A Phase 3b/4 Safety Trial of Flat Dose Nivolumab In Combination With Ipilimumab in Participants With Non-Small Cell Lung Cancer
Phase: PHASE4
Conditions: Lung Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase IIIb/IV Safety Trial of Flat Dose Nivolumab in Combination with Ipilimumab in 
Participants with Non-Small Cell Lung Cancer 
CheckMate 817, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 
 
NCT Number: NCT02869789 
Document Date (Date in which document was last revised): July 2nd, 2019 

Page:
1
Protocol Number:
CA209817
IND Number:
125,872
EUDRACT Number
2016-002621-10
Date
22-Jun-2016
Revised Date:
02-Jul-2019
Clinical Protocol CA209817
A Phase IIIb/IV Safety Trial of Flat Dose Nivolumab in Combination with Ipilimumab in 
Participants with Non-Small Cell Lung Cancer
CheckMate 817, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation
Revised Protocol Number: 06
Incorporates Administrative Letter 08
Clinical Trial Lead (Study Director / Medical Monitor)
3401 Princeton Pike
Lawrence Township, NJ 08648
Telephone (office):: 
24-hr Emergency Telephone Number
USA: 
International: 
Japan: 
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 
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Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Revised Protocol No.: 06
Date: 02-Jul-2019
2
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).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Revised Protocol No.: 06
Date: 02-Jul-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 06
02-Jul-2019
•
Removed required number of participants in each special population 
subgroup
•
Removed C1D1 physical exam from Table 2-2
•
Updated language to clarify that inhaled or topical steroids, and adrenal 
replacement steroid doses > 10 mg daily prednisone equivalent are 
allowed
•
Updated treatment after the end of the study language to align with 2 
year maximum treatment duration
•
Added FACT-L collection during survival follow-up, which may be 
collected in office or over telephone
Administrative 
Letter 08
02-Oct-2018
Updated Medical Director/Medical Monitor information
Revised 
Protocol 05
04-Jun-2018
•
Revised objectives and endpoints for Cohort C participants 
•
Updated sample size for Cohort C participants 
•
•
Updated protocol to align with nivolumab program standards
Administrative 
Letter 07
26-Mar-2018
•
Updated study personnel
•
Corrected errors in wording
Administrative 
Letter 06
28-Nov-2018
•
Corrected numbering Section 6.1.1 Inclusion Criteria for Cohort A1 
Special Population
Revised 
Protocol 04
25-Oct-2017
•
Addition of Cohort C participants with high tumor mutation burden 
with subsequent addition of objectives, endpoints, tissue and blood 
collection, background, rationale, and analyses.
•
Palliative radiotherapy language updated
•
Maximum treatment duration of 24 months added.
Administrative 
Letter 05
31-Aug-2017
•
Updated study personnel and study title 
Revised 
Protocol 03
27-Jul-2017
Revised protocol 03 incorporates language from previous revised protocols, 
amendments, and administrative letters. These changes include updating 
the revised protocol with:
•
Optional special population Cohort A1
•
•
BMS standard days for study follow-up
•
Change in title to reflect secondary endpoints
•
New study personnel added
Typographical errors were corrected for clarity.
Administrative 
Letter 04
12-Apr-2017
•
Updated study personnel and study title 
•
Clarified metagenomic analyses
Revised 
Protocol 02
09-Nov-2016
Incorporates Amendment 04
Amendment 04
09-Nov-2016
Added a cohort of 400 participants (Cohort B, second-line non-small cell 
lung cancer [NSCLC]) who will receive nivolumab plus ipilimumab. 
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Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Revised Protocol No.: 06
Date: 02-Jul-2019
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Document
Date of Issue
Summary of Change
Added specific exclusion criteria for patients with known epidermal growth 
factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) 
translocations sensitive to available targeted inhibitor therapy.
Revised 
Protocol 01
15-Sep-2016
Incorporates Amendment 03
Amendment 03
15-Sep-2016
Management algorithms updated per revised nivolumab IB
Original 
Protocol
22-Jun-2016
Not Applicable
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CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
OVERALL RATIONALE FOR THE REVISED PROTOCOL 06
The revised protocol removes the required number of participants in special population 
subgroups and collects FACT-L during survival follow-up. Additional changes were made to 
align protocol with program standards.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Section 5.2.1 All Cohorts 
(NSCLC
Removed 
required 
number 
of 
participants 
for
each 
special 
population subgroup
Required number of participants for 
each special population was removed
because of limited accrual.
Table 2-2: Treatment Phase 
Assessments (CA209817)
Removed physical exam at C1D1
Physical exam occurs at screening 
and does not need to be repeated at 
C1D1.
Table 2-3: Follow-up and 
Survival Procedures
(CA209817)
FACT-L
assessments 
may 
be 
administered in office or over the 
telephone.
FACT-L may be performed over the 
phone if office visit is not required 
for other assessments. 
Section 7.7.2 Other 
Restrictions and Precautions
Updated language to clarify that 
inhaled or topical steroids, and adrenal 
replacement steroid doses > 10 mg 
daily 
prednisone 
equivalent
are 
allowed.
Language updated to align with 
current program standards.
Section 7.8 Treatment After 
the End of the Study
Updated treatment after the end of the 
study 
Updated treatment after the end of 
the study to align language with 2 
year maximum treatment duration
Table 2-3: Follow-up and 
Survival Procedures 
(CA209817) - All 
participants
•
Added FACT-L collection during 
survival follow-up
•
Additional 
subsequent 
cancer 
therapy 
details 
added 
to 
subsequent therapy collection 
•
PRO collection added during 
survival follow-up visits to 
collect patient information
•
Additional information on data 
collection and timing provided 
for clarity
Revised Protocol No.: 06
Date: 02-Jul-2019
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR THE REVISED PROTOCOL 06 ............................. 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 06............................ 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Research Hypothesis ................................................................................ 
3.2 Background ....................................................................................................... 
3.2.1 Non-Small Cell Lung Cancer (NSCLC) Background .............................. 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
3.2.3 Ipilimumab Mechanism of Action ............................................................ 
3.2.4 Nivolumab Combined with Ipilimumab ................................................... 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Dosing ...................................................................................................... 
5.1.2 Data Monitoring Committee .................................................................... 
5.2 Number of Participants ..................................................................................... 
5.2.1 All Cohorts (NSCLC) ............................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.5 Justification for Dose ........................................................................................ 
5.5.1 Rationale for Schedule ............................................................................. 
5.5.2 Rationale for Nivolumab 240 mg Dose .................................................... 
5.5.3 Rationale for Two Year Duration of Treatment ....................................... 
5.5.4 Justification for Removing Retreatment ................................................... 
5.5.5 Rationale for Tumor Mutation Burden Testing ....................................... 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.1.1 Inclusion Criteria for Cohort A1 Special Population .............................. 
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 .................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Dose Delay Criteria for Cohorts A, B, and C .......................................... 
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BMS-936558 / BMS-734016
CA209817
nivolumab / ipilimumab
Revised Protocol No.: 06
Date: 02-Jul-2019
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7.4.1.1 Dose Delay Criteria for Special Population (Cohort A1) .............. 
7.4.2 Dose Reductions....................................................................................... 
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 for Cohorts A, B, and C ................ 
7.4.5.2 Criteria to Resume Ipilimumab for Cohorts A, B, and C ................ 
7.4.5.3 Criteria to Resume Nivolumab and Ipilimumab for Special 
Population (Cohort A1) ........................................................................ 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.2.1 Palliative Radiotherapy (All Cohorts) ............................................ 
7.7.3 Permitted Therapy ................................................................................... 
7.8 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Study Drug Discontinuation .................................................................... 
