subjects with multiple tumor 
types in CA209001, whereas multiple dose PK was evaluated in subjects in CA209003. In 
addition, a population pharmacokinetic (PPK) model was developed with data from subjects in 
CA209001, CA209002, and CA209003.
Single dose PK of nivolumab was evaluated in 39 subjects with multiple tumor types in study 
CA209001 in the dose range of 0.3 to 10 mg/kg. The median Tmax across single doses ranged 
from 1.6 to 3 hours with individual values ranging from 0.9 to 7 hours. The geometric means 
of Cmax and AUC(INF) of nivolumab administered at dosages of 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 
and 10 mg/kg demonstrated approximate dose proportionality. The geometric mean of clearance 
(CL), after a single intravenous (IV) dose, ranged from 0.13 to 0.19 mL/h/kg, while mean volume 
of distribution during the terminal phase (Vz) varied between 83 to 113 mL/kg across doses. There 
was moderate variability in PK parameters among subjects, with coefficient of variation (CV) of 
20% to 32% in Cmax, 39% to 47% in AUC(INF), 17% to 43% in clearance, and 23% to 40% in 
Vz. The mean terminal elimination half-life of nivolumab is 17 to 25 days, which is consistent 
with the half-life of endogenous IgG4, indicating that the elimination mechanism of nivolumab 
may be similar to that of IgG4. Both elimination and distribution of nivolumab appear to be 
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independent of dose in the dose range studied. Additional details are provided in the investigator 
brochure. A preliminary PPK model was developed by nonlinear mixed effect modeling using data 
from 379 subjects in CA209001, CA209002 and CA209003. Clearance (CL) of nivolumab is 
independent of dose in the dose range (0.1 to 10 mg/kg) and tumor types studied. The body weight 
normalized dosing produces approximately constant trough concentrations over a wide range of 
body weights, and hence is appropriate for future clinical trials of nivolumab.
3.2.1.2 
Mechanism of Action of Ipilimumab
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), an activation-induced T-cell surface 
molecule, is a member of the CD28:B7 immunoglobulin superfamily that competes with CD28 for 
B7. CTLA-4 mediated signals are inhibitory and turn off T cell-dependent immune responses. 
ipilimumab is a fully human monoclonal IgG1 that binds to the CTLA-4 antigen expressed on a 
subset of T cells from human and nonhuman primates. The proposed mechanism of action for 
ipilimumab is interference of the interaction of CTLA-4 with B7 molecules on APCs, with 
subsequent blockade of the inhibitory modulation of T-cell activation promoted by the CTLA 4/B7 
interaction.
22
3.2.2 
Rationale for Combination of Nivolumab and Ipilimumab
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN- 
production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased 
antitumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer models. 
In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased 
the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and 
dual blockade increased tumor infiltration of T effector cells and decreased intratumoral T 
regulatory cells, as compared to either agent alone.
23
In the clinical setting, the combination of nivolumab and ipilimumab was evaluated in CA209004 
(MDX1106-04), a Phase 1b multiple ascending dose study in subjects with treatment naive and 
previously treated advanced melanoma. Results showed promising activity with higher, tolerable 
toxicity profile compared to ipilimumab alone. Based on this, CA209069 was conducted, a 
randomized double blind Phase 2 study of nivolumab in combination with ipilimumab versus 
ipilimumab monotherapy in subjects with BRAF-wild type (WT) and mutant, with untreated 
unresectable or metastatic melanoma. The regimens used were: nivolumab 1mg/kg plus 
ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks 
versus ipilimumab 3 mg/kg every 3 weeks for 4 doses.24
In subjects with BRAF-WT tumors treated with nivolumab and ipilimumab combination, there 
was improved ORR at 61% (44/72), with 22% (16/72) complete responses (CR), as compared to 
11% (4/37) ORR with 0 CRs in those treated with ipilimumab alone. The median PFS was not 
reached in the combination versus 4.4 months for ipilimumab alone (HR = 0.4). Improved clinical 
outcomes (PFS and ORR) with nivolumab and ipilimumab combination was confirmed by 
CA209067, a randomized Phase 3 study. In subjects with previously untreated, unresectable or 
metastatic melanoma (n = 945), the median PFS was 11.5 months (95% CI, 8.9 to 16.7) in the 
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nivolumab plus-ipilimumab group, 6.9 months (95% confidence interval [CI], 4.3 to 9.5) in the 
nivolumab group, and 2.9 months (95% CI, 2.8 to 3.4) in the ipilimumab group. Significantly 
longer progression-free survival was observed in the nivolumab-plus-ipilimumab group than in the 
ipilimumab group (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; 
P < 0.001) and in the nivolumab group than in the ipilimumab group (hazard ratio, 0.57; 99.5% 
CI, 0.43 to 0.76; P < 0.001). The hazard ratio for the comparison between the nivolumab plus 
ipilimumab group and the nivolumab group was 0.74 (95% CI, 0.60 to 0.92).
25
Table 3.2.2-1: 
Treatment-related adverse events from selected cohorts in
CA209012 (NSCLC)
Arma
No. Subjects 
/ arm
Follow-up 
time 
(median, 
wks)
No. Subjects 
still on 
treatment
Subjects 
with drug-
related AEs
No. Subjects 
with Grade 
3-4 drug-
related AEs
No. subjects 
d/c due to 
drug-related 
AEs 
(all Grades)
Nb
31
88.1 
5 (16%) 
26 (83.9%) 
9 (29%) 
4 (13%)
Ob
40
46.9 
7 (18%) 
29 (72.5%) 
16 (40%) 
3 (8%)
Pb
38
55.9 
9 (24%) 
31 (81.6%) 
14 (36.8%) 
4 (10.5%)
Qb
39
51.1 
7 (18%) 
28 (71.8%) 
13 (33.3%) 
5 (12.8%)
Fc
52
62.2 
5 (13%)  
37 (71%) 
10 (19%) 
5 (10%)
a N: nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks x 4, followed by nivolumab 3 mg/kg every 2 weeks; 
O: nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks; P: Nivolumab 3 mg/kg every 
2 weeks plus ipilimumab 1 mg/kg every 12 weeks; Q: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg 
every 6 weeks; F: nivolumab 3 mg/kg every 2 weeks
b based on February 2016 database lock
c based on March 2015 database lock
Table 3.2.2-2: 
Efficacy of First-Line Treatment of Nivolumab/Ipilimumab
Combination in CA209012 (NSCLC)
Nivo 1 + Ipi 1
Q3W 
N (n=31)
Nivo 1 + Ipi 1
Q6W
O (n=40)
Nivo 3 Q2W + Ipi 1
Q12W 
P (n=38)
Nivo 3 Q2W+ Ipi 1
Q6W 
Q (n=39)
Confirmed ORR, % 
(95% CI)
19
(7.5, 37.5)
33
(19, 49)
47
(31, 64)
39
(23, 55)
PFS rate at 24 wks 
(95% CI)
52 (33, 68) 
47 (31, 62) 
65 (47, 78)
47 (31, 62)
mPFS, mos
(95% CI)
7.8 (2.1, 11.7) 
5.6 (2.7, 9.7) 
8.1 (5.6, 11.6) 
3.9 (2.6, 13.2)
1 year OS rate, % 
(95% CI)
65 (45, 79)
NC
NC
69 (52, 81)
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Table 3.2.2-2: 
Efficacy of First-Line Treatment of Nivolumab/Ipilimumab
Combination in CA209012 (NSCLC)
Nivo 1 + Ipi 1
Q3W 
N (n=31)
Nivo 1 + Ipi 1
Q6W
O (n=40)
Nivo 3 Q2W + Ipi 1
Q12W 
P (n=38)
Nivo 3 Q2W+ Ipi 1
Q6W 
Q (n=39)
Median length of 
follow-up, months
20.3
(2-28)
10.8
(0.4-19)
12.9
(1, 18)
11.7
(1, 18.2)
Clinical activity was observed in all combination cohorts (Table 3.2.2-2), but numerically higher 
response rates were observed in cohorts evaluating the approved dose of nivolumab 3 mg/kg, with 
confirmed response rates of 39 - 47% (cohorts P and Q). Some differences in terms of response 
rate and PFS were observed between cohort P and Q, which is possibly due to different factors 
such as the small sample size in both cohorts, limited follow-up as well as the imbalance between 
the two arms in terms of smoking status.
Table 3.2.2-3: 
Efficacy by Tumor with PD-L1 Expression (≥1%) in CA209012
Nivo 1 + Ipi 1
Q3W
(Arm N n=12)
Nivo 1 Q2W + Ipi 
1 Q6W
(Arm O n=21)
Nivo 3 Q2W + Ipi 
1 Q12W
(Arm P n=21)
Nivo 3 Q2W + Ipi 
1 Q6W
(Arm Q n=23)
ORR, %
25
36
57
57
mPFS, months
(95% CI)
2.6
(1.6, )
5.1
(2.6, )
8.1
(5.6, )
10.6
(3.6, )
PFS rate at 24 wks, 
% (95% CI)
42
(15, 67)
43
(21, 63)
75
(50, 89)
65
(42, 81)
1 year OS rate,
% (95% CI)
58
(27, 80)
NC
90
(66, 97)
83
(60, 93)
When clinical activity was analyzed by PD-L1 expression, there appeared to be higher efficacy in 
subjects with PD-L1 expressing tumors, however interpretation is limited by the small number of 
subjects. Those with PD-L1 ≥1% expressing tumors treated with nivolumab and ipilimumab 
combination in cohorts P and Q had response rates of 57%. PFS appeared to be also higher in these 
subsets as well. 
Using different cutoff levels for PD-L1 expression, the ipilimumab + nivolumab combination is 
consistently superior to nivolumab monotherapy in terms of ORR.
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Figure 3.2.2-1: 
Nivolumab Plus Ipilimumab in First-line NSCLC (CA209012): 
Efficacy Across All Tumor PD-L1 Expression Levels
Combination data based on a February 2016 database lock; monotherapy data based on a March 2015 database lock
In this study, patients with first line PD-L1 negative NSCLC will also receive the combination of 
nivolumab and ipilimumab.
In CA209012 study, given that the number of patients receiving nivolumab 3mg/kg combined with 
ipilimumab 1mg/kg every 6 or 12 weeks was too small, the interpretation of the efficacy data 
reported in this study
 is challenging.
There is an ongoing phase III CA209227 trial that has included a large cohort of PD-L1 < 1% 
patients receiving nivolumab 3 mg/kg Q2w + ipilimumab 1 mg/kg Q6w. This study is under the 
oversight of an independent DMC, which has recommended that the trial continue as planned.  
Recently, BMS announced that study CA209227 has met its co-primary endpoint of PFS 
comparing nivolumab + ipilimumab in high TMB NSCLC, regardless of PD-L1 expression.
Although follow-up is still limited, the PFS and ORRs observed in these cohorts are highly 
encouraging. With comparable efficacy and safety data from cohorts P and Q, the nivolumab plus 
ipilimumab every 6 week dosing schedule (cohort Q) is the selected regimen moving forward.26
Aside from utilizing the approved nivolumab dose in NSCLC, it would also provide the highest 
dose and frequency
 of ipilimumab feasible in a combination regimen.
In updated data from CA209012 as of 18-Feb-2016 indicate 21% of subjects remain on therapy in 
cohorts P+Q. The primary reason for treatment discontinuation was disease progression in 18 
subjects (47.4%) in cohort P, and 20 subjects (51.3%) in cohort Q. The median number of doses 
of nivolumab and ipilimumab was 17 and 3 on cohort P (range 1 to 40/1 to 7), with 8 and 2 in 
cohort Q (range 1-40/1 - 14). There were 8 subjects in cohort P and 15 in cohort Q with disease 
progression within 3 months of study start. Subject characteristics were consistent with a typical 
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advanced/metastatic NSCLC population and roughly balanced across cohorts considering the 
small sample size.
In view of the safety and efficacy data seen with nivolumab every 2 weeks and ipilimumab every 
6 weeks in subjects with NSCLC, it is recommended to proceed with combination dosing for the 
Study CA209592. See Section 3.2.2.1 for nivolumab Q2Week 240 mg dosing rationale.
3.2.2.1 
Rationale for Nivolumab Flat Dosing
Nivolumab has been extensively studied in the NSCLC patient population in studies CA209003, 
CA209063, CA209017, and CA209057, with body weight normalized dosing (mg/kg). Nivolumab 
pharmacokinetics (PK) and exposures of participants in these studies have been characterized by 
population pharmacokinetic (PPK) analysis of data collected from these studies, together with PK 
data from several phase 1, 2, and 3 clinical studies of nivolumab monotherapy in solid tumors. 
Nivolumab PK was determined to be linear, with dose proportional exposures over a dose range 
of 0.1 to 10 mg/kg. Nivolumab clearance and volume of distribution was found to increase with 
increasing body weight, but the increase was less than proportional, indicating that a mg/kg dose 
represents an over-adjustment for the effect of body weight on nivolumab PK.
Flat dosing offers several advantages over body weight normalized dosing, including reduced 
potential for dosing errors and shortened dosage preparation time. A flat dose of 240 mg every 
2 weeks is expected to produce the equivalent average exposure to 3 mg/kg every 2 weeks at the 
median body weight of ~80 kg in nivolumab-treated participants.
A
 PPK
 model
 predicted
 overall
 nivolumab
 exposures
 across
 participants
 with
 a
 wide
 range
 of
 body 
weight (35-160 kg) for a 240 mg every 2 weeks flat dose to be similar to that from 3 mg/kg every 
2 weeks. Although the flat dose is expected to lead to higher exposure in lighter patients, relative 
to the exposure in heavier patients given the relationship between nivolumab PK and body weight, 
the predicted median and 95th percentile of exposures from these regimens are maintained well 
below those in 10 mg/kg every 2 weeks, which was established as a safe and well-tolerated dose.
In addition, the relationship between nivolumab exposure produced by 3 mg/kg and efficacy has 
been found to be relatively flat. Taken together, the PK, safety, and efficacy data indicate that the 
safety and efficacy profile of 240 mg nivolumab will be similar to that of 3 mg/kg nivolumab.
3.2.3 
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab
Long infusion times place a burden on subjects and treatment centers. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of 30 minutes duration in 
subjects will diminish the burden provided no change in safety profile. Previous clinical studies of 
nivolumab monotherapy and ipilimumab monotherapy and the combination of nivolumab and 
ipilimumab have used a 60 minute infusion duration for nivolumab and 90-minute infusion 
duration for ipilimumab (1 - 3 mg/kg dosing for both). However, both nivolumab and ipilimumab 
have been administered at up to 10 mg/kg with the same infusion duration.
Nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg safely 
over long treatment duration. In Study CA209010, (a Phase 2, randomized, double blinded, dose 
ranging study of nivolumab in subjects with advanced/metastatic clear cell RCC) a dose 
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association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 
0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1 - 2 and were 
manageable. An infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided 
at 10 mg/kg) is not expected to present any safety concerns compared to the prior experience at 
10 mg/kg nivolumab dose infused over a 60-minute duration.
Similarly, ipilimumab at 10 mg/kg has been safely
 administered
 over
 90
 minutes.
 In
 the
 CA184022
 