8.1.1.1 Nivolumab Discontinuation for Cohorts A, B, and C ..................... 
8.1.1.2 Ipilimumab Dose Discontinuation for Cohorts A, B, and C ........... 
8.1.1.3 Nivolumab and Ipilimumab Dose Discontinuation for Special 
Population (Cohort A1) ........................................................................ 
8.1.2 Disease Progression ................................................................................ 
8.1.3 Additional Guidance on Treatment Discontinuation ............................... 
8.1.4 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Electrocardiograms ................................................................................. 
9.4.2 Clinical Safety Laboratory Assessments .................................................. 
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Clinical Protocol
BMS-936558 / BMS-734016
CA209817
nivolumab / ipilimumab
Revised Protocol No.: 06
Date: 02-Jul-2019
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9.4.3 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetic Assessment ............................................................................ 
9.5.1 Pharmacokinetic and Immunogenicity Collection and Processing: All 
Cohorts ........................................................................................................ 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
9.8 Biomarkers ........................................................................................................ 
9.8.1 Tumor Tissue Specimens .......................................................................... 
9.8.1.1 Cohorts A, A1,and B ....................................................................... 
9.8.1.2 Cohort C.......................................................................................... 
9.9 Healthcare Resource Utilization and Health Economics .................................. 
9.10 Patient Reported Outcomes ............................................................................. 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Other Analyses ....................................................................................... 
10.3.3.1 Patient Reported Outcomes .......................................................... 
10.3.3.2 Pharmacokinetic Analyses ............................................................ 
10.3.4 Interim Analyses ..................................................................................... 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERANCE CONSIDERATIONS .................................... 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 6 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
APPENDIX 7 COUNTRY SPECIFIC AMENDMENTS ............................................ 
APPENDIX 8 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 9 FACT-L ................................................................................................. 
APPENDIX 10 COUNTRY SPECIFIC AMENDMENT ............................................ 
APPENDIX 11 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
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Clinical Protocol
BMS-936558 / BMS-734016
CA209817
nivolumab / ipilimumab
Revised Protocol No.: 06
Date: 02-Jul-2019
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Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
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SYNOPSIS
Clinical Protocol CA209817
Protocol Title: A Phase 3b/4 Safety Trial of Flat Dose Nivolumab in Combination with Ipilimumab in Participants 
with Non-Small Cell Lung Cancer
Study Phase:
Phase 3b/4
Rationale:
Given the promising efficacy data observed with combined programmed death-1 (PD-1) and cytotoxic T 
lymphocyte-associated antigen 4 (CTLA-4) blockade, and the expected logistical benefits of flat nivolumab dosing, 
a need was identified to characterize the safety of nivolumab flat dosing in combination with weight-based 
ipilimumab administration. The combination will initially be studied as first-line (Cohort A) or second-line (Cohort 
B) therapy in Stage IV or recurrent non-small cell lung cancer (NSCLC), administered as nivolumab 240 mg every 
(q) 2 weeks plus ipilimumab 1 mg/kg q6 weeks. Additionally, Cohort C will assess the combination in first line 
NSCLC participants whose tumors harbor a high mutation burden.
An optional exploratory analyses and data generation will be conducted in separate special population (Cohort A1) 
participants with nivolumab flat dosing in combination with weight-based ipilimumab administration at participating 
sites. Typically, ECOG PS 2, renal and hepatic impaired patients, asymptomatic brain metastases, and HIV patients 
are excluded from NSCLC trials. Limited data is available in these subpopulations. This study will allow for 
additional safety data with nivolumab plus ipilimumab in these special populations at participating sites.
Study Population:
Participants with metastatic or recurrent NSCLC in Cohorts A, B, C, and optional A1 cohort. 
Objectives and Endpoints:
Objectives
Endpoints
Primary
•
To characterize the safety of nivolumab 
administered 
as 
a 
flat 
dose 
in 
combination 
with 
weight-based 
ipilimumab dosing in Cohorts A, B, 
and C. 
•
The primary objective of the study will be assessed by 
summarizing the number and percentage of participants who 
experience high grade (Grade 3-4 and Grade 5) treatment-
related select and immune-mediated adverse events (imAEs) 
in Cohorts A, B, and C, analyzed separately. The select AEs 
of interest are the following: pneumonitis, interstitial 
nephritis, diarrhea/colitis, hepatitis, rash, endocrinopathies, 
and hypersensitivity/infusion reaction events.
Secondary
To assess progression-free survival (PFS), 
overall survival (OS), duration of response 
(DOR) of nivolumab administered as a flat 
dose in combination with weight-based 
ipilimumab dosing in Cohorts A, B, and C.
•
PFS defined as the time from first dosing date to the date of 
the first documented tumor progression, as determined by 
investigators (per Response Evaluation Criteria in Solid 
Tumors [RECIST] v1.1), or death due to any cause, 
whichever occurs first.
•
OS defined as the time from first dosing date to the date of 
death.
•
DOR defined as the time between the date of first confirmed 
response to the date of the first documented tumor progression 
(per RECIST 1.1), or death due to any cause, whichever 
occurs first
To assess the objective response rate (ORR)
in Cohorts A, B, and C.
•
ORR is defined as the number and percentage of participants 
with a best overall response (BOR) of confirmed complete 
response (CR) or partial response (PR). Best overall response 
(BOR) is defined as the best response designation, recorded 
Revised Protocol No.: 06
Date: 02-Jul-2019
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Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Objectives
Endpoints
between the date of first dose and the date of the initial 
objectively documented tumor progression per RECIST v1.1 
or the date of subsequent therapy, whichever occurs first.
To assess patient reported outcomes (PROs) 
in all treated participants
•
Patient reported outcomes (PROs): assessment of changes in 
disease-related symptoms and function dimensions of Health 
Related Quality of Life (HRQoL) using Functional 
Assessment of Cancer Therapy-Lung (FACT-L)
Exploratory
•
To characterize the pharmacokinetics, 
immunogenicity, 
 
of nivolumab administered as a flat 
dose in combination with weight-based 
ipilimumab dosing.
•
The pharmacokinetic (PK) objective will be measured from 
serum concentration. Samples will be collected to characterize 
the PK of nivolumab in combination with ipilimumab and to 
explore exposure-safety and exposure-efficacy relationships.
•
Exploratory immunogenicity 
 analyses will be 
performed.
•
To assess safety in the NSCLC special 
population cohort (A1)
•
Treatment-related select AEs, SAEs, and immune-mediated 
AEs in the NSCLC special population cohort.
•
To estimate the efficacy of nivolumab 
administered 
as 
a 
flat 
dose 
in 
combination 
with 
weight-based 
ipilimumab dosing in the NSCLC 
special population cohort (A1).
•
Progression-free survival (PFS) 
•
Objective Response Rate (ORR) 
•
Overall survival (OS)
•
Duration of Response (DOR) 
•
Participant reported outcomes (PROs)
•
To assess the feasibility of prospective 
TMB testing in Cohort C
•
Screen failure rate (Cohort C)
Overall Design:
•
Four cohort, open-label study of first-line (Cohort A), second-line (Cohort B), first-line special population 
(Cohort A1), and first-line high TMB (Cohort C) receiving nivolumab and ipilimumab treatment
•
Participants will receive treatment with nivolumab 240 mg as a 30 minute infusion every 2 weeks and 
ipilimumab 1 mg/kg as a 30 minute infusion every 6 weeks, starting on Day 1, until progression, unacceptable 
toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs 
first.
•
Follow up data will be collected for up to 5 years. At the conclusion of the study, participants who are 
determined to be benefitting from study treatment may be eligible to continue receiving study drug as described 
in Section 7.8.
Revised Protocol No.: 06
Date: 02-Jul-2019
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Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Number of Participants: 
Approximately 500 participants are expected to be enrolled in each of the primary cohorts: Cohort A (first-line 
NSCLC) and Cohort B (second-line NSCLC) to achieve approximately 400 treated participants in each cohort. 
An additional, special population of NSCLC patients, Cohort A1, will include approximately 200 treated 
participants. Site participation in Cohort A1 is optional.
For Cohort C (first-line NSCLC), an estimated 300 participants will be screened to achieve approximately 
100 participants with high TMB. Participation in Cohort C will be limited to US sites due to the TMB processing 
being conducted at a single US-based facility.
Treatment Arms and Duration:
Study treatment: 
Study Drug for CA209817
Medication
Potency
Investigational Product (IP)
/Non-IP
Nivolumab
10 mg/ml
IP
Ipilimumab
5 mg/ml
IP
Participants in Cohort A (first-line NSCLC), Cohort B (second-line NSCLC), Cohort C (first-line NSCLC with high 
TMB), and special population cohort (A1) will receive treatment with nivolumab 240 mg as a 30 minute infusion 
every 2 weeks and ipilimumab 1 mg/kg as a 30 minute infusion every 6 weeks, starting on Day 1, until progression, 
unacceptable toxicity, withdrawal of consent, 24 months of treatment from first dose, or the study ends, whichever 
occurs first.
Revised Protocol No.: 06
Date: 02-Jul-2019
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Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA209817)
Procedure
Screening
Visit
(≤42 days)
Notes
Eligibility Assessments
Informed Consent
X
Informed Consent may be obtained within 42 days prior to first dose and initial IVRS call prior to any 
study specific procedure
Inclusion/Exclusion Criteria
X
Section 6
All inclusion/exclusion criteria should be assessed prior to first dose
Medical History
X
Safety Assessments
Physical Measurements/Physical 
Examination
X
Include Height and WeightWithin 42 days prior to first dose
Vital Signs
X
Including BP, HR, & temperature. Obtain at the screening visit and within 72 hours prior to first dose.
Assessment of Baseline Signs and 
Symptoms
X
Assess within 14 days prior to first dose.
Serious Adverse Events (SAEs)
Collected after signing the informed consent
Concomitant Medication Collection
X
Collect within 14 days prior to first dose through the study treatment period.
Pregnancy Test (WOCBP only) 
X
Section 6.1
Within 24 hours prior to Day 1/Negative pregnancy test required at Screening. (An extension up to 72 
hours prior to start of study drug may be permissible in situations where results cannot be obtained 
within the standard 24 hour window). 
FSH Level
X
Post-menopausal females under age 55 years must have serum FSH level > 40 mIU to begin study 
treatment (Appendix 4).
Revised Protocol No.: 06
Date: 02-Jul-2019
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Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
Table 2-1:
Screening Procedural Outline (CA209817)
Procedure
Screening
Visit
(≤42 days)
Notes
Laboratory Tests
X
Section 9.4.2
CBC w/differential, Chemistry panel within 14 days prior to first dose.
Hep B/C (HBV sAg, HCV antibody or HCV RNA), within 28 days prior to first dose.
HIV test for all participants in Germany. 
ECG (12-lead) 
X
Section 9.4.1
Obtained only for participants who have met all eligibility criteria
Efficacy Assessments
Radiographic Tumor 
Assessments(chest, abdomen, 
pelvis, brain)
X
Section 9.1.1, Appendix 6
Performed within 28 days prior to first dose. 
CT with IV contrast of Chest, Abdomen, Pelvis and all known or suspected sites of disease should be 
imaged at the screening visit. MRI with gadolinium may be obtained if CT iodinated contrast is 
contraindicated.
MRI of brain without and with gadolinium 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 for further details
Biomarker Assessments
Archived Tumor Tissue or Recent 
Tumor Biopsy
X
Section 9.8.1
For Cohorts A, A1, and B: 
Fresh or archival sample, obtained within 12 months prior to enrollment. If archived slides are to be 
submitted, they must not have been cut > 6 months prior to submission, as sample may have degraded. 
One formalin-fixed paraffin embedded tumor tissue block or a minimum of 10 to 15 unstained tumor 
tissue sections are acceptable.
For Cohort C:
•
Fresh or archival sample, obtained within 3 months prior to enrollment.
•
Submission of 10 unstained tumor tissue sections for TMB testing by Foundation Medicine unless 
TMB results from Foundation Medicine is already available (Note: participants may not enter 
treatment phase unless known results are TMB high)
Submission of 5 additional slides for PD-L1 testing if results are not already available from another 
BMS study, or a commercially available complementary diagnostic using an acceptable antibody (ie, 
28-8, 22-C3, SP263). PD-L1 results obtained using antibody SP142 are not acceptable.
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nivolumab / ipilimumab
Table 2-1:
Screening Procedural Outline (CA209817)
Procedure
Screening
Visit
(≤42 days)
Notes
EGFR Mutation and ALK 
Translocation Statuses
X
To be performed for all non-squamous participants (unless harboring known KRAS mutation). EGFR 
and ALK tests may be performed locally or at a central laboratory. May be performed outside the 
Screening period window, eg, > 42 days prior to first dose.
IVRS /Clinical Drug Supplies
IRT
X
Section 7.2 For participant number assignment at the time informed consent is obtained
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Table 2-2:
Treatment Phase Assessments (CA209817)
Procedurea
Cycle 1
Day 1
Each Subsequent 
Cycle
Day 1
(± 5 Days)
Day 15 and 
29 of each 
Cycle
(± 5 Days)
Notes
For purposes of this table, a cycle refers to 6 weeks of 
treatment.
Safety Assessments
Physical Measurements
X
X
Include Height and Weight
Targeted Physical Exam
X
ECOG Performance Status
X
X
See Appendix 5
Vital Signs
X
X
See Section 9.4.
Vital signs should be assessed at each on-study visit prior to 
dosing.
Adverse Event Assessments
Continuously during the study
Section 9.2. SAEs should be approved within 5 days from entry. 
Review of Concomitant Medications
X
X
Laboratory Tests
X
X
Section 9.4.2
Within 72 hrs prior to dosing.
Note: C1D1 labs do not need to be repeated if they were 
performed within 14 days of dosing.
Creatinine clearance will be measured every 6 weeks for 
participants with renal impairment.
Pregnancy Test (WOCBP only) 
X
X
To be evaluated at least every 6 weeks
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BMS-936558 / BMS-734016
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Table 2-2:
Treatment Phase Assessments (CA209817)
Procedurea
Cycle 1
Day 1
Each Subsequent 
Cycle
Day 1
(± 5 Days)
Day 15 and 
29 of each 
Cycle
(± 5 Days)
Notes
For purposes of this table, a cycle refers to 6 weeks of 
treatment.
Efficacy Assessments
Radiographic Tumor Assessment
(CT chest and known sites of disease. 
Repeat CT/MRI of abdomen with or 
without pelvis is required for 
participants with metastases in those 
areas at baseline, or if clinically 
indicated.)
Section 9.1
Tumor assessments should occur every 6 weeks (± 7 days) up to Week 48, then every 12 weeks until documented 
radiographic disease progression. 
Participants with a history of known brain metastasis must have 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 for further details.
Patient Reported Outcomes
FACT-L
X
X
The FACT-L will be administered on Day 1 for the first 3 Cycles 
(Cycle 1 Day 1, W6 and W12). Thereafter it will be administered 
every 2 Cycles (Weeks 24, 36, 48, etc). 