study, where ipilimumab was administered up to a dose of 10 mg/kg, on-study drug related 
hypersensitivity events (Grade 1 - 2) were reported in 1 (1.4%) subject in the 0.3 mg/kg and in 
2 (2.8%) subjects in the 10 mg/kg group. There were no drug-related hypersensitivity events 
reported in the 3 mg/kg group. Across the 3 treatment groups, no Grade 3 - 4 drug-related 
hypersensitivity events were reported and there were no reports of infusion reactions. Ipilimumab 
10 mg/kg monotherapy has also been safely administered as 90 minute infusion in large Phase 3 
studies in prostate cancer (CA184043)
 and
 as adjuvant therapy
 for Stage 3 melanoma (CA184029), 
with infusion reactions occurring in subjects. Administering 1 mg/kg of ipilimumab represents 
one-tenth of the 10 mg/kg dose.
Overall, infusion reactions including high-Grade hypersensitivity reactions have been uncommon 
across nivolumab or ipilimumab clinical studies or the combination of nivolumab and ipilimumab. 
Furthermore, a 30-minute break after the first infusion for the combination cohort will ensure the 
appropriate safety monitoring before the start of the second infusion. Overall, a change in safety 
profile is not anticipated with 30-minute infusion of nivolumab, ipilimumab or combination.
3.2.4 
Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease
Accumulating clinical evidence indicates some subjects treated with immune system stimulating 
agents may develop progression of disease (by conventional response criteria) before 
demonstrating clinical objective responses and/or stable disease. This phenomenon was observed 
in approximately 10% of subjects in the Phase 1 study of nivolumab and also with ipilimumab 
monotherapy.
21
Two hypotheses have been put forth to explain this phenomenon. First, enhanced inflammation 
within tumors could
 lead
 to an
 increase
 in
 tumor size which
 would appear as
 enlarged
 index
 lesions
and as newly visible small non-index lesions. Over time, both the malignant and inflammatory 
portions of the mass may then decrease leading to overt signs of clinical improvement. 
Alternatively, in some individuals, the kinetics of tumor growth may initially outpace anti-tumor 
immune activity. With sufficient time, the anti-tumor activity may dominate and become clinically 
apparent. Therefore subjects will be allowed to continue study therapy after initial investigator 
assessed RECIST 1.1 defined progression if they are assessed to be deriving clinical benefit and 
tolerating study drug. Such subjects must discontinue study therapy upon evidence of further 
progression as defined in Section 8.1.2.
3.2.5 
Rationale for Tumor Mutational Burden Testing
In patients with advanced disease, access to tumor tissue can be challenging and often results in 
limited collection for investigation in clinical trials. This challenge underscores the value for 
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investigating surrogate biomarkers of clinical outcomes using less invasive sampling techniques, 
such as blood collection. Recently the phase 2 POPLAR and phase 3 OAK studies, from 
Roche/Genentech confirmed retrospective data analysis reported analytic and clinical validation 
for the blood TMB (bTMB) assay.
27Using the Foundation Medicine
's assay, these studies 
indicated that high
 bTMB
 associated with
 response
 to atezolizumab in individuals with previously-
treated non-small cell lung cancer. 
Next Generation Sequencing (NGS), also known as Ultra-deep sequencing allows the detection of 
multiple mutations in several genes through parallel sequencing of several DNA fragments. 
 
 
 bTMB data will be generated using 
NGS, through generation of a short fragment DNA library, single fragment clonal amplification 
and massive parallel sequencing and data analysis.
Based on the Part 2 expansion cohort in this study, tumor TMB and blood TMB will be collected 
at baseline. The association of tissue and blood TMB analyses with clinical outcomes will be 
assessed independently.
3.2.6 
Research Hypothesis
Immunomodulatory and pharmacodynamic changes in the peripheral blood and tumor tissue are 
expected in subjects with advanced or metastatic NSCLC receiving nivolumab + ipilimumab. 
Although no hypotheses will be formally tested, the CA209592 study will characterize the 
potential association between biomarkers, including tumor mutational burden, in peripheral blood 
and tumor tissue with clinical efficacy measures, and generate hypotheses for future studies.
3.3 
Benefit/Risk Assessment
Patients with advanced or metastatic NSCLC represent an important unmet medical need. The 
clinical
 activity
 of
 nivolumab
 plus
 ipilimumab
 observed
 to date
 suggests
 the
 potential
 for
 improved
 
clinical outcomes in .subjects with NSCLC.
Published data from CA209012 study in first line NSCLC, showed confirmed response rates of 
39-47% with nivolumab 3 mg/kg Q2w and ipilimumab 1 mg/kg Q6w or Q12w. Activity was 
observed in both PD-L1 expressing and non-expressing tumors. However, higher response rates 
were observed in patients whose tumors express PD-L1 (≥1%) with a confirmed response rate of 
57%).
The safety profile of nivolumab and nivolumab plus ipilimumab is characterized by immune-
related toxicities, such as diarrhea, rash, pneumonitis, liver toxicity, and endocrinopathies. The 
frequencies and intensities of these events in the combination are variable and depend on the 
specific doses and schedule used. In the dosing schedules selected, these events were mostly low 
grade, and manageable with the use of corticosteroids.
To assure an ongoing favorable risk/benefit assessment for participants enrolled into CA209592, 
high-grade, treatment-related adverse events will be closely monitored throughout the conduct of 
the trial. The Medical Monitor will be responsible for reviewing, on a systematic and continuous 
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basis, the safety of participants on this study. This includes a review of serious and non-serious 
adverse events.
More detailed information about the known and expected benefits and risks and reasonably 
anticipated adverse events (AEs) of nivolumab and ipilimumab may be found in the Investigator’s 
Brochures.
4 
OBJECTIVES AND ENDPOINTS
Table 4-1: 
Objectives and Endpoints for Part 1
Objectives
Endpoints
Primary
• To evaluate baseline tumor mutational burden as a 
candidate biomarker of clinical efficacy of 
nivolumab and ipilimumab combination therapy.
• To investigate the potential association between 
candidate biomarkers in peripheral blood and tumor 
tissue at baseline and on-treatment with clinical 
efficacy measures. 
• The clinical efficacy will be measured by the analysis 
endpoint of objective response rate (ORR). The 
association of ORR with candidate biomarkers in 
peripheral blood and tumor tissue at baseline and on-
treatment will be assessed. Candidate biomarkers may 
include:
o Baseline tissue TMB and blood TMB
o Potential biomarkers/signatures (including PD-
L1 expression) both at baseline and on treatment
o Immunomodulatory and pharmacodynamic 
activity
Secondary
• To evaluate efficacy in patient subgroups defined 
by baseline discovery biomarkers.
• ORR, disease control rate (DCR)
• Duration of response (DOR) and time to response 
(TTR)
• Progression free survival (PFS) 
• Overall survival (OS) 
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Table 4-1: 
Objectives and Endpoints for Part 1
Objectives
Endpoints
The objectives and endpoints for Part 2 are listed in Table 4-2.
Table 4-2: 
Objectives and Endpoints for Part 2.
Objectives
Endpoints
Primary
• To evaluate the association between baseline tissue 
TMB/bTMB and clinical efficacy (ORR) for 
participants in Part 2
• The clinical efficacy will be measured by the 
analysis endpoint of objective response rate 
(ORR). The association of ORR with baseline 
tissue TMB and bTMB will be assessed 
Secondary
• To investigate bacterially generated and human 
components enteric biomarkers and identify potential 
associations with clinical outcomes, including safety 
and efficacy for participants
• ORR, PFS, OS
• Incidence of AES, SAEs, and select AEs
• Objective response rate (ORR):The proportion of patients with best overall response (BOR)
of RECIST 1.1 defined confirmed complete response (CR) or partial response (PR) in a pre-
defined study population.
• Disease control rate (DCR):The proportion of patients with best overall response (BOR) of 
RECIST 1.1 defined complete response (CR), partial response (PR), or stable disease (SD) in 
a pre-defined study population
• Duration of response (DOR): DOR is defined as the time between the date of the first 
confirmed response (CR/PR) to the date of the first documented tumor progression (per 
RECIST 1.1) or death due to any cause. Participants who neither progress nor die will be 
censored on the date of their last evaluable tumor assessment. Participants who started any 
subsequent anti-cancer therapy without a prior reported progression will be censored at the last 
evaluable tumor assessment prior to or on the date of initiation of subsequent anti-cancer 
therapy.
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• Time to response (TTR):TTR is measured from the time of first dosing date to the time the 
criteria for CR/PR are first met.
• Progression free survival (PFS):PFS is defined as the time from first dosing date to the date 
of the first documented tumor progression (per RECIST) or death due to any causes.
Participants who neither progress nor die will be censored on the date of their last evaluable 
tumor assessment. Participants who started any subsequent anti-cancer therapy without a prior 
reported progression will be censored at the last evaluable tumor assessment prior to or on the 
date of initiation of subsequent anti-cancer therapy.
• Overall survival (OS):OS is defined as the time from first dosing date to the date of death. If 
a participant didn’t die, OS will be censored on the last date the participant was known to be 
alive.
5 
STUDY DESIGN
5.1 
Overall Design
Protocol CA209592 is an open-label, exploratory Phase 2 trial evaluating nivolumab combined 
with ipilimumab in participants ≥18 years old with histologically confirmed advanced or 
metastatic NSCLC, with no prior systemic anticancer therapy given as primary therapy for 
advanced disease.
In Part 1, participants will undergo screening evaluations to determine eligibility within 28 days 
prior to treatment assignment, and approximately 100patients will be treated with at least 50 PD-
L1 positive patients and 50 PD-L1 negative patients. Tumor sample for PD-L1 status assessment 
is required at screening.
Upon determination of PD-L1 status (cut-off of 1%), 2 cohorts will be defined: PD-L1 positive 
and negative, and patients in each cohort will receive nivolumab + ipilimumab.
In Part 2, approximately 150 participants will be treated with nivolumab + ipilimumab regardless 
of their PD-L1 status.
All participants (Part 1 and Part 2) will be treated with the following:
• nivolumab 240mg IV every 2 weeks + ipilimumab 1 mg/kg IV every 6 weeks until disease 
progression, unacceptable toxicity, withdrawal of consent, the study ends, or a maximum 
treatment duration
 of
 2
 years,
  whichever
 occurs
 first. Participants will be permitted to continue 
on nivolumab +/- ipilimumab beyond initial RECIST 1.1 defined progression, as long as they 
meet the criteria described in Section 8.1.2.
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1: 
Study Design Schematic Part 1 and Part 2
The analysis of the primary endpoint ORR will take place after the last treated subject is followed 
for at least 6 months. Additional survival analysis will be conducted with longer follow-up.
The analysis of the primary endpoint ORR for Part 2 will take place after at least 150 subjects are 
followed for at least 6 months. Additional survival analysis will be conducted with longer 
follow-up.
5.1.1 
Data Monitoring Committee and Other External Committees
A Data Monitoring Committee (DMC) will not be utilized for this study, given the following:
1) This study is an open-label study.
2) Data from the ongoing Phase I CA209012 study has demonstrated a favorable benefit/risk 
profile and a manageable safety that is consistent with prior experience with these agents.
3) Safety data will be closely monitored by BMS, with real time review and assessment of SAEs 
as they are received, and periodic review of all adverse events data for potential new safety 
signals.
5.2 
Number of Participants
Part 1:The planned sample size is approximately 100 patients. Approximately up to 150 
participants are expected to be enrolled to achieve 100 treated participants in the trial. For this 
hypothesis-generating study, the sample size is mainly decided by operational feasibility. No 
formal hypothesis testing will be conducted. Participation in Part 1 is restricted to sites in the US.
Part 2: Approximately 200 participants are expected to be enrolled to achieve 150 treated 
participants. Sites in US and Europe may participate in Part 2. 
5.3 
End of Study Definition
The duration of the study from start of enrollment to analysis of the primary endpoint is expected 
to be approximately 48 months. The study will end once additional survival follow-up has 
concluded.
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5.4 
Scientific Rationale for Study Design
Clinical activity of nivolumab and ipilimumab combination has shown superior efficacy over 
monotherapy in different tumor types including NSCLC. Although efficacy is superior in PD-L1 
positive patients, responses were also observed in subjects with tumors that are not expressing PD-
L1 ligand.
Unfortunately, not all patients will respond to immune checkpoint blockade, therefore there is the
need for a better understanding of factors that can predict response and progression.
CA209592 study has been designed to explore the immunomodulatory and pharmacodynamic
activity of nivolumab and ipilimumab, and potential biomarkers/signatures correlated with 
response and safety in both PD-L1 positive and negative subjects.
5.5 
Justification for Dose
The dose and schedule of nivolumab and ipilimumab in this trial was selected in part based on the 
data observed in the CA209012 study28, which demonstrated activity of the combination of 
nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks in both PD-L1+ and 
PD-L1- tumors, coupled with a manageable safety profile.
Nivolumab flat dosing offers several advantages over body weight normalized dosing, including 
reduced potential for do
29sing errors and shortened dosage preparation time. A flat dose of 240 mg 
every 2 weeks is expected to produce the equivalent average exposure to 3 mg/kg every 2 weeks 
at the median body weight of ~80 kg in nivolumab-treated participants.
CA209-592 will include nivolumab 240mg
 every
 2
 weeks
 plus
 ipilimumab
 1
 mg/kg
 every
 6
 weeks.
5.6 
Duration of Treatment with Nivolumab plus Ipilimumab
The optimal duration of immunotherapy is an important question and continues to be investigated.  
Clinical trials across different tumors types in the nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 2-4 
months, and emerging data suggests that benefit can be maintained in the absence of continued 
treatment. A
 recent
 analysis
 in
 a
 melanoma study
 suggests
 the
 majority
 of
 patients who discontinue 
nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of further 
treatment.
30Furthermore, a limited duration of ipilimumab, including only 4 induction doses, 
resulted in long term survival in patients with metastatic melanoma, with a sustained plateau in 
survival starting around 2 years after the start of treatment.31
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129
 subjects
 with
 NSCLC),
 specified
 a
 maximum
 treatment duration
 of
 2
 years.
 