On the day of study visits that include FACT-L assessment, the 
assessment will be performed PRIOR to any study procedures 
and treatment. Section 9.10
Pharmacokinetic (PK) and Immunogenicity Assessments
PK Samples
Throughout the study
Section 9.5.1
Immunogenicity Samples
Throughout the study
Section 9.5.1
Clinical Drug Supplies
IRT Vial Assignment
X
X
X
Section 7.2. Within 3 business days prior to dosing
Nivolumab 240 mgb,c
X
X
X
Section 7.1c
Ipilimumab 1 mg/kgc
X
X
Section 7.1c
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a If a dose is delayed, the procedures scheduled for that same time point should be delayed to coincide with when the time point’s dosing actually occur (except 
radiographic tumor assessments).
b Continues until disease progression, discontinuation due to unacceptable toxicity, 24 months of treatment, withdrawal of consent, or study closure.
c Dosing window: nivolumab ± 5 days unless dose frequency is less than 12 days and ipilimumab ± 5 days unless dose frequency is less than 37 days)
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Table 2-3:
Follow-up and Survival Procedures (CA209817) - All participants
Procedure
Follow-Up 
Visits 1 & 2a
Survival 
Follow-up Visitsb
Notes
Safety Assessments
Targeted Physical Examination
X
Section 9.4.1. To assess for potential late emergent study drug related issues.
Vital Signs
X
Section 9.4
Adverse Event Assessment
X
Section 9.2. SAEs should be approved within 5 days from entry. 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.
Review of Concomitant Medications
X
Laboratory Tests
X
Section 9.4.2. Required at Visit 1. Repeat at Visit 2 only if study drug 
related toxicity persists. 
Pregnancy Test (WOCBP only)
X
Section 9.2.5
Patient Reported Outcomes
FACT-L
X
X
For participants who have discontinued study therapy, but continue to be 
followed for radiographic progression per Section 9.1.1, the FACT-L must 
be collected at each visit.
On the day of study visits that include FACT-L assessment, the assessment 
will be performed PRIOR to any study procedures and treatment. FACT-L
assessments may be administered in office or over the telephone.
Section 9.10
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Table 2-3:
Follow-up and Survival Procedures (CA209817) - All participants
Procedure
Follow-Up 
Visits 1 & 2a
Survival 
Follow-up Visitsb
Notes
Efficacy Assessments
Radiographic Tumor Assessment 
(CT chest and known sites of disease. 
Repeat CT/MRI of abdomen with or 
without pelvis is required for 
participants with metastases in those 
areas at baseline, or if clinically 
indicated.)
X
X*
Section 9.1.1. For participants who discontinue study treatment for reasons 
other than progressive disease, follow up scans should be performed every 
6 weeks (± 1 wk) up to Week 48, then every 12 weeks until progressive 
disease, initiation of subsequent systemic therapy, lost to follow-up, or 
withdrawal of consent. 
*Radiographic assessments for participants who have not experienced 
progressive disease must be obtained every 6 weeks (± 7 days), and not
delayed until follow-up visits 1 & 2.
Collection of Survival Status and 
Subsequent Therapy Information
X
X
Collect every 3 months in Survival Visits until death, lost to follow-up, or 
withdrawal of study consent. May be performed by phone contact or office 
visit.
Additional subsequent cancer therapy details such as regimen, setting of the 
regimen, line of therapy, start date and end date of each regimen, best 
response to the regimen and date of progression after second line therapy 
will be collected.
a Follow-Up Visit 1 to occur 35 days from the last dose (± 7 days) or coinciding with the date of discontinuation of study drug (± 7 days) if the date of 
discontinuation is greater than 42 days from the last dose. Follow-Up Visit 2 to occur 80 days from Follow-Up Visit 1 (± 7 days) .  Patients should be 
monitored continuously (at least up to 100 days after the last dose) as an adverse reaction with nivolumab or nivolumab in combination with ipilimumab may 
occur at any time during or after discontinuation of therapy.
b Survival Follow-Up Visits to occur approximately every 3 months (± 14 days) from Follow-Up Visit 2.. Survival visit may be conducted in person or by 
telephone. BMS may request that survival data be collected on all treated participants outside of the 3 month specified window. At the time of this request, 
each participant will be contacted to determine their survival status unless the subject has withdrawn consent for all contact.
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3
INTRODUCTION
Nivolumab Monotherapy 
Nivolumab is now approved in the United States (US) and European Union (EU) to treat 
metastatic non-small cell lung cancer (NSCLC) in patients with progression on or after platinum-
based chemotherapy.1  
The approval in squamous NSCLC was based on the results of CA209017, a randomized phase 3 
trial of nivolumab versus docetaxel. In this study, nivolumab demonstrated superior overall 
survival (OS) compared with docetaxel (median OS: 9.2 vs 6.0 months), with a clinically 
meaningful and statistically significant improvement observed (hazard ratio [HR] = 0.59; 
P = 0.0002). Improvement in survival was observed for nivolumab regardless of programmed 
death-ligand 1 (PD-L1) expression, though there was a trend for better efficacy for those with 
PD-L1 expressing tumors.2 The objective response rate (ORR) was also significantly higher in 
the nivolumab group compared with the docetaxel group: 20.0% vs 8.8% (P = 0.0083).
The approval in non-squamous NSCLC was also based on a second Phase 3 study, CA209057, 
which met its primary endpoint of superior overall survival of nivolumab vs docetaxel in 
participants with previously treated non-squamous NSCLC at a preplanned interim analysis.3
Participants in the nivolumab group had a 27% reduction in risk of death (HR = 0.73; 
P = 0.0015). Interaction p-values, reported for PD-L1 expression subgroups by each of the 
predefined expression levels, suggested a clinically important signal of a predictive association. 
Nivolumab also significantly improved ORR vs docetaxel (P = 0.0246), with ORR as high as 
36% in participants with PD-L1 expressing tumors. OS approximately doubled with nivolumab 
vs docetaxel across the PD-L1 expression continuum. In contrast, no difference in OS was seen 
between nivolumab and docetaxel when PD-L1 was not expressed in the tumor. 
Updated efficacy data for CA209017 and CA209057 is available with a minimum survival 
follow-up of 24.2 months in each study.4,5 Nivolumab continued to demonstrate superior OS 
compared with docetaxel in both studies, with a clinically meaningful improvement observed; in 
CA209017, the HR was 0.62 (95% CI: 0.47, 0.80) and in CA209057, the HR was 0.74 (95% CI: 
0.61, 0.88). In both studies the updated analysis for investigator-assessed confirmed ORR (and 
also the median duration of response [DOR] in CA209057) was unchanged from what was 
reported in the final clinical study report [CSR]. In the CA209017 final CSR, the median DOR 
for nivolumab was not reached; in the updated analysis, the median DOR was 25.20 months for 
nivolumab and 8.41 months for docetaxel.
In general, nivolumab has been well tolerated to date, with a favorable safety profile consistent 
with anticipated toxicities based on an immunostimulatory mechanism of action.6
Nivolumab in Combination with Ipilimumab
Preclinical data indicate that the combination of programmed death-1 (PD-1) and cytotoxic T 
lymphocyte-associated antigen 4 (CTLA-4) receptor blockade may improve antitumor activity. 
In vitro combinations of nivolumab plus ipilimumab increase interferon (IFN)-γ production 2- to 
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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.7
Nivolumab and ipilimumab have been shown to have complementary activity in metastatic 
melanoma. CTLA-4 and PD-1 inhibit antitumor immunity through complementary and 
non-redundant mechanisms.8
High ORRs (including complete responses), a prolonged DOR, and a favorable OS rate of 79% 
at 2 years were observed in a Phase 1 dose-escalation study, CA209004, involving participants 
with advanced melanoma who received the combination regimen of nivolumab and 
ipilimumab.9,10 Based on this, 2 large studies examining the combination of nivolumab and 
ipilimumab were performed (CA209067 and CA209069) and showed that the combination of 
nivolumab and ipilimumab has a favorable ORR. In CA209067, nivolumab 1 mg/kg in 
combination with ipilimumab 3 mg/kg demonstrated an ORR of 58%, numerically higher than 
either as single agents. In CA209069, the same combination doses achieved an ORR of 61%, 
significantly greater than that of ipilimumab alone (Table 3-1).