 Among 
16 subjects with non-small cell lung cancer (NSCLC) who discontinued nivolumab after 
completing 2 years of treatment, 12 subjects were alive >5 years and remained progression-free 
without any subsequent therapy. In the CA209003 NSCLC cohort, the overall survival (OS) curve 
begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.32These 
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survival outcomes are similar to phase 3 studies in previously treated NSCLC, in which nivolumab 
treatment was continued until progression or unacceptable toxicity (2 year OS rates of 23% and 
29%, and 3 year OS rates of 16%-18% for squamous and non-squamous NSCLC respectively).33
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in subjects with previously treated, PD-L1-positive, advanced 
NSCLC which specified a  maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR = 0.72, p = 0.00017) and 
pembrolizumab 10 mg/kg (HR = 0.60, p < 0.00001) compared to docetaxel, with an OS plateau 
developing beyond 2 years in both pembrolizumab arms. Among 690 patients who received 
pembrolizumab, 47 patients completed 2 years of pembrolizumab and stopped treatment. Most 
were able to maintain their response, including those with stable disease, with only 2 patients (4%) 
having confirmed progression after stopping at 2 years.34
Keynote-006 was a randomized phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2 year duration of pembrolizumab 
treatment. 104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
treatment. With a median follow-up of 9 months after completion of pembrolizumab, the estimated 
risk of progression or death was 9% in these patients.
35
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 2 
years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression.  Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; HR=0.42 (95% CI, 
0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note,  
the PFS curves in both groups plateau approximately 1 year after randomization (ie, 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.36
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, in 
this study, treatment will be given for a maximum of 2 years from the start of study treatment.
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6 
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1 
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
and laboratory testing.
2) Type of Participant and Target Disease Characteristics
a) Subjects with histologically confirmed Stage IV or recurrent NSCLC (per the 7th 
International Association for the Study of Lung Cancer classification [Goldstraw 2007]), 
squamous
 or non-squamous
 histology, with
 no prior systemic
 anticancer
 therapy
 (including 
EGFR and ALK inhibitors) given as primary therapy for advanced or metastatic disease. 
Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last administration 
of the prior regimen occurred at least 6 months prior to enrollment.
Prior chemoradiation for locally advanced disease is also permitted as long as the last 
administration of chemotherapy or radiotherapy (which ever was given last) occurred at 
least 6 months prior to enrollment.
b) Measurable disease by CT or MRI per RECIST 1.1 criteria. Tumor assessment performed 
within 28 days of start of study treatment.
c) All participants must have tissue submitted during screening. This may include either a 
formalin-fixed paraffin-embedded (FFPE) tissue block or a minimum of 15 unstained 
tumor tissue slides. 
Part 1: For cohort assignment purposes (PD-L1 status determination), archival tissue 
samples  3 months old will be allowed to determine PD-L1 IHC results. Fresh pre-dose 
biopsy samples (5 cores: 3 in FFPE and 2 in HypoThermosol®) will still need to be 
submitted.
Part 2: a fresh biopsy (preferred) or archival sample ( 3 months old) is required for 
enrollment, but treatment may start before test results are received.  
d) ECOG Performance Status 0 or 1.
3) Age and Reproductive Status
a) Males and Females, ages 18 years (or age of majority) and older.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment.
c) Women must not be breastfeeding.
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s)
 of
 contraception
 (Appendix 4) for the duration of treatment followed by a period 
of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug 
to undergo five half-lives. WOCBP treated with nivo + ipi combination should use an 
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adequate method to avoid pregnancy for 5 months (30 days plus the time required for 
nivolumab to undergo five half-lives) after the last dose of investigational drug.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of treatment followed by a period 
of 90 days (duration of sperm turnover) plus the time required for the investigational drug 
to undergo five half-lives. Males treated with nivo + ipi combination who are sexually 
active with WOCBP must continue contraception for 7 months (90 days plus the time 
required for nivolumab to undergo five half-lives) after the last dose of investigational 
drug. In addition, male participants must be willing to refrain from sperm donation during 
this time. 
f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, (Appendix 4) 
which have a failure rate of < 1% when used consistently and correctly.
6.2 
Exclusion Criteria
1) Medical Conditions
a) Subjects with known EGFR mutations which are sensitive to available targeted inhibitor 
therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] 
substitution mutations) are excluded. All subjects with non-squamous histology must have 
been
 tested for EGFR
 mutation
 status; use of
 an FDA-approved
 test
 is
 strongly
 encouraged. 
Non-squamous subjects with unknown or indeterminate EGFR status are excluded.
b) Subjects with known ALK translocations which are sensitive to available targeted inhibitor 
therapy are excluded. If tested, use of an FDA-approved test is strongly encouraged. 
Subjects with unknown or indeterminate ALK status may be enrolled.
c) Subjects with untreated CNS metastases are excluded. 
i) Subjects are eligible if CNS metastases are adequately treated and subjects are 
neurologically returned to baseline (except for residual signs or symptoms related to 
the CNS treatment) for at least 2 weeks prior to enrollment. In addition, participants 
must be either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily 
prednisone (or equivalent) for at least 2 weeks prior to treatment assignment.
d) 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.
e) Subjects with an active, known or suspected autoimmune disease. 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.
f) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
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enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
g) Subjects with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity. 
h) Subjects with serious or uncontrolled medical disorders and any known medical condition 
that, in the investigator’s opinion, would increase the risk associated with study 
participation or study drug administration or interfere with the interpretation of safety 
results.
i) Subjects with a known history of a positive test for human immunodeficiency virus (HIV) 
or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally. See Appendix 8.
2) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
b) Treatment with botanical preparations (eg herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 2 
weeks prior to treatment.
3) Physical and Laboratory Test Findings
Screening laboratory values that meet the following criteria (using CTCAE v4):
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100 x 103/μL
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine > 1.5 x ULN,unless creatinine clearance  40 mL/min (measured or 
calculated using the Cockroft-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
f) AST > 3.0 x ULN 
g) ALT > 3.0 x ULN 
h) Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome who must have a total 
bilirubin level of < 3.0x ULN).
i) Any positive test for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g. 
Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody 
(anti-HCV) positive (except if HCV-RNA negative)
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components.
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5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3 
Lifestyle Restrictions
Not applicable. No restrictions are required
6.4 
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently registered for treatment. A minimal set of screen failure information is required
to ensure transparent reporting of screen failure participants, to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes date of consent, demography, screen failure 
details, eligibility criteria, and any serious AEs.
6.4.1 
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (i.e., participant has not been randomized / has 
not been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or Lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to treatment assignment is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7 
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study treatment 
allocation.
Study treatment includes both Investigational [Medicinal] Product (IP/IMP) and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
• nivolumab
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• ipilimumab
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications
 used
 as
 support
 or escape
 medication
 for
 preventative,
 diagnostic,
 or
 therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
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Table 7-1: 
Study treatments for CA209592
Product Description / Class 
and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
nivolumab/BMS -936558-01
Solution for Injection
10 mg/ml 
IP 
Open Label
10 mL vial containing a clear to opalescent, 
colorless to pale yellow liquid; may contain 
particulates;
5 vials/carton
Store at 2-8°C; Protect 
from light and freezing.
ipilimumab
Solution for Injection
5 mg/ml 
IP 
Open Label
40mL vial containing a clear to slightly 
opalescent, colorless to pale yellow liquid. 
May contain particulates;
4 vials/carton
Store at 2-8°C; Protect 
from light and freezing.
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7.1 
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1: 
Selection and Timing of Dose
Study Treatment
Unit dose strength(s)/
Dosage level(s)
Dosage formulation
Frequency of Administration
Route of 
Administration
nivolumab
+
240mg
Every 2 weeks
IV
ipilimumab
1 mg/kg
Every 6 weeks
IV
7.1.1 
Dosing Details
Participants should
 begin
 study
 treatment
 within
 3
 calendar
 days
 of
 treatment
 assignment in
 IWRS. 
All participants will receive nivolumab at a flat dose of 240mg as a 30 minute IV infusion, on 
Day 1, Day 15, and Day 29 of each treatment cycle (every 2 weeks), and ipilimumab at a dose of 
1 mg/kg as a 30 minute IV infusion on Day 1 and every 6 weeks. Treatment will continue until 
progression, unacceptable
 toxicity, withdrawal
 of
 consent,
 the
 study
 ends, or a
 maximum
 treatment 
duration of 2 years, whichever occurs first. 
Participants may be dosed with nivolumab no less than 12 days from the previous dose. There is 
no premedication recommended.
Instructions for dilution of nivolumab injection are provided in the nivolumab IB, or pharmacy 
manual. Care must be taken to assure sterility of the prepared solution as the product does not 
contain any antimicrobial preservative or bacteriostatic agent. 
Instructions for dilution of ipilimumab injection are provided in the ipilimumab IB or pharmacy 
manual. Ipilimumab is to be administered as a 30 minute IV infusion. 
Dosing calculations for ipilimumab should be based on the body weight assessed at baseline. It is 
not necessary to re-calculate subsequent doses if the participants’ weight is within 10% of the 
weight used to calculate the previous dose. All doses should be rounded up or to the nearest 
milligram per institutional standard.
When study drugs (nivolumab and ipilimumab) are to be administered on the same day, nivolumab 
is to be administered first. Nivolumab infusion must be promptly followed by a saline flush to 
clear the line of nivolumab before starting the ipilimumab infusion. The second infusion will 
always be the ipilimumab study drug and will start after the infusion line has been flushed, filters 
changed and patient has been observed to ensure no infusion reaction has occurred.  The time in 
between infusions is expected to be approximately 30 minutes but may be more or less depending 
on the situation. Separate infusion bags and filters should be used when administering nivolumab 
and ipilimumab on the same day. Participants should be carefully monitored for infusion reactions. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.4.3.
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Treatment with nivolumab (±ipilimumab) beyond initial investigator-assessed RECIST 1.1 
defined progression is permitted if the participant has investigator assessed clinical benefit and is 
tolerating the study drugs (as specified in Section 8.1.2).
No dose modifications are allowed for nivolumab. Doses of nivolumab and/or ipilimumab may be 
interrupted,
 delayed,
 or
 discontinued
 depending
 on
 how
 well the participant tolerates
 the
 treatment. 
Dosing visits for nivolumab can be skipped at D15 and D29 only. For more details, see Section 
7.4.1 (dose delays), Section 7.4.5(resuming treatment), and Section 8. (Discontinuation). 
7.2 
Method of Treatment Assignment
All participants will be centrally enrolled using an Interactive Response Technology (IRT). Before 
the study is initiated, each user will receive log in information and directions on how to access the 
IRT.
Study
 treatment
 will be
 assigned and
 dispensed at the
 study
 visits as
 listed
 in
 Schedule of
 Activities
 
(Section 2).
7.3 
Blinding
This is an open-label study, blinding procedures are not applicable.
7.4 
Dosage Modification
7.4.1 
Dose Delay Criteria 
Dose delay criteria apply to all drug-related AEs. Treatment delays are allowable up to 6 weeks 
for nivolumab and 12 weeks for ipilimumab from the last dose (any dose delays greater than this
will require approval from the medical monitor).
Tumor assessments for all participants should continue as per protocol even if dosing is delayed.
Nivolumab and ipilimumab administration should be delayed for the following:
• Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
• Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
• Grade 3 skin, drug-related adverse events
• Grade 3 drug-related laboratory abnormality with the following exceptions:
o Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
o Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation 
• Any AE, laboratory abnormality or inter-current illness which, in the judgment of the
investigator, warrants delaying the dose of study medication.
Participants that have drug-related toxicities that meet the criteria for dose delay, should have both 
drugs (ipilimumab and nivolumab) delayed until retreatment criteria are met. (Exceptions apply to 
the retreatment criteria after dose delay of ipilimumab and nivolumab for Grade ≥3 amylase and 
lipase abnormalities that are not associated with symptoms or clinical manifestations of 
pancreatitis and that are attributed to ipilimumab alone.)
Rescheduling:
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Nivolumab may be delayed until the next planned ipilimumab dose if the next ipilimumab dose is 
scheduled within the next 12 days. This will permit periodic ipilimumab dosing to be synchronized 
with nivolumab. Dosing for nivolumab can be skipped at D15 and D29 only.
Ipilimumab should be dosed at the specified interval regardless of any delays in intervening 
nivolumab doses. However, in order to maintain periodic synchronized dosing of ipilimumab and 
nivolumab, the dosing days of nivolumab (every 2 weeks ±3 days) and ipilimumab (every 6 weeks 
±5 days) may be adjusted within the permitted window, as long as consecutive nivolumab doses 
are given at least 12 days apart. Ipilimumab may be delayed beyond the 5 day window if needed 
to synchronize with the next nivolumab dose.
If an ipilimumab dose is delayed beyond 6 weeks from the prior ipilimumab dose, then subsequent 
ipilimumab doses should rescheduled to maintain the 6 week interval between consecutive 
ipilimumab doses.
A dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 8.1.1.
7.4.2 
Dose Reductions
There will be no dose reductions for nivolumab or ipilimumab.
7.4.3 
Treatment of Infusion Reactions
Since nivolumab and ipilimumab contains only human immunoglobulin protein sequences, they 
are unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 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) 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 or ipilimumab (as applicable) administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but 
responds promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic 
medications indicated for ≤24 hours):
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nivolumab
• 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 or 
ipilimumab (as applicable) 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 or ipilimumab (as applicable)
infusions. If necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be 
used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae (eg, renal 
impairment, pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory 
support indicated):
• Immediately discontinue infusion. 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 or ipilimumab (as applicable) 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).
7.4.4 
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered immuno-
oncology agents in this protocol. Early recognition and management of AEs associated with 
immuno-oncology agents may mitigate severe toxicity. Management Algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs:
• Gastrointestinal
• Renal
• Pulmonary
• Hepatic
• Endocrinopathy
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• Skin
• Neurological
• Myocarditis
The above algorithms are found in both the nivolumab and ipilimumab Investigator Brochures, as 
well as in Appendix 7.
7.4.5 
Criteria to resume dosing
7.4.5.1 
Criteria to resume nivolumab dosing
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions: 
• Subjects may resume treatment in the presence of Grade 2 fatigue
• Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity
• For subjects with Grade 2 AST, ALT, or Total bilirubine elevations, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete.
• Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 8.1.1) should have treatment permanently discontinued. 
• Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor.
• Subjects with Grade 1-3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may resume treatment after consultation with the BMS 
Medical Monitor. 
• Participants who received systemic corticosteroids for management of any drug-related
toxicity must be off corticosteroids or have tapered down to an equivalent dose of prednisone
≤10 mg/day.
• Participants who delay study treatment due to any Grade ≥3 amylase or lipase abnormality
that is not associated with symptoms or clinical manifestations of pancreatitis, and that is
assessed by the investigator to be related to ipilimumab and not to nivolumab, may resume
nivolumab when the amylase or lipase abnormality has resolved to Grade < 3. The BMS
Medical Monitor should be consulted prior to resuming nivolumab in such participants.
• Dose delay of nivolumab which results in treatment interruption of > 6 weeks requires 
treatment discontinuation, with exceptions as noted in Section 8.1.1.
One exception to note is when ipilimumab and nivolumab doses are delayed due to drug-related 
Grade ≥3 amylase or lipase abnormalities not associated with symptoms or clinical manifestations 
of pancreatitis. If the investigator assesses the Grade ≥3 amylase or lipase abnormality to be 
related to ipilimumab and not related to nivolumab, nivolumab may be resumed when the amylase 
or lipase
 abnormality
 resolves
 to Grade
 <
 3
 but ipilimumab may only be resumed when the amylase 
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or lipase abnormality resolves to Grade 1 or baseline. Investigator attribution of this toxicity to the 
ipilimumab dosing must be clearly noted in the participant’s medical chart. The BMS Medical 
Monitor should be consulted prior to resuming nivolumab in such participants.
See Section 8for treatment discontinuation criteria.
7.4.5.2 
Criteria to resume ipilimumab dosing
Participants may resume treatment with ipilimumab
 when
 drug-related
 AE(s)
 resolve(s)
 to Grade 1 
or baseline value, with the following exceptions:
• Participants may resume treatment in the presence of Grade 2 fatigue.
• Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity. 
• Participants with baseline Grade 1 AST/ALT or total bilirubin elevations 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.
• Participants with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters (Section 8.1.1) should have treatment permanently discontinued.
• Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor.
• Participants who received systemic corticosteroids for management of any drug-related 
toxicity must be off corticosteroids or have tapered down to an equivalent dose of prednisone 
≤10 mg/day.
• Subjects with Grade 1-3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may resume treatment after consultation with the BMS 
Medical Monitor. 
• Dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 8.1.1. Although there is 
overlap among the discontinuation criteria, if discontinuation criteria are met for ipilimumab, 
but not for nivolumab, treatment with nivolumab may continue if ipilimumab is discontinued.
Ipilimumab may not be resumed sooner than 6 weeks (±5days) after the prior ipilimumab dose.
In general, participants who meet criteria to resume ipilimumab will also have met criteria to 
resume nivolumab, so it should be feasible to synchronize dosing of both drugs when resuming 
ipilimumab. In order to facilitate this, the dosing days of nivolumab and ipilimumab may be 
adjusted within the permitted ±5 day window, as long as consecutive nivolumab doses are given 
at least 12 days apart.
One exception to note is when ipilimumab and nivolumab doses are delayed due to drug-related 
Grade ≥3 amylase or lipase abnormalities not associated with symptoms or clinical manifestations 
of pancreatitis. If the investigator assesses the Grade ≥3 amylase or lipase abnormality to be 
related to ipilimumab and not related to nivolumab, nivolumab may be resumed when the amylase 
or lipase
 abnormality
 resolves
 to
 Grade
 <
 3
 but ipilimumab may only be resumed when the amylase 
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or lipase abnormality resolves to Grade 1 or baseline. Investigator attribution of this toxicity to the 
ipilimumab dosing must be clearly noted in the participant’s medical chart. The BMS Medical 
Monitor should be consulted prior to resuming nivolumab in such participants.
See Section 8for treatment discontinuation criteria.
7.5 
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets).
• Required storage conditions for nivolumab and ipilimumab are provided in Table 7-1.
• Further guidance on preparation of nivolumab and ipilimumab for infusion will be provided in 
a separate Pharmacy Manual.
• Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2.
7.6 
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. Sites should discuss discrepancies with the participant at each on-treatment study 
visit. 
7.7 
Concomitant Therapy
7.7.1 
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to study drug administration in the study are 
described below. Medications taken within 4 weeks prior to study drug administration and at any 
time during the study must be recorded on the CRF.
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event):
• Immunosuppressive agents
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• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.2)
• Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of the disease under study). Allowable palliative radiation is described in Section 7.7.2.2.
• Any botanical preparation (eg herbal supplements or traditional Chinese medicines) intended 
to treat the
 disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.
No concomitant medications (prescription, over-the-counter or herbal) are to be administered 
during study unless they are prescribed for treatment of specific clinical events. Any concomitant 
therapies must be recorded on the CRF.
7.7.2 
Other Restrictions and Precautions
7.7.2.1 
Corticosteroids 
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of treatment 
assignment are excluded. Participants are permitted the use of topical, ocular, intra-articular, 
intranasal, and inhalational corticosteroids (with minimal systemic absorption). Adrenal 
replacement steroid doses > 10 mg daily prednisone are permitted. A brief (less than 3 weeks) 
course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of 
non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact 
allergen) is permitted.
7.7.2.2 
Palliative Radiotherapy
Prior palliative radiotherapy must have been completed at least 2 weeks prior to treatment. 
Non-target bone lesions that do not include lung tissue in the planned radiation field and CNS 
lesions may be treated with palliative radiotherapy while participants remain on study treatment. 
The potential for overlapping toxicities with radiotherapy and nivolumab/ipilimumab currently is 
not known; however, anecdotal data suggests that it is tolerable. As concurrent radiotherapy and 
nivolumab/ipilimumab have not been formally evaluated, in cases where palliative radiotherapy is 
required for a tumor lesion, then nivolumab/ipilimumab 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 plus ipilimumab. This is also applicable to subjects that discontinue 
ipilimumab and receive nivolumab alone.
Details of palliative radiotherapy should be documented in the source records and case report form 
(CRF). Details in the source records should include: dates of treatment, anatomical site, dose 
administered and fractionation schedule, and AEs. 
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Participants requiring palliative radiotherapy should be carefully assessed for disease progression. 
Participants considered as having progressive disease are required to discontinue study therapy, 
unless eligible to continue treatment beyond progression per the guidance in Section 8.1.2.
7.7.2.3 Imaging Contraindications
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants with renal insufficiency should be assessed as to 
whether or not they should receive contrast and if so, what type and dose of contrast is appropriate.
7.8 
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration specified in 
Section 7.1.Study treatment will be provided via an extension of the study, a rollover study 
requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of BMS.
BMS reserves
 the
 right to terminate
 access
 to BMS
 supplied
 study
 treatment if any
 of
 the
 following 
occur: a) the study is terminated due to safety concerns; b) the development of nivolumab and/or 
ipilimumab is terminated for other reasons, including but not limited to lack of efficacy and/or not 
meeting the study objectives; c) the participant can obtain medication from a government 
sponsored or private health program. In all cases BMS will follow local regulations.
8 
DISCONTINUATION CRITERIA
8.1 
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
• Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified
follow-up procedures, as outlined in Section 2. The only exception to this is when a participant 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by participant to provide this information
o Participants should notify the investigator of the decision to withdraw consent from 
future follow-up in writing, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the 
withdrawal is from further treatment with study treatment only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF 
page.
o In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as 
appropriately directed in accordance with local law.
o If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent.
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• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant
• Termination of the study by Bristol-Myers Squibb (BMS)
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness
Discontinuation of the study treatment for abnormal liver tests should be considered by the
investigator when a participant meets one of the conditions outlined in Section 9.2.7OR 
Appendix 7 or if the investigator believes that it is in best interest of the participant.
When study treatment is discontinued, the reason for the discontinuation must be documented in 
the participant’s medical records and entered on the appropriate case report form (CRF) page.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study treatment will be permanently 
discontinued in an appropriate manner (e.g., dose tapering if necessary for participant safety). 
Please call the BMS Medical Monitor within 24 hours of awareness of the pregnancy. If the 
investigator determines a possible favorable benefit/risk ratio that warrants continuation of study 
treatment, a discussion between the investigator and the BMS Medical Monitor/designee must 
occur.
8.1.1 
Nivolumab or Ipilimumab Dose Discontinuation
Treatment with nivolumab or ipilimumab must be permanently discontinued for any of the 
following:
• Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment.
• Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
⎯Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation
⎯Grade 3 drug-related endocrinopathies, adequately controlled with only 
physiologic hormone replacement do not require discontinuation. Adrenal 
insufficiency requires discontinuation regardless of control with hormone 
replacement. 
⎯Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except:
Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation.
Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:
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• Grade ≥3 drug-related AST, ALT or Total Bilirubin requires 
discontinuation. In most cases of Grade 3 AST or ALT elevation, 
study drug(s) will be permanently discontinued. If the investigator 
determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug(s), a discussion between the investigator 
and the BMS Medical Monitor/designee must occur.
• Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
• Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
⎯Grade 4 neutropenia ≤7 days
⎯Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
⎯Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset
• Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, 
may not require discontinuation after discussion with and approval from the BMS Medical 
Monitor.
• Any 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/ 
ipilimumab dosing.
• Any event that leads to delay in dosing lasting > 6 weeks (or 12 weeks for ipilimumab) from 
the previous dose requires discontinuation, with the following exceptions:
1. Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. 
2. Dosing delays lasting > 6 weeks (or 12 weeks for ipilimumab) from the previous 
dose that occur for non-drug-related reasons may be allowed if approved by the 
BMS medical monitor. 
• In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of 
this event. In most cases, the study drug will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for participant safety). Please contact the Sponsor or 
designee within 24 hours of awareness of the pregnancy. If the investigator determines a 
possible favorable benefit/risk ratio that warrants continuation of study drug, a discussion 
between the investigator and the Sponsor or designee must occur.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks (or 12 weeks 
for ipilimumab), the BMS medical monitor must be consulted. Tumor assessments should continue 
as per protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory 
studies should also continue every 6 weeks or more frequently if clinically indicated during such 
dosing delays.
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The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab. Although there is overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
If a participant meets criteria for discontinuation and investigator is unable to determine whether 
the event is related to both or one study drug, the participant should discontinue both nivolumab 
and ipilimumab and be taken off the treatment phase of the study. Continuation of ipilimumab 
after discontinuation of nivolumab is not allowed on study.
8.1.2 
Disease Progression 
In general, study treatment must be discontinued at the time of disease progression per RECIST 
1.1 criteria. However, accumulating evidence indicates a minority of subjects treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD.
21
Participants may be permitted to continue study treatment with nivolumab (with or without 
ipilimumab) beyond initial investigator assessed RECIST 1.1 defined PD, upon approval by the 
BMS Medical Monitor or Study Director, as long as they meet the following criteria:
• Investigator-assessed clinical benefit.
• Tolerance of study therapy
• Stable performance status
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases) 
• Participant provides written informed consent prior to receiving additional nivolumab 
treatment. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply.
Upon progression, a radiographic assessment/scan should be performed within 6 weeks of initial 
investigator-assessed progression to determine whether there has been a decrease/ limited change
in the tumor size or continued
 PD. The
 assessment of
 clinical
 benefit should be balanced by clinical 
judgment as
 to whether
 the
 participant
 is
 clinically deteriorating and unlikely to receive any benefit 
from continued treatment with nivolumab.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment (with or without ipilimumab), the participant should remain on the trial and continue 
according to the Schedule of Activities in Section 2.
For participants who continue nivolumab (with or without ipilimumab) beyond progression, 
further progression is defined as an additional 10% increase in tumor burden with a minimum 
5 mm absolute increase from time of initial PD. This includes an increase in the sum of diameters 
of all target lesions and/ or the diameters of new measurable lesions compared to the time of initial 
PD. Nivolumab treatment should be discontinued permanently upon documentation of further 
progression.
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New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
8.1.3 
Post Treatment Study Follow-Up
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window (Refer to Section 2). At the time of this request, each participant will 
be contacted to determine their survival status unless the participant has withdrawn consent for all
contacts or is lost to follow-up.
8.1.4 
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
• Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
• The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
• In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.2 
Lost to Follow-Up
• All reasonable efforts must be
 made
 to locate
 participants
 to determine
 and re
port
 their
 ongoing 
status. This includes follow-up with persons authorized by the participant.
• Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
• If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
• If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
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contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
• The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
• If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9 
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and timing are summarized in the Schedule of Activities (Section 2).
• Protocol waivers or exemptions are not allowed.
• All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
• Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before treatment assignment. The investigator will 
maintain a screening log to record details of all participants screened and to confirm eligibility 
or record reasons for screening failure, as applicable.
• Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities.
Additional measures beyond those described in Section 2, including non-study required laboratory 
tests, should be performed as clinically indicated or to comply with local regulations. Laboratory 
toxicities (eg, suspected drug induced liver enzyme evaluations) will be monitored during the 
follow-up phase via on site/local labs until all study drug related toxicities resolve, return to 
baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure andAppendix 7.
Some of the assessments referred to in this protocol may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or
assessments may be performed as clinically necessary or where required by institutional or local
regulations.
9.1 
Efficacy Assessments
Overall survival
 is one of
 the secondary endpoints in this study. Every
 effort will be made to collect 
survival data on all participant including those withdrawn from treatment for any reason, who are 
eligible
 to participate
 in
 the
 study
 and
 who
 have
 not withdrawn
 consent
 for
 survival
 data
 collection. 
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If the death of a participant is not reported, all dates in this study representing a date of participant 
contact will be used in determination of the participant’s last known date alive. 
9.1.1 
Imaging Assessment for the Study
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled timepoints and/or at an outside institution) should be collected for
RECIST 1.1 tumor assessment and reviewed.
9.1.1.1 
Efficacy Assessments using CT scan or MRI
The imaging assessment schedule is provided in Table 9.1.1.1-1.
Baseline imaging is required within 28 days prior to first dose, including CT chest, CT/MRI 
abdomen, and pelvis (with contrast, unless contraindicated), plus any area that is being monitored. 
Participants must have an MRI of the brain at screening. Participants with a history of brain 
metastasis should have surveillance MRI approximately every 12 weeks, or sooner if clinically 
indicated.
Tumor assessments should continue every 8 weeks (± 1 week) from first dose for the first 
12 months on treatment, then every 12 weeks (± 1 week) until documented radiographic disease 
progression. CT chest and CT/MRI abdomen and pelvis (with contrast, unless contraindicated), 
plus any area that is being monitored. Use the same imaging method as was used at screening.
After 3 years on study, tumor assessments for long-term survivors can be performed at a frequency 
per institutional guidelines or every 24 weeks based on NCCN surveillance guidelines.
In Part 1, anadditional planned optional CT scan is suggested at W5, to guide tumor biopsy as 
needed and to support predicting tumor response based on early tumor growth characteristics using 
a mathematical tumor growth model. 
For participants who discontinue study treatment for reasons other than radiographic PD, follow-
up scans should continue to be performed according to the on-study assessment schedule until PD, 
withdrawal of consent, start of subsequent therapy, death, or lost to follow-up.
Participants who remain on therapy beyond initial progression, will have an assessment performed 
within 6 weeks to confirm progression (see section 8.1.2).
Table 9.1.1.1-1: 
Imaging Assessment Schedule (Part 1 and Part 2)
Study Day
Event Relative to Dosing 
CT
Biopsyc
Part 1
Screeninga, ,c
pre-dose
X
X
Cycle 1 Day 15 (Week 3)
pre-dose
Cycle 1 Day 29 
(Week 5)
-
Xe
X
Cycle 2 Day 15
pre-dose
X
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Table 9.1.1.1-1: 
Imaging Assessment Schedule (Part 1 and Part 2)
Study Day
Event Relative to Dosing 
CT
Biopsyc
(Week 9)
Every 8 weeks(± 1 week) from first 
dose, for first 12 months on treatment
-
X
After 12 months on treatment, Every 
12 weeks(± 1 week) until documented 
radiographic disease progression.
-
X
Progression
-
X
X
Part 2
Screeninga, ,c
pre-dose
X
Every 8 weeks (± 1 week) from first 
dose, for first 12 months on treatment
-
X
After 12 months on treatment, Every 12 
weeks (± 1 week) until documented 
radiographic disease progression.f
-
X
a Screening assessments should be performed within 28 days of treatment assignment.
cAt screening, a fresh biopsy will be taken prior to treatment.
e W5 optional CT Scan, to guide biopsy as needed and to support predicting the tumor response based on early tumor 
growth characteristics using a mathematical tumor growth model.
f After 3 years on study, tumor assessments for long-term survivors can be performed at a frequency per institutional 
guidelines or every 24 weeks based on NCCN surveillance guidelines.
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9.2 
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant
's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3.
9.2.1 
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE information should begin at initiation of study treatment until 
100 days after the last dose of study therapy, at the timepoints specified in the Schedule of 
Activities (Section 2). Non-serious AE information should also be collected from the start of a 
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placebo lead-in period or other observational period intended to establish a baseline status for the 
participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later protocol-
specified procedure (e.g., a follow-up skin biopsy).
• The investigator must report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure. Medical occurrences that begin 
before the start of study treatment but after obtaining informed consent will be recorded on the 
appropriate section of the eCRF section.
• All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
For participants assigned to treatment and never treated with study drug, SAEs should be collected 
for 30 days from the date of treatment assignment.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2 
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
9.2.3 
Follow-up of AEs and SAEs
• Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
• Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•  All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
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After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.2).
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated.
 For events
 which
 are
 potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
Further information on follow-up procedures is given in Appendix 3.
9.2.4 
Regulatory Reporting Requirements for SAEs
• Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
• An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European
 Directive
 2001/20/EC
 and
 FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5 
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3
In most cases, the study
 treatment will be permanently discontinued in an appropriate manner (e.g., 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24
hours of awareness of the pregnancy.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
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disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6 
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
• Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value).
9.2.7 
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2andAppendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), AND;
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), AND;
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8 
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.2.8.1 Immune-mediated adverse events
Immune-mediated adverse events (IMAE) are AEs consistent with an immune-mediated 
mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection 
or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology 
which were exacerbated by the induction of autoimmunity. Information supporting the assessment 
will be collected on the subject’s case report form.
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9.3 
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 9.2).In the event of an overdose the [investigator/treating physician] 
should:
1) Contact the Medical Monitor immediately.
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities.
3) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9.4 
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities. Safety 
assessments include AEs, physical examinations, vital signs, ECOG performance status, 
assessment of signs and symptoms, laboratory tests, and pregnancy tests as outlined in Section 2.
9.4.1 
Clinical Safety Laboratory Assessments
• Investigators must document their review of each laboratory safety report.
• Screening laboratory assessments should be done locally within 14 days of first dose.
• On-study laboratory assessments should be done locally within 72 hours prior to each dose, as 
outlined in the Schedule of Activities in Section 2.
• Laboratory assessments should be performed locally at Follow-Up Visit 1, and should be 
repeated at Follow-Up Visit 2 if study related toxicity persists.
Table 9.4.1-1: 
Laboratory Assessment Panels
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN) or Serum Urea Level
Sodium
Potassium
Chloride
Calcium
Phosphorus
Lipase
Amylase
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Table 9.4.1-1: 
Laboratory Assessment Panels
Glucose
Albumin (screening only)
Magnesium
TSH, every 6 weeks (Free T3 and T4 performed at 
screening and reflex to free T3 and T4 if TSH is abnormal
at subsequent timepoints)
Creatinine clearance (CLcr)- screening only
Urinalysis (As clinically indicated)
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive on the dipstick
Serology
Serum for hepatitis C antibody or hepatitis C RNA, hepatitis B surface antigen, HIV-1 and -2 antibody (screening 
only) Testing for HIV must be performed at sites where mandated locally. See Appendix 8.
Other Analyses
Pregnancy test (WOCBP only: as described inSection 2.)
9.4.2 
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
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9.6 
Biomarkers
The biomarker sampling schedule is provided in Table 9.6-1for Part 1 and in Table 9.6-2for 
Part 2.
Part 1: a biopsy should be taken during the screening period and up to 4-5 core biopsies are 
recommended at each tumor biopsy collection time point. An assessment of biopsy quality by a 
pathologist/cytopathologist is encouraged at the time of procedure.
 