Table 3-1:
Best Objective Response Rate of Nivolumab in Combination with 
Ipilimumab and as a Single Agent
Nivo 3 mg/kg 
+Ipi 1 mg/kg
Nivo 1 mg/kg + 
Ipi 3 mg/kg
Nivo 
3 mg/kg
Ipi 3 mg/kg
CA2090049
40%
50%
NA
NA
CA20906711
NA
58%
44%
19%
CA20906912
NA
61%
NA
11%
NA = Not Applicable
In a Phase 1 study in participants with previously untreated, advanced NSCLC (CA209012), the 
combination of nivolumab plus ipilimumab was evaluated at several different doses and 
schedules. While the schedule evaluated in melanoma was not found to be tolerable in NSCLC, 
the study identified alternative schedules with an acceptable tolerability profile and encouraging 
activity, with confirmed ORRs of up to 57% in PD-L1+ participants.13 See Section 3.2.4 for 
more information. A Phase 3 study (CA209227) evaluating nivolumab monotherapy, nivolumab 
in combination with ipilimumab, and nivolumab in combination with chemotherapy, versus 
chemotherapy in first-line NSCLC is currently ongoing.
Incorporating a flat 240 mg dose of nivolumab into the combination regimen is expected to 
simplify treatment with nivolumab without impacting the overall safety profile of the 
combination. Detailed rationale for the use of a flat 240 mg dose of nivolumab is provided in 
Section 5.5.2. 
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nivolumab / ipilimumab
Tumor Mutation Testing 
Tumor mutation 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.14 Additional information is found in Section 5.5.5.
3.1
Study Rationale
Given the promising efficacy data observed with combined PD-1 and CTLA-4 blockade, and the 
expected logistical benefits of flat nivolumab dosing, a need was identified to characterize the 
safety of nivolumab flat dosing in combination with weight-based ipilimumab administration. 
The combination (nivolumab 240 mg q2 weeks plus ipilimumab 1 mg/kg q6 weeks) will be 
studied as first-line (Cohorts A, A1, and C) and second-line (Cohort B) treatment for Stage IV or 
recurrent NSCLC.
In CA209012, both the q6 week and q12 week cohorts were associated with improved and 
manageable tolerability compared to the cohorts with more frequent ipilimumab dosing 
(q3 weeks). Both cohorts also had encouraging efficacy with enhanced benefit observed in 
participants with PD-L1 expression, with the q6 week cohort having numerically higher median 
progression-free survival (PFS) compared to the q12 week cohort. With both schedules showing 
a similar safety and efficacy profile, and considering the imbalances in cohorts favoring the q12 
week cohort, the q6 week schedule was chosen to avoid any potential loss of efficacy with less 
frequent dosing with longer follow-up.
3.1.1
Research Hypothesis
There is no formal statistical hypothesis. Analyses to characterize select and immune-related 
adverse events (imAEs) and efficacy in terms of objective response rate will be descriptive.
3.2
Background
3.2.1
Non-Small Cell Lung Cancer (NSCLC) Background
Lung cancer is the most common cancer worldwide, with 1.8 million new cases diagnosed 
yearly, and an estimated 1.6 million deaths worldwide.15 NSCLC represents approximately 85% 
of all lung cancers and includes squamous cell carcinoma, adenocarcinoma, and large cell 
carcinoma, but in the broadest sense, may include any epithelial tumor that lacks a small-cell 
component. Non-squamous NSCLC accounts for approximately 75% to 85% of all NSCLC, and
encompasses a variety of histological subtypes other than squamous, including adenocarcinoma, 
large cell carcinoma, and less common subtypes.16,17,18,19
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First-Line Treatments for NSCLC
Metastatic or recurrent NSCLC remains an area of high unmet medical need as patients have a 
poor prognosis (5-year survival rate of ~ 1% for stage IV disease).20 For the last several decades, 
chemotherapy doublets (mostly platinum-based) have been the recommended standard of care 
for initial treatment of metastatic or recurrent (ie, advanced) NSCLC. This recommendation is 
based on prolongation of OS relative to best supportive care (BSC)21,22,23,24,25 or single agent 
chemotherapy.26 Efficacy with first-line standard-of-care platinum-based chemotherapy regimens 
is modest (median OS: 10-13 months; median PFS: 5-6 months), and the vast majority of 
subjects experience disease progression with the first year of treatment, with only 10%-20% of 
subjects progression free at 18 months, and less than one-fourth to one-fifth of patients are still 
alive at 2 years.27 More recently, tyrosine kinase inhibitors have been shown to be the optimal 
first-line therapy for patients with NSCLC tumors harboring known driver mutations (epidermal 
growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], and proto-oncogene 
tyrosine-protein kinase 1 [ROS-1]), but acquired resistance to these agents limits their long-term 
efficacy. First-line therapies that provide durable clinical benefit are needed for this high-risk 
population of patients with metastatic or recurrent NSCLC.
Currently, first-line treatment of NSCLC with immunotherapy agents is showing promise. 
Recently published initial data from the Keynote-024 study show that first-line treatment with 
pembrolizumab (a PD-L1 inhibitor) in participants with at least 50% PD-LI expression, produced 
an ORR of 44.8% compared with 27.8% for doublet chemotherapy and this resulted in a 
significant OS advantage for pembrolizumab (median OS was not reached in either group, HR = 
0.60, 95% CI 0.41, 0.89, P = 0.005).28
Second-Line Treatments for NSCLC
Nivolumab monotherapy and other PD-L1 inhibitors have become the standard of care for 
second-line treatment of NSCLC. As mentioned in Section 3, nivolumab has been approved as 
therapy for metastatic NSCLC in patients with progression on or after platinum-based 
chemotherapy. This approval is based on superior OS compared with docetaxel in 2 phase 3 
studies (CA209017 and CA209057). Bristol-Myers Squibb (BMS) is currently investigating the 
combination of nivolumab and ipilimumab as second-line treatment of NSCLC in several 
ongoing studies. Despite the recent advances with immuno-oncology drugs (improvement in 
OS), many patients do not derive long-term benefit with from monotherapy with checkpoint 
inhibitors.
Therapeutic options for mutation wild-type non-squamous NSCLC are particularly limited after 
failure of front-line chemotherapy. Overall, this group of patients only has an OS of about 
8 months after progression from platinum agents. Once resistance to tyrosine kinase inhibitors 
(TKIs) occurs, the patients who have EGFR mutations or ALK translocations will have a rapid 
disease progression.
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Unlike patients with non-squamous histology NSCLC, patients with squamous cell NSCLC have 
generally not benefitted from (and in fact may be negatively impacted by) several new agents, 
including pemetrexed and bevacizumab.29,30 Therapeutic options for squamous cell NSCLC 
have been particularly limited after failure of front-line chemotherapy.