 
Please refer to the lab manual for specific tumor collection instructions. 
Participants must have tissue submitted for PD-L1 IHC testing prior to the start of treatment. 
Samples should not be taken from target lesions. Samples will be sent to a third party to stain and 
score for PD-L1
 expression
 using
 the
 PD-L1
 IHC 28-8 pharmDx
 kit (Dako). Stained
 tissue
 samples 
will be assessed by a pathologist at a central lab identified by the Sponsor and scored as PD-L1 
expressing if membrane staining is observed in ≥1% tumor cells among a minimum of 
100 evaluable tumor cells. 
An additional tumor biopsy will be collected at Cycle 1 Day 29 (Week 5) to evaluate potential 
pharmacodynamic biomarkers of response/safety to nivolumab + ipilimumab. Changes in 
candidate biomarkers at this time point may inform of early changes within the tumor 
microenvironment that contribute to efficacy. PD-L1 will be assessed in this on-treatment biopsy 
as indicated for the pre-treatment biopsy, above.
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A tumor biopsy will be collected in subjects at progression. Changes in candidate biomarkers in 
this setting may inform of the mechanism(s) underlying acquired resistance and may inform of 
potential combination approaches to prevent/delay or reverse resistance. PD-L1 will be assessed 
in biopsy as indicated for the pre-treatment biopsy, above.
Collected tumors may be further analyzed by additional modalities, including, but limited to:
• IHC and/or cytometry (eg, flow-, chip- mass-spec based) to determine the abundance of 
immunoregulatory and other proteins such as
 PD-L1, 
 
•
• Genetic mutation detection methods;
• DNA and RNA sequencing (eg, whole exome/genome sequencing, whole transcriptome 
RNAseq and/or T-cell receptor sequencing);
•
The biomarker sampling schedule is provided in Table 9.6-1for Part 1.
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Table 9.6-1: 
Biomarker Assessment Schedule for Part 1
Study Day
Screening
Cycle 1 Day1
(Week 1)
Cycle 1 Day 29
(Week 5)
Cycle 2 Day 15
(Week 9)
Cycle 3 Day 1
(Week 13)
Progression
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Part 2biomarker samples (blood and tumor tissue) for TMB analyses will be collected at 
screening. Fresh biopsy tissue is preferred for enrollment; follow lab manual for details. Archival 
tissue samples that are less than 3 months old may be submitted. For archival tissue, FFPE tissue 
block (preferred) or submission of 15 unstained tumor tissue sections for PDL-1 and TMB testing 
will be required. 
 
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9.6.10 
Tumor Mutational Burden Evaluation in Tissue and Blood Part 2
Fresh biopsy is preferred or archival sample ( 3 months old) are required for enrollment. For 
archival tissue, FFPE tissue block (preferred) or submission of 15 unstained tumor tissue sections 
for PDL-1 and TMB testing will be required. If fresh biopsy tissue is obtained, the collection of 
plasma/serum must be collected within 7 days.
Based on the Part 2 expansion cohort in this study, tumor TMB and blood TMB will be collected 
at baseline. The association of tissue and blood TMB analyses with clinical outcomes will be 
assessed independently.
9.6.11 
Additional Research Collection
Additional research collections and retention are mandatory for all subjects, except where 
prohibited by local laws or regulations. This protocol will include residual sample storage for 
additional research (AR).
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients. 
 This may also include genetic/genomic exploration aimed
 at exploring
 disease 
pathways, progression and response to treatment etc. 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development to ensure the 
research supports appropriate and well-defined scientific research activities.
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Samples will be securely stored by the BMS Biorepository in 
 or at a BMS approved 
third party storage management facility.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual
Additional research samples will be retained for 15 years or the maximum allowed by applicable 
law. No additional sampling is required for residual collections. 
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Table 9.6.11-1: 
Residual Sample Retention for Additional Research Schedule
Sample Type
Timepoints for which residual samples will be retained
All
All samples 
9.7 
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10 
STATISTICAL CONSIDERATIONS
10.1 
Sample Size Determination 
Part 1:The planned sample size is approximately 100. Approximately up to 150 participants are 
expected to be enrolled to achieve 100 treated participants in the trial. For this hypothesis 
generating study, the sample size is mainly decided by operational feasibility, and sample size 
calculation is provided to illustrate the design characteristics of the study. Biomarker hypotheses 
generated from the study will be validated by analyzing data from other ongoing trials or data from 
future trials.
One of the co-primary objectives is to evaluate tumor mutational burden as a candidate biomarker 
of clinical efficacy of nivolumab and ipilimumab combination therapy. For this co-primary 
objective, the primary endpoint that will be used to measure clinical efficacy is objective response 
rate (ORR). 
 
.
One of the co-primary objectives of the study is to investigate the potential association between 
candidate biomarkers in peripheral blood and tumor tissue at baseline and on-treatment with 
clinical efficacy measures. For this co-primary objective, the primary endpoint that will be used to 
measure clinical efficacy is objective response rate (ORR). Patients can be divided into sub-groups 
by candidate biomarkers. No formal hypothesis testing
 will
 be
 conducted
 on
 ORR in overall patient 
population or in patient sub-groups. However, to evaluate the association between candidate 
biomarkers with ORR while factoring in the correlation among biomarkers, a multiple logistic 
regression or a penalized regression method (Elastic Net
38, implemented in SAS procedure 
GLMSELECT) may be used to select important biomarkers simultaneously. More specifically, 
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patient sub-groups can be identified by biomarkers as covariates in the model, and an important 
sub-group can be chosen based on biomarker effects estimated from the model. For example, the 
risk of each patient can be calculated based on estimated covariates, and a suitable cutoff point of 
patient level risk can be used to identify sub-groups of interest. Other methods can be used to 
define sub-groups. No matter what methods are used, scientific rationales need to be provided to 
support the patient sub-groups defined. For patient sub-groups identified, ORR and the associated 
confidence interval will be calculated, and the estimation bias due to selection bias will be adjusted 
by re-sampling method. 
Although no formal hypothesis testing will be performed, the operating characteristics can also be 
illustrated in the hypothesis testing framework. 
 
 
 The power calculation was conducted in EAST 6 using Wald test statistics, and the 
null response rate of 0.23 was chosen based on data from LUX-Lung 339and 640study.
Part 2: The planned sample size is approximately 150 participants. Approximately 200 
participants are expected to be enrolled to achieve 150 treated participants.
 
 
In study CA209568, a TMB analysis determined a TMB cutpoint that subjects at or above the 
cutpoint were predicted to experience therapeutic benefit from nivolumab in combination with 
ipilimumab. An exploration will be done for Part 2 subjects to confirm the cutpoint identified in 
CA209568. Within the TMB-evaluable subjects, it is expected that approximately 1/3 of those 
providing TMB will be categorized as being above the cutpoint, ie, 
 
 Table 10.1-1 presents the exact 95% CIs for some of the 
plausible scenarios of observed ORRs for TMB cutpoint positive (TMB+) participants in Part 2 
based on blood TMB, as well as TMB based on tumor tissue.
Table 10.1-1: 
Part 2 ORR and width of 95% CI 
ORR (# of Responders)
95% Exact CI
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Table 10.1-1: 
Part 2 ORR and width of 95% CI 
ORR (# of Responders)
95% Exact CI
95% CI based on Clopper-Pearson method
Combining Part 1 and Part 2 subjects together, about 250*60%*1/3=50 participants will be above 
the cutpoint. 
Table 10.1-2 presents the exact 95% CIs for some scenarios of observed ORRs for TMB cutpoint 
positive (TMB+) subjects for the entire study.
Table 10.1-2: 
Part 1 and Part 2 ORR and width of 95% CI 
 
ORR (# of Responders)
95% Exact CI
10.2 
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population or analysis data 
set
Description
All enrolled patients 
All  subjects  who  signed an informed consent form and were 
registered into the IRT system.
All treated patients
All  patients  who received at least one dose of any study 
medication.
All treated patients with 
evaluable  baseline  tumor  
biopsy data
All treated patients with evaluable baseline tumor biopsy data 
will be included in data analyses. 
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Population or analysis data 
set
Description
Complete biomarker data set All treated patients with evaluable mandatory baseline tumor 
biopsy and at least one post baseline tumor biopsy.
All baseline TMB evaluable 
patients
All treated patients with evaluable baseline tumor mutational
burden. 
10.3 
Statistical and Computational Analyses
The association between ORR and tumor mutational burden will be explored using logistic 
regression model among treated patients evaluable for tumor mutational burden.
Due to limited participants as compared with the number of biomarkers that will be evaluated for 
the second co-primary objective, a multiple logistic regression model, or penalized regression 
methods (Elastic Net38, implemented in SAS procedure GLMSELECT) will be used to assess the 
potential association between candidate biomarkers in peripheral blood and tumor tissue at 
baseline and on-treatment with clinical efficacy measures. The primary endpoint will be ORR, and 
other clinical efficacy measures will be analyzed as part of the secondary endpoints. 
 
The analysis of the primary endpoint ORR will take place after the last treated subject is followed 
for 
. Additional survival analysis will be conducted with longer follow up.
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
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10.3.1 
Efficacy Analyses
Endpoint 
Analysis Methods
Primary:
ORR
In Part 1, logistic regression model and ROC analysis will be used to 
evaluate tumor mutational burden as a candidate biomarker of ORR of 
nivolumab and ipilimumab combination therapy. 
Multiple logistic regression or penalized regression will be used to screen for 
(baseline and post baseline) biomarkers simultaneously
ORR will be calculated for sub-groups identified by logistic or penalized 
regression methods, and the confidence interval by Clopper-Pearson method 
will be provided
In Part 2, ROC analysis will be used to confirm cutoffs for baseline tissue 
TMB and blood TMB that identify subjects who will experience therapeutic 
benefit based on ORR. Logistic regression will be conducted.
ORR will be calculated for TMB (tissue and blood) sub-groups and the 
confidence interval by Clopper-Pearson method will be provided.
Secondary
DCR, DOR,
TTR, PFS, and 
OS
The analysis conducted for ORR will be repeated for other efficacy endpoints 
of interest. For PFS, OS and DOR, for selected patient sub-groups, Kaplan-
Meier
 curves
 will
 be
 provided,
 and
 median
 of
 time
 to events and the associated 
confidence interval will be calculated. 
Descriptive summary statistics of TTR will be provided for patients with a
BOR of CR or PR.
Exploratory
10.3.2 
Safety Analyses
All safety analyses will be performed on all treated participants.
Endpoint 
Analysis Methods
Primary
Event rate
AEs, including death, SAE, and AEs defined by safety monitoring test, will be 
summarized for all treated participants, and by sub-groups when applicable.
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10.3.4 
Other Analyses 
The population pharmacokinetics analysis and pharmacodynamic analyses will be presented 
separately from the main clinical study report. 
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11 
REFERENCES
1 Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determine sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348:124-
8.
2 Kowanetz M, Zou W, Shames DS, et al. Tumor mutation burden (TMB) is associated with 
improved efficacy of atezolizumab in 1L and 2L+ NSCLC patients. Oral presentation at: The 
17th Annual World Conference on Lung Cancer; December 4-7, 2016; Vienna, Austria.
3 Peters S, Creelan B, Hellmann MD, et al. Impact of tumor mutation burden on the efficacy of 
first-line nivolumab in stage IV or recurrent non-small
 cell
 lung
 cancer:
 an
 exploratory
 analysis 
of CheckMate 026. Oral presentation at the Annual Meeting of the American Association of 
Cancer Research; April 1-5, 2017; Washington, DC, USA.
4 Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for 
PD-L1-positive non-small-cell lung cancer. NEJM. 2016; 375:1823-33. 
5 Gandara DR, Kowanetz M, Mok TSK, et al. Blood-based biomarkers for cancer 
immunotherapy: Tumor mutational burden in blood (bTMB) is associated with improved 
atezolizumab (atezo) efficacy in 2L+ NSCLC (POPLAR and OAK). Annals of Oncology. 
2017:28, 5, 1.
6 Jemal A, Bray F, Center MM. et al. Global Cancer Statistics CA Cancer J Clin 2011;61:69–
90.
7 NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. v.2.2014. 
www.nccn.org.
8 Mellman I, Coukos G & Dranoff G. Cancer immunotherapy comes of age. Nature 2011 Dec 
22;29 4 8 0:480-89.
9 Brahmer JR, Drake CG, Wollner I, et al. Phase I Study of Single-Agent Anti–Programmed 
Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, 
Pharmacodynamics, and Immunologic Correlates. J Clin Oncol 2010;28:3167-3175.
10 Nivolumab (BMS-936558) Investigator Brochure, version 12, 2013.
11 Amos S M., Duong CPM, Westwood JA, et al. Autoimmunity associated with immunotherapy 
of cancer. Blood 2011;118:499-509.
12 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-
1 antibody in cancer. N Eng J Med 2012; 366: 2443-54.
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13 Langer CJ, Gadgeel SM, Borghaei H, et al. Randomized, phase 2 study of carboplatin and 
pemetrexed with or without pembrolizumab as first-line therapy for advanced NSCLC: 
EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY, 2016
14 Reck M,  Socinski MA, Cappuzzo F, et al. Primary PFS and safety analyses of a randomized 
phase III study of carboplatin + paclitaxel +/ bevacizumab, with or without atezolizumab in 
1L non-squamous metastatic nsclc (IMPOWER150). Annals of Oncology 2017. 28: 11, 1 
15  Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39.
16 Zitvogel L. Tesniere A, Kroemer G. Cancer despite immuosurveillance: immunoselection and 
immunoseubersion. Nat Rev Immunol. 2006;6:715-27.
17 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunodediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
18 Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2004;23:515-48.
19 Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
200;192(7):1027-34.
20 Sharpe
 AH,
 Wherry
 EJ,
 Ahmed
 R,
 et al. The
 function
 of
 programmed
 cell
 death
 1
 and
 its
 ligand 
in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45.
21 Wolchok JD, Hoos A, O
'Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-20
22 Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: Releasing the restraints 
on anti-tumor immunity for patients with melanoma. Cancer J 2012; 18:153-159
23Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands 
infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. 
PNAS 2010; 107: 4275-80.
24 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus Ipilimumab in advanced 
melanoma. New Engl J Med 2013; 369: 122-33.
25 Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. N Engl J Med 2015;373:23-34.
26 An Open-Label, Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus 
Platinum-doublet Chemotherapy Versus Platinum Doublet Chemotherapy in Subjects With 
Stage IV Non-Small Cell Lung Cancer (NSCLC) (CheckMate 227) ClinicalTrials.gov 
Identifier: NCT02477826
27 Gandara DR, Paul SM, Kowanetz M et al. Blood-based tumor mutational burden as a predictor 
of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 
2018 Sep;24(9):1441-1448.
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28 Hellmann, MD, Gettinger, SN, Goldman, JW, et al. J Clin Oncol 34, 2016 (suppl; abstr 3001).
29 Schadendorf D et al Efficacy and quality of life outcomes in patients with advanced melanoma 
(MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to 
toxicity in a phase III trial (CheckMate 067). 2016 Annual Meeting of the European 
Association of Dermato-Oncology; August 31-September 3, 2016; Vienna, Austria.
30 Schadendorf D et al Efficacy and quality of life outcomes in patients with advanced melanoma 
(MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to 
toxicity in a phase III trial (CheckMate 067). 2016 Annual Meeting of the European 
Association of Dermato-Oncology; August 31-September 3, 2016; Vienna, Austria.
31 Schadendorf D, et al. Pooled Analysis of Long-Term Survival Data from Phase II and Phase 
III
 Trials
 of
 Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 2015; 33: 1889-
94.
32 Brahmer J, et al.  Five-year follow-up from the CA209-003 study of nivolumab in previously 
treated advanced non-small cell lung cancer: clinical characteristics of long-term survivors. 
Oral presentation presented at: American Association for Cancer Research (AACR) Annual 
Meeting; April 1-5, 2017; Washington, DC, USA.
33 Felip E et al., Three-year follow-up from Checkmate 017/057: Nivolumab versus docetaxel in 
patients with previously treated advanced non-small lung cancer (NSCLC). Poster discussion 
presentation at the European Society of Medical Oncology Annual Meeting. 2017 Sep 8-12; 
Madrid, Spain.  Poster 1301PD
34 Herbst RS et al. KEYNOTE-010: Durable clinical benefit in patients with previously treated, 
PD-L1-expressing NSCLC who completed pembrolizumab. Poster presentation at the World 
Conference on Lung Cancer 2016 Dec 4-7; Vienna, Austria.
35 Robert C et al. Long-term outcomes in patients with ipilimumab-naive advanced melanoma in 
the phase 3 KEYNOTE-006 study who completed pembrolizumab treatment; Journal of 
Clinical Oncology 2017 35:15_suppl, 9504-9504
36 Spigel DR, et al. Randomized results of continuous vs 1-year fixed-duration in patients with 
advanced non-small cell lung cancer. Oral presentation at the European Society of Medical 
Oncology Annual Meeting. 2017 Sep 8-12; Madrid, Spain
38 Zou H and Hastie T, Regularization and variable selection via the elastic net. J. R. Statist. Soc. 
B 2005, 67, 301-320
39 Sequist LV et al, Phase III study of afatinib or cisplatin plus pemetrexed in patients with 
metastatic lung adenocarcinoma with EFGR mutations. J Clin Oncol. 2013, 31(27), 3327-3334
40 Wu YL et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian 
patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 
6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014, 15(2), 213-222
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12 
APPENDICES
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APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ACLS
advanced cardiac life support
AI
accumulation index
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
A-V
atrioventricular
β-HCG
beta-human chorionic gonadotrophin
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
Cexpected-tau 
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
cm
centimeter
Cmax, CMAX 
maximum observed concentration
Cmin, CMIN 
minimum observed concentration
CNS
Central nervous system
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Term
Definition
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
DMC
Data monitoring committee
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4
thEdition)
EA
extent of absorption
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
ESR
Expedited Safety Report
F
bioavailability
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
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
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Term
Definition
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
L
liter
LAM
Lactation amenorrhea method
LC
liquid chromatography
LDH
lactate dehydrogenase
ln
natural logarithm
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR
medical research
MS
mass spectrometry
MTD
maximum tolerated dose
μg
microgram
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Term
Definition
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF 
Half life
TID, tid
ter in die, three times a day
Tmax, TMAX 
time of maximum observed concentration
UV
ultraviolet
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
WNOCBP 
women notof childbearing potential
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APPENDIX 2 
STUDY GOVERANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
• Good Clinical Practice (GCP), 
• as defined by the International Council on Harmonisation (ICH)
• in accordance with the ethical principles underlying European Union Directive 2001/20/EC
• United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
• applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study
 will
 not
 use
 the
 services
 of
 study
 personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(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, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
• IRB/IEC for 
• Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee
 will
 provide
 the
 investigator
 with
 an
 appropriate
 (i.e., Global
 or Local)
 sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
• Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
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• Allow time necessary for participant or participant
's legally acceptable representative to 
inquire about the details of the study.
• Obtain an informed consent signed and personally dated by the participant or the participant
's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
• Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant
's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant
's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant
's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality
 of
 records that could
 identify
 subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects
' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
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. 
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STUDY TREATMENT RECORDS
Records for study treatments nivolumab or ipilimumab  (whether supplied by BMS, its vendors, 
or the site) must substantiate study treatment integrity and traceability from receipt, preparation, 
administration, and through destruction or return. Records must be made available for review at 
the request of BMS/designee or a Health Authority.
If
Then
Supplied by BMS (or its 
vendors):
Records or logs must comply with applicable regulations and 
guidelines and should include:
• amount received and placed in storage area
• amount currently in storage area
• label identification number or batch number
• amount dispensed to and returned by each participant, including 
unique participant identifiers
• amount transferred to another area/site for dispensing or storage
• nonstudy disposition (eg, lost, wasted) 
• amount destroyed at study site, if applicable
• amount returned to BMS
• retain samples for bioavailability/bioequivalence, if applicable 
• dates and initials of person responsible for Investigational 
Product dispensing/accountability, as per the Delegation of 
Authority Form.
Sourced by site, and not 
supplied by BMS or its 
vendors (examples 
include IP sourced from 
the sites stock or 
commercial supply, or a 
specialty pharmacy)
The investigator or designee accepts responsibility for documenting 
traceability and study drug integrity in accordance with requirements 
applicable under law and the SOPs/standards of the sourcing 
pharmacy.   
These records should include:
• label identification number or batch number 
• amount dispensed to and returned by each participant, including 
unique participant identifiers
• dates and initials of person responsible for Investigational 
Product dispensing/accountability, as per the Delegation of 
Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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 
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explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be usedSpaces may be left blank only 
in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee.
The confidentiality
 of
 records that could
 identify
 subjects
 must
 be
 protected,
 respecting
 the
 privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool.  The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of
 any inspections scheduled by regulatory
 authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
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RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site.
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any
 unused
 study
 treatments
 supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (e.g., 
cytotoxics or biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or commercial supply, or a specialty 
pharmacy)
It is the investigator’s or designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
• On-site disposal practices must not expose humans to risks from the drug.
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• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
• Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
• Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
• Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
• External Principal Investigator designated at protocol development
• National Coordinating Investigator 
• Study Steering Committee chair or their designee
• Participant recruitment (eg, among the top quartile of enrollers)
• Involvement in trial design
• Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
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APPENDIX 3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered
 study
 treatment
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
• New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
• Signs, symptoms,
 or the
 clinical
 sequelae
 of
 a
 suspected
 overdose
 of
 either
 study
 intervention
 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
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DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
• elective surgery, planned prior to signing consent
• admissions as per protocol for a planned medical/surgical procedure
• routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
• medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
• admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
• admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
• The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
• The investigator will use clinical judgment to determine the relationship.
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
• There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
• The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
• SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
• SAEs must be recorded on the SAE Report Form.
−The required method for SAE data reporting is through the eCRF.
−The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
• Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact(required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
• Premenarchal
• Premenopausal female with 1 of the following:
−Documented hysterectomy
−Documented bilateral salpingectomy
−Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination,or medical history interview.
• Postmenopausal female
−A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment. 
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
b 
−oral 
−intravaginal 
−transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation
b 
−oral 
−injectable 
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Highly EffectiveMethods That Are User Independent
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb
• Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)
c
• Intrauterine device (IUD)
c
• Bilateral tubal occlusion
• Vasectomizedpartner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
• Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
• It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
• WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
• Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
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Unacceptable Methods of Contraception
• Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
• Diaphragm with spermicide
• Cervical cap with spermicide
• Vaginal Sponge with spermicide
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
• Periodic abstinence (calendar, symptothermal, post-ovulation methods)
• Withdrawal (coitus interruptus).
• Spermicide only
• Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
• Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
• Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 
• Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 5 
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUSa
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 6 
RECIST 1.1 GUIDELINES
1 
EVALUATION OF LESIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1 
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3. 20 mm by chest x-ray
Malignant lymph nodes:To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image 
is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, saggital or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
1.2 
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques.
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2 
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total
 (and
 a
 maximum
 of
 two lesions
 per organ)
 representative
 of
 all
 involved
 organs
 should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple nontarget lesions involving 
the same
 organ
 as
 a
 single
 item on
 the
 case
 record
 form
 (eg,
 ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
3 
RESPONSE CRITERIA
3.1 
Evaluation of Target Lesions
Complete Response (CR):Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR):At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive
 Disease
 (PD):At least
 a
 20%
 increase
 in
 the
 sum
 of
 diameters
 of
 target
 lesions,
 taking 
as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression).
Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
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3.1.1 
Special Notes on the Assessment of Target Lesions
3.1.1.1 
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress
 to below
 10 mm
 on
 study. This
 means
 that when
 lymph
 nodes
 are
 included
 as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
3.1.1.2 
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived from
the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error. To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if it 
is below 5 mm.
3.1.1.3 
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
3.2 
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
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Complete Response (CR):Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10mm short
 axis).
 