3.2.2
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.31,32,33
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex 
process involving the integration of numerous positive as well as negative co-stimulatory signals 
in addition to antigen recognition by the T-cell receptor.34 Collectively, these signals govern the 
balance between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes 
CD28, CTLA 4, ICOS, and BTLA.1 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of interleukin (IL)-2, IL-10, IL-13, IFN-γ and Bcl-xL. PD-1 expression also been 
noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.35 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon 
various host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a 
universal loss of tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (median effective 
concentration [EC50] 0.39-2.62 nM), and inhibits the binding of PD-1 to its ligands PD-L1 and 
PD-L2 (50% inhibitory concentration [IC50] ≤1 nM). Nivolumab binds specifically to PD-1 and 
not to related members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. Blockade 
of the PD-1 pathway by nivolumab results in a reproducible enhancement of both proliferation 
and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a cytomegalovirus (CMV) 
restimulation assay with human peripheral blood mononuclear cells (PBMC), the effect of 
nivolumab on antigen specific recall response indicates that nivolumab augmented IFN-γ 
secretion from CMV specific memory T cells in a dose-dependent manner versus isotype-
matched control. In vivo blockade of PD-1 by a murine analog of nivolumab enhances the anti-
tumor immune response and results in tumor rejection in several immunocompetent mouse tumor 
models (MC38, SA1/N, and PAN02).36
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nivolumab / ipilimumab
3.2.3
Ipilimumab Mechanism of Action
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin superfamily that competes with CD28 for B7. CTLA-4 mediated signals are 
inhibitory and turn off T cell-dependent immune responses.37 Ipilimumab is a fully human 
monoclonal immunoglobulin (Ig)G1κ 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 antigen presenting cells 
(APCs), with subsequent blockade of the inhibitory modulation of T-cell activation promoted by 
the CTLA 4/B7 interaction.
3.2.4
Nivolumab Combined with Ipilimumab
CA209012 was a multi-cohort Phase 1 trial evaluating the safety and tolerability of nivolumab as 
either a monotherapy or in combination with other agents including ipilimumab, at different 
doses and schedules in participants with chemotherapy-naïve advanced NSCLC. The primary 
endpoint of the study was safety with secondary endpoints of ORR and 24-week PFS. 
Exploratory endpoints included OS and efficacy by PD-L1 expression. In this study, participants 
were tested for PD-L1 expression and 68% of participants in the q12 week cohort and 77% of 
participants in the q6 week cohort expressed PD-L1.
The efficacy and safety results of the 3 dosing schedules in CA209012 (nivolumab 3 mg/kg q2 
weeks plus ipilimumab 1 mg/kg q12 weeks, nivolumab 3 mg/kg q2 weeks plus ipilimumab 
1 mg/kg q6 weeks, and nivolumab 3 mg/kg q2 weeks as monotherapy) are described in Table 
3.2.4-1 and Table 3.2.4-3.13 Updated efficacy results for the 2 combination cohorts are provided 
in Table 3.2.4-2.
Table 3.2.4-1:
CA209012 Efficacy Results
Nivo 3 Q2W
+ Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W
+ Ipi 1 Q6W
(n = 39)
Nivo 3 Q2W
(n = 52)
Confirmed ORR, %
(95% CI)
47
(31, 64)
39
(23, 55)
23
(13, 37)
Median duration of response, mo (95% CI)
NR (11.3, NR)
NR (8.4, NR)
NR (5.7, NR)
Median length of follow-up, mo (range)
12.9 (0.9–18.0)
11.8 (1.1–18.2)
14.3 (0.2–30.1)
Table 3.2.4-2:
CA209012 Updated Efficacy Results 
Nivo 3 Q2W
+ Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W
+ Ipi 1 Q6W
(n = 39)
Confirmed ORR, %
(95% CI)
47
(31, 64)
39
(23, 55)
1 year OS Rate, %
83.3
69.0
Minimum length of follow-up, mo
16
16
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The rate of treatment-related AEs in the q12 weeks (82%) and q6 week (72%) cohorts were 
comparable to monotherapy (72%) (Table 3.2.4-3). In the study, Grade 3/4 AEs were 37%, 33%, 
and 19% for the q12 weeks, q6 weeks and nivolumab monotherapy cohorts, respectively. 
Treatment-related Grade 3-4 AEs lead to discontinuation in 5% and 8% of participants in the 
q12 week and q6 week cohorts, respectively and were similar to nivolumab monotherapy. There 
were no treatment-related deaths. The treatment-related select AEs in participants administered 
the optimized dosing scheduled (3 mg/kg of nivolumab q2 weeks plus 1 mg/kg of ipilimumab q6 
weeks) were skin related (36%), gastrointestinal (23%), endocrine (20%), and pulmonary (5%) 
and there were ≤5% treatment related grade 3/4 AEs per category.
Table 3.2.4-3:
CA209012 Safety Results
Nivo 3 Q2W + Ipi 1 
Q12W 
(n = 38)
Nivo 3 Q2W + Ipi 1 
Q6W 
(n = 39)
Nivo 3 Q2W
(n = 52)
Reason for Discontinuation
Death, n (%)
Disease Progression, n (%)
Study Drug Toxicity, n (%)
Unknown, n (%)
Other reason, n (%)
11 (28.9)
9 (23.7)
0
1( 2.6)
1( 2.6)
15( 38.5)
13( 33.3)
0
0
2( 5.1)
33( 63.5)
31( 59.6)
0
1( 1.9)
1( 1.9)
Any 
Grade
Grade 3/4
Any 
Grade
Grade 
3/4
Any 
Grade
Grade 
3/4
Treatment-related AEs, %
82
37
72
33
72
19
Treatment-related AEs leading 
to discontinuation, %
11
5
13
8
10
10
All SAEs, %
60.5
62
41
Treatment-related select AEs, 
%
Grade 1/2
Grade 3/4
Grade 1/2
Grade 
3/4
Grade 1/2
Grade 
3/4
Skin related 
Gastrointestinal
Endocrine 
Pulmonary
37
18
8
5
3
5
3
5
5
5
5
3
21
10
14
4
4
2
0
2
3.3
Benefit/Risk Assessment
Patients with metastatic or recurrent NSCLC represent an important unmet medical need. The 
clinical activity of nivolumab plus ipilimumab observed to date in NSCLC suggests the potential 
for improved clinical outcomes in first-line and second-line settings.
CA209012 showed confirmed response rates of 39% to 47% with nivolumab 3 mg/kg q2 weeks 
and ipilimumab 1 mg/kg q6 weeks or q12 weeks. Activity was observed in both PD-L1 
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expressing and non-expressing NSCLC, however, higher response rates were observed in 
patients whose tumors express PD-L1 (≥1%, confirmed response rate of 57%). Updated efficacy 
results from CA209012, show that the confirmed response rates were unchanged, but the 1-year 
OS rates were 83.3% and 69.0% with nivolumab 3 mg/kg q2 weeks plus ipilimumab 1 mg/kg 
q12 weeks and nivolumab 3 mg/kg q2 weeks plus ipilimumab 1 mg/kg q6 weeks, respectively.
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. Nivolumab and 
ipilimumab combination therapy has shown improved efficacy over either agent alone in 
melanoma. The flat dose of nivolumab 240 mg is not anticipated to change the overall 
risk/benefit ratio for the combination.
To assure an ongoing favorable risk/benefit assessment for participants enrolled into CA209817, 
high-grade, treatment-related AEs will be closely monitored throughout the conduct of the trial. 
The Medical Monitor will be responsible for reviewing, on a systematic and continuous basis, 
the safety of participants on this study. This includes a review of serious AEs (SAEs) and non-
serious AEs. 
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of nivolumab and ipilimumab may be found in the Investigator Brochure.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To characterize the safety of nivolumab 
administered as a flat dose in combination 
with weight-based ipilimumab dosing in 
Cohorts A, B, and C.
•
The primary objective of the study will be assessed by 
summarizing the number and percentage of participants 
who experience high grade (Grade 3-4 and Grade 5) 
treatment-related select and immune-mediated adverse 
events (imAEs) in Cohorts A, B, and C, analyzed
separately. The select AEs of interest are the following: 
pneumonitis, 
interstitial 
nephritis, 
diarrhea/colitis, 
hepatitis, 
rash, 
endocrinopathies, 
and 
hypersensitivity/infusion reaction events.
Secondary
•
To assess progression-free survival (PFS), 
overall survival (OS), duration of response 
(DOR) of nivolumab administered as a flat 
dose in combination with weight-based 
ipilimumab dosing in Cohorts A, B, and C.
•
PFS defined as the time from first dosing date to the date 
of the first documented tumor progression, as determined 
by investigators (per Response Evaluation Criteria in Solid 
Tumors [RECIST] v1.1), or death due to any cause, 
whichever occurs first.
•
OS defined as the time from first dosing date to the date of 
death.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
DOR defined as the time between the date of first 
confirmed response to the date of the first documented 
tumor progression (per RECIST 1.1), or death due to any 
cause, whichever occurs first
•
To assess the objective response rate 
(ORR) in Cohorts A, B, and C.
•
ORR is defined as the number and percentage of 
participants with a best overall response (BOR) of 
confirmed complete response (CR) or partial response 
(PR). Best overall response (BOR) is defined as the best 
response designation, recorded between the date of first 
dose and the date of the initial objectively documented 
tumor progression per RECIST v1.1 or the date of 
subsequent therapy, whichever occurs first.
•
To assess patient reported outcomes 
(PROs) in all treated participants
•
Patient reported outcomes (PROs): assessment of changes 
in disease-related symptoms and function dimensions of 
Health Related Quality of Life (HRQoL) using Functional 
Assessment of Cancer Therapy-Lung (FACT-L)
Exploratory
•
To characterize the pharmacokinetics, 
immunogenicity, 
 of 
nivolumab administered as a flat dose in 
combination 
with 
weight-based 
ipilimumab dosing.
•
The pharmacokinetic (PK) objective will be measured 
from serum concentration. Samples will be collected to 
characterize the PK of nivolumab in combination with 
ipilimumab 
and 
to 
explore 
exposure-safety 
and 
exposure-efficacy relationships.
•
Exploratory immunogenicity 
 analyses will 
be performed.
•
To assess safety in the NSCLC special 
population cohort in optional Cohort A1 
•
Treatment-related select AEs,
SAEs,
and immune-
mediated AEs in the NSCLC special population cohort.
•
To estimate the efficacy of nivolumab 
administered as a flat dose in combination 
with weight-based ipilimumab dosing in 
the NSCLC special population cohort in 
optional Cohort A1
•
PFS, ORR, OS, DOR, PROs
•
To assess the feasibility of prospective 
TMB testing in Cohort C
•
Screen failure rate (Cohort C)
5
STUDY DESIGN
5.1
Overall Design
In this Phase 3b/4 open-label study of nivolumab in combination with ipilimumab in multiple 
tumor types, participants will receive flat dose nivolumab combined with weight-based 
ipilimumab treatment as described in Section 7.1. Cohort A will include participants with 
NSCLC receiving nivolumab in combination with ipilimumab as first-line treatment. Cohort B 
will include participants with NSCLC receiving nivolumab in combination with ipilimumab as 
second-line treatment. Cohort C will evaluate the safety of flat dose nivolumab with weight-
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based ipilimumab as first-line treatment in patients with NSCLC whose tumor harbors a high 
mutation burden, as well as the clinical activity and the feasibility of prospective TMB testing in 
the setting of first-line NSCLC. An additional special population (Cohort A1) will include 
participants in special population subgroups and will include with one of the following criteria 
(as defined in Section 6.1.1): ECOG PS 2 or ECOG PS ≤1 with asymptomatic untreated brain 
metastases, renal dysfunction, hepatic dysfunction, or HIV. Follow up data will be collected for 
up to 5 years. Participants who are determined to be benefitting from study treatment after 
analysis of the primary endpoint is completed may be eligible to continue receiving study drug as 
described in Section 7.8. The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
CA209817 Study Design Schematic
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical 
laboratory evaluations will be performed at selected times throughout the dosing interval. 
Participants will be closely monitored for adverse events (AEs) throughout the study.
5.1.1
Dosing
Participants in all cohorts will receive nivolumab 240 mg q2 weeks in combination with 
ipilimumab 1 mg/kg q6 weeks until disease progression, unacceptable toxicity, 24 months 
treatment from first dose, or other stopping criteria as described in Section 8.
5.1.2
Data Monitoring Committee 
When required, adjudicated events will be submitted to Health Authorities for review on a 
specified timeframe in accordance with the adjudication documentation.
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A Data Monitoring Committee (DMC) will not be utilized for this study, with the following 
rationale: 
1) This study is a 4-cohort, open-label study (Cohort A, Cohort A1, Cohort B, and Cohort C).
2) Data from the ongoing Phase 1 CA209012 study has demonstrated that the combination of 
nivolumab and ipilimumab at the schedule proposed for the current CA209817 study has a 
manageable safety profile that is consistent with prior experience with these agents.
3) The ongoing CA209227 Phase 3 study is utilizing the same treatment combination and 
schedule for 2 of the 6 cohorts in the trial, and is being conducted with DMC oversight. The 
DMC convened on 28-Jun-2016, reviewing available data on 378 treated participants 
(including > 100 participants treated with nivolumab + ipilimumab), and recommended that 
the study continue as planned.
4) 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 AE data for potential new safety 
signals. 
5) Safety data for participants enrolled in the NSCLC special population cohort will be 
reviewed by the BMS Medical Monitor on a monthly basis until all participants have been 
enrolled in the cohort and have been followed for at least 3 months.
5.2
Number of Participants
5.2.1
All Cohorts (NSCLC)
Approximately 500 participants are expected to be enrolled in Cohort A (first-line NSCLC) and 
in Cohort B (second-line NSCLC) to achieve approximately 400 treated participants in each 
cohort.
An additional special population NSCLC cohort (Cohort A1) will include approximately 200 
treated participants in the special population subgroup. These subgroups include participants 
with the following criteria (as defined in Section 6.1.1): ECOG PS 2 or ECOG PS ≤1 with
asymptomatic untreated brain metastases, renal dysfunction, hepatic dysfunction, or HIV. Site 
participation in Cohort A1 is optional.
An estimated 300 participants will be screened to achieve approximately 100 TMB high treated
participants in Cohort C (first-line NSCLC). Participation in Cohort C will be limited to US sites.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of trial is 
defined as the last visit for the last participant. 
5.4
Scientific Rationale for Study Design
The CA209817 study has been designed to demonstrate that flat dose nivolumab can be safely 
combined with weight-based ipilimumab dosing. With a sample size of 400 treated participants 
in the NSCLC Cohort A and 400 treated participants in the NSCLC Cohort B, the study will 
adequately characterize the safety profile of nivolumab 240 mg q2 weeks in combination with 
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ipilimumab 1 mg/kg q6 weeks in participants with metastatic or recurrent NSCLC receiving 
first-line or second-line treatment. 
Cohort C will assess the safety of flat dose nivolumab and weight-based ipilimumab combination 
treatment in high TMB patients with NSCLC in the first line setting. Additionally, the clinical 
activity of the combination and TMB testing feasibility will be evaluated in the same 1L NSCLC
cohort. Participants will have tissue screened prospectively for high TMB, defined as ≥ 10 
mutations per million base pairs (MB). Analysis of internal data from ongoing immuno-oncology 
studies in the BMS lung program showed that a cut-off of 10 mutations/MB defined the highest 
efficacy when balanced against prevalence in the population of NSCLC patients treated with 
nivolumab (with or without ipilimumab). Participants in Cohorts A, A1, and B will have 
retrospective testing of TMB if sufficient tissue is available.
Exploratory analyses and data generation will be conducted in special population participants
(Cohort A1) with nivolumab flat dosing in combination with weight-based ipilimumab 
administration at participating sites. Typically, ECOG PS 2, renal and/or hepatic impaired 
patients, asymptomatic brain metastases, and HIV patients are excluded from NSCLC trials. 