Non-CR/Non-PD:Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD):Unequivocal progression (see comments below) of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
3.2.1 
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1 
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (see examples in Appendix 2 and further details below). A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
3.2.1.2 
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target
 disease
 cannot
 be
 easily
 quantified
 (by
 definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall
 disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as ‘sufficient 
to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore the increase must be substantial.
3.2.2 
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
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to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. 
 
 
 
 
3.3 
Response Assessment
3.3.1 
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
3.3.2 
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 3.3.2-
1provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. When patients have non-measurable (therefore non-target) 
disease only, Table 3.3.2-2is to be used. 
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Table 3.3.2-1: 
Time Point Response - Patients With Target (+/- Non-Target) 
Disease
Target Lesions 
Non-Target Lesions 
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 3.3.2-2: 
Time Point Response - Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
3.3.3 
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks later. In this circumstance, the best overall response can be interpreted as in Table 3.3.3-
1.
Special note on response assessment:When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
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overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 3.3.3-1: 
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD durationbmet, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD durationbmet, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD durationbmet, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD durationbmet, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD durationbmet, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
b Minimum criteria for SD duration is 6 weeks.
3.3.4 
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
28 days after the criteria for response are first met. For this study, the next scheduled tumor 
assessment can meet this requirement.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
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initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
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APPENDIX 7 
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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GI Adverse Event Management Algorithm 
Rule out non-inflammatory 
causes. If non-inflammatory cause is 
identified, tr
eat accord
ingly 
and continue 1-0 therapy. Op
iates/n
arcotics 
ma  mask s m toms of erforatio
n. ln
fliximab should not be used 
in cases of 
oerforatio'"'n~o~r~s~e=
o!si~
s ·~-------------~ 
Grade of Diarrhea/ 
Management 
Follow-up 
Colitis 
(Na CTCAE v41 
Grade 1 
Diarrhea:< 4 stools/day over baseline; 
l&lilii; 
asymptomatic 
Grade 2 
,12iarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 hrs; 
not interfering with AOL 
Colitis: abdominal pain; blood in stool 
Grade3-4 
Djarrhea (G3)• 27 stools per day over 
baseline; incontinence: IV fluids 224 
hrs; interfering with 
AOL 
Colitis 1631: severe abdominal pain. 
medical intervention indicated, 
peritoneal signs 
64: rire-threatening. penoration 
• Continue 1-0 
therapy per 
prot
ocol 
• Symptomatic treatment 
• Delay 1
-0 therapy 
per protocol 
• Symptomatic treatment 
• D
iscontinue 1-0 therapy per 
prot
ocol 
• 1.0 to 2.0 mg/
'q,/day 
methylp
rednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opponunistic i
nfections 
• Cons
ider low
er endoscopy 
• Close monitoring 
for \Vorsening symptoms. 
• Educate patient to 
repon worsening immediately 
If 
\Vorsens: 
• Treat as Grade 2 or 3/4 
I
f Improves to 
grade 1: 
• Resume 1·0
 
therapy 
per protocol 
If 
persists> 
S-7 days or recur: 
o.s~ 1 . o mg/kg/dny methylprednis.olone or oral equivalent 
When symptoms 
Improve to 
grad~ 1 
, t
o.per steroids over 
a 
t least 
1 month, consider prophylactic antibiotics for 
opportunlstlelnfectlons, \
'Ind resume 
1
·0 thernpy per 
protocol. 
If 
worsens or persists> 3-S d ays with oral steroids: 
• Treat as grade 3/4 
If 
improves: 
• Continue steroids until grade l
.
 
then taper over at 
least 
1 month 
If 
persist
s > 3-S days. or recurs after improvement: 
• Add infti
ximab S mg/kg (if 
no contraindication). 
Note: fnftixima
b should 
not be used in 
cases of 
perforation or sepsis 
Patients on tv 
steroids ma y be switched t o a n equiva.lentd
ose of o 
ra.I 
corticosteroids (e.g. 
pred nisone) at 
start of tapering or earlier, once sustained clini
cal impl
'O\lem en 
t is 
o~X<rvecl. Lower bioavailabili
tyof oral corticosteroids should be t aken into 
account when switching to the 
eq uivalen 
t dose of oral corticosteroids 
. 
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Renal Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If 
non-inflammatory cause, tr
eat accord
ing
ly and continue 1-0 
therapy. 
Grade of Creatinine 
Elevation 
(NCI CTCAE v4) 
Grade 1 
Creat
in
ine > ULN and > 
than baseline but '1.Sx 
baseline 
Grade 2-3 
Creatinine > 1.Sx baseline 
to< 
6x ULN 
Grade 4 
Creatinine > 6x ULN 
'"-~~1111-a_n_a_g_e_m_e_n_t~~---'I
! ~ ~~~~~~~F-o_ll_o_w-~u-p~~~~~~~ 
Continue 1-0 therapy per protocol 
Monitor creatinine weekly 
Delay 1-0 therapy per protocol 
Monitor creatinine every 2-3 days 
0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
Consider renal biopsy with 
nephrology 
consult 
Discontinue 1-0 therapy per 
protocol 
Monitor creatini
ne dai
ly 
1.0-2.0 mg/'q/day 
methylprednisolone IV 
or IV 
equivalent 
Consult nephrologi.st 
Consider renal b
iopsy 
If 
returns to 
baseline: 
·Resume routine creatinine monitori
ng per protocol 
I
f worsens: 
·Treat as Grade 2 or 3/4 
If returns to 
Grade 1: 
•Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infection.s, and resume 1
40 therapy 
and routine creatinine monitoring per protoool 
I
f elevations persist> 7 davs or \Vorsen: 
•Treat as Grade 4 
If returns to Grade 1 : Taper steroids over at least 1 month and 
add prophylactic 
antibiotics for opportunistic 
infections 
Patients on IV steroi ds 
may be switdled to an equiv
alent d ose of oral cortic
o ste 
roids (e.g. prednis
one) at start 
of tap ering or earlie
r, once sustained c
li nic
al i mprovement is 
observed .
. LO\\
'er bioavailabifity 
of oral corticosteroids 
shoul d b.e taken i nto 
account 
when switch 
ing to 
the 
equiva
.
lentdo
se o 
f oral corticos
t eroids. 
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Pulmonary Adverse Event Management Algorithm 
Rule out non-infl
a:mmatory causes. If 
non-inflammatory .cause,. tr
eat accor dingly 
and continue 1-0 
therapy. Eva
luat e with imaging  and pulmonary 
consultation. 
Grade of 
Pneumonitis 
(NCI CTCAE v4) 
Grade  1 
Rad
iographic <flanges only 
Grade 2 
Mild to 
moderate new 
symptoms 
Grade 3-4 
Severe new symptoms; 
New/worsening hypoxia; 
Life-threatening 
;=====
M
=a=n
=
a=
g=
e=m
=
e=nt
=======:I 
!
;:::============
F=
o=
llo
=w-
==u=p
============::::; 
Consider delay of 1-0 
therapy 
Monitor for symptoms every 2-3 
days 
Consider Pulmonary and 10 
~omu lts 
Delay 1-0 therapy per protocol 
Pulmonary and 10 consul
ts 
Monitor symptoms daity, consider 
hospi
talization 
1.0 
mg/~dav methyl-
prednisolone IV 
or oral equivalent 
Consider bronchoscopy, lung 
biopsy 
Discontinue 1
40 therapy per 
protocol 
Hospitalize 
Pulmonary and ID consults 
2-4 mg/~day 
methylprednisolone IV or IV 
equivalent 
Add prophylactic antibiotics for 
opportuni.
stic infections 
Consider bronchoscopy, lung 
biopsy 
• Re-4mag:e at least f!"Jery 3 \Veeks 
If worsens:
: 
• Treat a.s Grade 2 or 3-4 
• Re-image every 1-3 days 
If 
improves: 
• When symptoms return to near baseline, taper 
steroids over 
at least 1 month and then 
resume 1-0 
therapy per protocol 
and consider prophylactic antibiotics 
If 
not improving after 2 weeks or \Vorsening: 
•  Treat as Grade 34
 
If imeroves to baseline: 
• Taper steroids over at least 6 weeks 
If 
not improving 
after 48 hours or worsening: 
• Add additional immunosuppre
.
ssion 
Patients on IV steroids may be S\vitched to an equivale.
nt dose of oral cortic
osteroids {e.g.  prednisone} at statt of tapering or ea.rtier, once sustained clini
cal 
improvement is observed. lo
wer bioavailabil
ity oforalcorticosteroidsshou1d be taken into account wtien swit
ching 
to the equivalent dose of oral cotticosteroids 
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Hepatic Adverse Event Management Algorithm 
Rule out non-inflamm ato,..., causes. If non-infl
ammatory cause, treat 
accor din gly 
and continue 1-0 
th
erapy. Consider imaging for obstruction. 
Grade of 
Liver Test 
I 
Management 
I I 
Follow-up 
Elevation 
(NCI CTCAE v4) 
Grade  1 
AST or ALT> ULN to 
3.0 x 
ULN and/or T. tHli > ULN 
to 
1.5 x ULN 
Grade 2 
AST or ALT> 3.0 to< 
5 x 
ULN and/or T. bili > 1.5 
tos3xULN 
Grade 3-4 
AST or ALT> 5 x ULN or 
T.bili >3 x ULN 
• Continue 1-0 
therapy per protocol 
• Delay 1-0 
tflerapy per protocol 
• Increase frequency of monitoring 
to 
every 3 days 
• Disoontinue 1
-0 therapy• 
• Increase frequency of monitoring 
to 
every 1-2 days 
• 1.0 to 
2.0 mg/kg/day 
metllyfprednisolone rv or rv 
equivalent• 
• Add prophylactic antibiotics 
for 
opportunistic infections 
• Consult 
gastroenterologis
t 
• Conti
nue lF1 monitoring per protoool 
If 
\Vorsens: 
• Treat as Grade 2 or 3-4 
If retu™ to baseline: 
·Resume routine monitoring, resume 1-0 therapy per protocol 
I
f elevations oersist > 5--7 days or worsen : 
0.5-1 mg/kg/day methylprednis
olone or oral equivalent and 
\Vhen LFT returns to grade 1 or baseline, taper 
steroids over at 
least 1 month. consider prophylactic 
antibiotics for 
opportunistic infections, and resume 1
-0 therapy per protocol 
If 
returns to 
grade 2: 
• Taper steroids over at least 1 month 
If does not improv
e in >3-5 davs. \Vorsens or rebounds: 
Add mycophenolat
e mofetil 1 g BIO 
If 
no response wit
hin an additional 3-5 days, consider other 
immunosuppressants per local guidelines 
Patients on IV 
steroids may be switched to 
an equivalent dose of oral corticosteroids (e 
.g. prednisone}at start oftaperingor earlier, once sustained clinical 
i
.mprove.ment is 
observed. tow
er 
bioavai
labiljtyof 
OJal corticosteroids should be taken into account when switching to 
the equi
valent dose of oral corticosteroids. 
•r
he reco mmended starting 
dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone rv 
. 
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Endocrinopathy Adverse Event Management Algorithm 
Rule out non-inflaT1matory causes. If non-inflammatory cause, treat accordingly and continue 1-0 
th
erapy. Cons
ider visual field testing, endocr 
inology 
consu 
ltation, a nd imaging. 
Asymptomatic 
TSH elevation 
Symptomatic 
endocrinopathy 
Suspicion of 
adrenal crisis (e.g. 
severe dehydration, 
hypotension, shock 
out of proportion to 
current illness 
Continue 1-0 th
erapy per protocol 
If 
TSH < 0.5 x LLN. or 
TSH '> 2 x ULN. or consistently out of range in 
2 subsequent measurements: in
cl•de fT4 at 
subsequent cycles as clinically indicated; consider endocrin,
llogy consult 
• Evaluate endocrine function 
• Consider pituital)' 
scan 
Svmptomatic \Vi
th abnormal lab/pituitarv 
scan: 
Delay 1
40 therapy per protocol 
1-2 mg/kg/day methylprednisolone IV or PO equivalent 
Initiate appropriare hormone tflerapy 
No abnormal lab/pitui
tary MRI scan but svmptoms persist: 
• Repeat labs in 1-3 weeks I 
MRI in 1 month 
• Delay or 
discontinue I 0 therapy 
per protocol 
• Rule out sepsis 
• Stress dose of IV neroids witfl mineraloconicoid acti
vity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out then treat a
.s 
above for 
symptomatic enct>crinopathy 
I
f impr
oves (with or 
without hormone 
replacementl: 
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
in
fections 
Resume 1-0 therapy per protocol 
Patients with adrenal 
insuff
iciency 
may need to 
continue steroids witfl 
mineralocorticoid component 
Patients on IV 
steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone} at start of tapering or earlier
,. o nce 
sustainec clinical 
improvement is observed. Lower bioavailabil
ity of oral corticosteroids should be taken into account when  s\vitching to 
the equivalent dose of o 
ral corticostero 
ids. 
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Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause; tr
eat accordingly and continue 1-0 th
erapy. 
Grade of 
Rash 
(NCI CTCAE v4) 
Grade  1-2 
Covering s 30% 
BSA-
Grade 3-4 
Covering >30% BSA; 
Life threatening 
consequences•" 
Management 
• Symptomatic therapy (e.g. antihi.
stamines, 
topical steroids} 
• Continue 1-0 therapy per protocol 
Delay o 
r disoontinue 1-0 therapy per 
protocol 
Consider skin 
biopsy 
Dermatology consult 
1.0-2.0 mg/tqjday IV methylpr
edni.
solone 
IV or IV equivalent 
Follow-up 
If oersi.
sts > 1-2 \Veeks or recurs: 
Consider skin biopsy 
Delay 1-0 
therapy per protocol 
Consider 0.5-1.0 mg/kg/day methylprednisolone IV or 
oral equivalent. Once improving • taper 
steroids over 
at least 1 month; consider prophylactic antibiotics for 
opportunistic infections; and resume 1-0 
therapy per 
protocol 
If worsens: 
• Treat as Grade 3-4 
If 
improves to 
Grade 1: 
• Taper steroids over at lea.
st 1 month and add 
prophylactic antibiotics for opponunistic infections 
• Re.
sume 1-0 
therapy per protocol 
Patients on IV 
steroids may be switched to 
an equivalent dose of ora.
I 
corticosteroids {e 
.g. prednisone) at start oftaperingor earlier, once sustained cli
nical 
i.mprovement is 
observed. lowe
r bioavai
lability 
of 0tal 
corticost eroids should be ta
.ken int
o account when switching to 
t he equivalent dose of oral cortic
osteroids
. 
•Refer to 
NCI CTCAE v4 for 
t erm-specific grading criteria. 
"If SJS/TEN is suspected, withhold 1-0therapy and refer patient 
for specialized care for assessment and treatment. 
tfSJS or TEN is d i
agnosed, permanently 
discontinue 
1-0 
therapy. 
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Neurological Adverse Event Management Algorithm 
Rule 
ou: non-inflammatory causes. If non-inflammatory cause, tr
eat accord 
ingly and continue 1
-0 th
erapy. 
Grade of 
Neurological 
Toxicity 
(NCI CTCAE v4) 
Grade 1 
Asymptomatic or 
mild symptoms: 
Intervention not 
indicated 
Grade 2 
Moderate svmptoms; 
Limiting instrumental 
AOL 
Grade 3-4 
Severe svmptoms; 
Limiting self-care 
Alll; 
Life-threatening 
Management 
• Continue 1
-0 therapy per protocol 
• Delay 1
40 tllerapy per protocol 
• Treat symptoms per local guidelines 
• Consider 0.5 t o 1.0 mg/kg/day 
metllylprednisolone rv or PO 
equivalent 
• Disoontinue 1
-0 therapy per protocol 
• Obtain neurology consult 
• Treat symptoms per local guidelines 
• 1.0-2.0 mg/'q/day IV 
metllylprednisolone IV or rv equi
valent 
• Add prophylactic antibiotics for 
opportunistic infections 
Follow-up 
Continue to monitor the patient. 
If worsens: 
•  Treat a
.s Grade 2 or 3-4 
If 
jmpmm rg ba5efjne· 
•Resume 1
-0 therapy per protocol when improv
ed to baseline 
If worsens: 
·Treat as Grade 3~ 
If improves to Grade 2: 
•  Taper steroids over at least 1 month 
If worsens or atvpical presentation: 
• Consider IVl6 
or other immunosuppressi
ve th
erapies per 
loc
a
l guidelines 
Pati
ents on IV st ero
ids may be S\Vitched to an equiva
lent dose of oral corticosteroids (e.g. prednisone) at s
tart of tapering or 
earl i er~ 
o nce sustained clini
cal improvement is 
observed. LO\Ver bioava
ilability 
cf 
oral corticosteroids should be taken into acco unt v
o1hen 
switchin
g to the 
equivalent dose of oral corticosteroids. 
27-Jun -2019 

Clinical Protocol
CA209592
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 18-Dec-2019
123
Approved
1.0
v
6.0
Approved
930107032
6.0
v
Myocarditis Adverse Event Management Algorithm 
Grade  of 
Management 
Follow-up 
Myocarditis 
(NCI 
CTCAE v4) 
Grade 2 
• 
Delay 1
-0 ther apy; hosp
ita
l
ization \'l
it
h cardiac monit
oring 
• If 
\VOrsens, intensi
fy treatment accordi
ng tc 
• 
Urgent cardio
logy consulta
tion for eva
lua
tion and 
grade 
Symptoms with mikl to 
c:> 
management 
I• ~ 
Upon recovery, taper steroids over at least 
J 
moderate activity or 
0 
Troponin 
and BNP 
month wit
h close monit
oring of tr
oponir 
exertion 
0 
ECG ± continuous 
cardiac monit
or
ing 
and BNP as \'/ell 
as for ne\•
/ symptoms 
0 Echocardi
ogram 
Repeat cardiac MRI for po~t treatmen 
0 
cardi
ac MR
I 
assessment and card
io
logy follov1-up 
• Prompt initiation of 2 mg/kg/day methyfpredniso
lone IV or 
• Retreatment may be considered afte 
equiva
lent 
recovery 
and completion of 
steroid 
taper 
• Permanently discontinue 1
-0 therapy 
Grade 3: Severe with 
• Hospit
a
lize to intensive cardiac monit
oring 
symptoms at rest or 
• Cardiac eva
luation to in
clude: 
with minimal Bctivity or 
- Troponin a
nd BNP monitor
in
g 
• If no im
provement, consid
er add
itiona
l 
exertion: intervention 
- ECG ± continuous cardiac monitoring 
immunosuppress
ion 
indicated 
..-»\ - Echocard iog
ram 
•· 
- Cardiac MRI 
Upon recovery, taper steroids over at least 
J 
Grade 4 
: Life-
.....,. - Mvocard
i'al biopsy if 
feasible 
month  wit
h c
lose monit
oring of tr
oponir 
• Immedia
te initiat
ion of 2 mg/kg/day methyfprednisofone 
IV or 
and BNP as \'/
ell 
as for ne\•
/ symptoms 
threatening 
1 g IV 
bolus 
consequences: urgent 
• Cons
ider adding a 
second immunosuppressive agent 
• Repeat cardi
ac MRI for post treatment 
intervention indicated 
(e.g., continuous IV 
Addit
iona
lly, for G
'rade 4: 
assessments and cardiology 
follov1-up 
therapy 
or mechanical 
• Hospit
a
lize/trans
fer to ins
titution \V
ith expen 
ise in  
intens
ive 
hemodynami c support) 
cardiac monitoring 
• Cons
ider ATG as second agent given its immed
ia
te eff
ect 
Patients on rv 
siter
oids may be svtitched to a n eqLivalent dose of oral corticosteroids (eg, prednisooe} at 
start of tapering or earlier
, once sustained clinical improvement is 
observed. Lower bioavailabiflty of oral corticosteroids shoukl be taken into accoont \vhen switching to 
tlie 
eql.ivalent dose of oral corticosteroids. 
Prophylactic anti
biotics shouk:I be considered in the setting of ongoing immunosuppression. 
ATC = ant 
i-
thymocyte globulin; 6N~ = S..type natriuretic peptide; !CG= 
e 
lectrocardiogram; IV = intraveno us; MAI= magnetic resonance imaging 
27·Jun·2019 

Clinical Protocol
CA209592
BMS-936558
nivolumab
APPENDIX 8 
COUNTRY SPECIFIC REQUIREMENTS
Criteria for exclusion of HIV-positive subjects in GERMANY:
Section
Country-specific language
Section 2Flow Chart/Time and Events Schedule,
Screening Procedural Outline (CA209592) for Part 1 
and Part 2 - Laboratory Tests
Add “HIV testing” to the list of laboratory tests
Section 6.2 Exclusion Criteria No.1 Letter i)
“Subjects with a known history of a positive test for human 
immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS)” to be replaced with
“Positive test for HIV.”
Section 9.4.1 Clinical Safety Laboratory Assessments
Table 9.4.1-1 Laboratory Assessment Panels, Serology
Add “Testing for HIV must be performed at sites where 
mandated locally.”
Revised Protocol No.: 05
Date: 18-Dec-2019
124
Approved 1.0
v
6.0
Approved 
930107032
6.0
v

Clinical Protocol
CA209592
BMS-936558
nivolumab
APPENDIX 9 
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 04, 03-May-2019
The CA209592 protocol was revised to change 
 analytical 
correlation between tissue and blood TMB, and clarified ipilimumab dosing.
Summary of key changes for Revised Protocol 04
Section Number & Title
Description of 
Change
Brief Rationale
Synopsis
Table 2-1 Screening Procedural Outline (CA209592) for Part 1 
and Part 2
Table 2.-2: On Treatment Procedural Outline (CA209592) for 
Part 1
Table 2.-3: On Treatment Procedural Outline (CA209592) for 
Part 2
Table 9.6-1 Biomarker Assessment Schedule for Part 1
Table 9.6-2 Biomarker Assessment Schedule for Part 2
Synopsis Objectives and Endpoints
Table 2-1 Screening Procedural Outline (CA209592) for Part 1 
and Part 2
Section 3.1 Study Rationale
Section 3.2.5 3.2.5 Rationale for Tumor Mutation Burden 
Testing
Table 4-2 Objectives and Endpoints for Part 2
Section 9.6.10 Tumor Mutation Burden Evaluation in Tissue 
and Blood Part 2
Section 10.1 Sample Size Determination
Section 10.3.1 Efficacy Analysis
Section 10.3.5 Interim Analyses
Analytical 
correlation of 
blood TMB and 
tissue TMB was 
removed as a co-
primary endpoint.
This endpoint was 
removed because existing 
data was sufficient to 
support correlation.
Table 2-1 Screening Procedural Outline (CA209592) for Part 1 
and Part 2 9.1.1.1 
Table 2.-2: On Treatment Procedural Outline (CA209592) for 
Part 1
Table 2.-3: On Treatment Procedural Outline (CA209592) for 
Part 2
Section 9.1.1.1 Efficacy Assessments using CT scan or MRI
Updated brain 
imaging 
requirement at 
screening and 
during treatment, 
when clinically 
indicated.
Brain imaging is required
to rule out brain 
metastasis at screening 
and during treatment, 
when clinically indicated 
for safety.  
Revised Protocol No.: 05
Date: 18-Dec-2019
125
6.0
Approved 
930107032
6.0
v
Approved 1.0
v