Limited data are available in these subpopulations. The safety of nivolumab monotherapy has 
been demonstrated in patients aged ≥ 70 years or with ECOG PS 2 in the CA209-153 trial, and in 
patients with asymptomatic untreated brain metastases in the CA209-012 study.38 T
5.5
Justification for Dose
The dose and schedule of nivolumab and ipilimumab for use in all cohorts of the trial was 
selected based on the data observed in the CA209012 study.13 The CA209012 study 
demonstrated activity of the combination of nivolumab 3 mg/kg q2 weeks plus ipilimumab 
1 mg/kg q6 weeks in both PD-L1+ and PD-L1- tumors, coupled with a manageable safety 
profile.
While the CA209012 study implemented weight-based dosing of 3 mg/kg for nivolumab, a flat 
dose of 240 mg will be utilized in CA209817.
5.5.1
Rationale for Schedule
In CA209012, both the q6 week and q12 week cohorts were associated with improved and 
manageable tolerability compared to the cohorts with more frequent ipilimumab dosing 
(q3 weeks). Both cohorts also had encouraging efficacy in all participants and enhanced benefit 
in patients with PD-L1 expression, with q6 week cohort having numerically higher median PFS 
compared to the q12 week cohort. There were some imbalances observed between the q6 week 
and q12 week cohorts, as follows:
•
There were more never smokers in Cohort Q (q6 week schedule) than Cohort P (q12 week 
schedule). Current and former smokers have been shown to respond better to 
immunotherapy.
•
Participants in Cohort Q progressed, died or came off treatment more frequently in the first 
3 months; however, this did not appear to be related to the schedule.
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o
Overall treatment related AEs leading to discontinuation as rates were 11% and 13% in 
the q12 week and q6 week cohort, respectively. While there were more AEs leading to 
discontinuation in the first 3 months in Cohort Q (n = 3) versus Cohort P (n = 1), 2 of the 
3 patients who discontinued < 3 months on Cohort Q discontinued before receiving the 
2nd dose of ipilimumab, and, therefore, these discontinuations are unlikely to be due to 
the more frequent dosing on the q6 week cohort. 
o
There were early clinical progressors and (unrelated) deaths in the q6 week cohort 
compared to the q12 week cohort (8% and 15%), more likely due to imbalances in 
baseline characteristics, rather than differences in treatment schedule.
With both schedules showing a similar safety and efficacy profile, and considering imbalances in 
treatment arms favoring the q12 week cohort, the q6 week schedule was chosen to avoid any 
potential loss of efficacy with less frequent dosing with longer follow up.
5.5.2
Rationale for Nivolumab 240 mg Dose
Nivolumab monotherapy 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 in 
NSCLC 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.
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5.5.3
Rationale for Two Year Duration of Treatment
The optimal duration of immunotherapy is an important question and continues to be 
investigated. Accumulating evidence from different clinical trials across different tumor types 
with nivolumab and ipilimumab indicate that most of the responses occur early, with a median 
time to response of 2 to 4 months including in patients with NSCLC. 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.39 Furthermore, a limited 
duration of ipilimumab (including patients receiving only 4 induction doses) resulted in the long 
term survival of patients with metastatic melanoma, with a sustained plateau in survival starting 
at approximately 3 years.40
There is no randomized data evaluating stopping at 2 years, however, accumulating data suggests 
2 years of IO treatment may be sufficient for long term benefit. Data from Checkmate 003, a 
dose-escalation cohort expansion trial evaluating the safety and clinical activity of nivolumab in 
patients with advanced solid tumors, implemented stopping nivolumab monotherapy at 96 weeks 
(~ 2 years). The median follow-up was 60 months. Among the 16 participants enrolled in the 
NSCLC cohort, 12 participants were alive at > 5 years, did not receive further therapy after 
stopping nivolumab, and remained progression-free. Three of the 4 subjects that progressed prior 
to completion of 2 years of therapy, received subsequent therapy, and were alive at 5 years.41
Keynote-010, a phase 3 randomized control trial of pembrolizumab versus docetaxel for 
previously treated, PD-L1 positive, advanced NSCLC reported long term follow-up data. Data 
from participants who completed the maximum of 24 months of pembrolizumab suggests clinical 
benefit of pembrolizumab is durable after 2 years of treatment. The median follow-up was 
2.1 years (range, 1.5 to 3 years), most participants who completed 2 years of pembrolizumab and 
stopped treatment were able to maintain their response, including those with stable disease and 
with only 4% progressed after stopping at 2 years. The OS benefit was maintained and survival 
plateau above 30% was noted to develop after 2 years of treatment42, suggesting stopping 
therapy at 2 years did not have a clinically meaningful impact on overall survival. 
Long term follow-up data from Keynote-006, a phase 3 melanoma study, demonstrates 
pembrolizumab provides durable efficacy after stopping at the protocol-specified 2 year 
treatment duration. The median follow-up in the total population was 33.9 months. Among the 
104 (19%) participants who completed pembrolizumab, median exposure was 24.0 months. At a 
median follow-up of 9.0 months, 102 (98%) participants were alive. Responses were durable in 
participants who completed pembrolizumab with an estimated PFS (95% CI) of 91% (80-96) in 
all 104 patients, regardless of the response status.43
In Checkmate 153, patients who completed 1 year of nivolumab therapy were randomized to 
either continue or stop treatment after 1 year of therapy, with the option of retreatment upon 
progression. Results showed that in patients still on treatment at 1 year without progression, 
median PFS was significantly improved compared to those who stopped at 1 year (PFS: NR vs 
10.3 months; HR=0.42 [95% CI, 0.25 to 0.71]).44 While there was no statistically significant 
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difference in overall survival, there was a trend for patients on continued treatment to live longer 
(OS HR = 0.63 (95% CI: 0.33, 1.20), Subgroup analyses were consistent regardless whether 
patients had responded  to therapy or had stable disease at the time of randomization. This data 
suggest that in previously treated advanced NSCLC, continuing treatment beyond 1 year is 
favorable compared to stopping treatment at 1 year. Checkmate 153 was not designed to assess 2 
year duration of therapy.  However, the data suggests the risk of progression after 2 years of 
treatment is minimal, even in the absence of further treatment. The PFS plateaus seen at 2 years 
from first dose include participants who stopped after 1 year.44
Collectively, these data suggest that there is likely no benefit from treatment beyond two years in 
advanced or relapsed solid tumors. Therefore, CA209817 treatment will be given for up to 2 
years from start of treatment.
5.5.4
Justification for Removing Retreatment 
With a prior amendment, the option for retreatment on study in subjects who progress after 2 
years of treatment was removed from the protocol. Retreatment was originally included in 
CA209817 revised protocol 03 based on the assumption that it is biologically plausible that if a 
patient progresses after a checkpoint blockade agent has been discontinued, then reintroduction 
of the same agent could achieve tumor control, especially if the patient initially responded to 
treatment. 
However, accumulating evidence suggests that activity of retreatment is very limited. In 
Checkmate 153, 34 patients stopped therapy at 1 year and were retreated upon progression. 
Nivolumab retreatment did not appear to re-induce responses, although tumor burden appeared 
to be stable over several months in some patients. However, in the majority of patients, the tumor 
continued to progress suggesting that treatment should be changed, using preferentially an agent 
or approaches with a different MOA, either as standard of care, or through clinical trials.
5.5.5
Rationale for Tumor Mutation Burden Testing
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 I-O therapies, 
tumor types, and lines of treatment. The first published study of TMB as a biomarker of clinical 
outcomes was reported by Snyder et al45, 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.14 Additional studies of pembrolizumab and atezolizumab in NSCLC have been 
generally consistent with these results.46
TMB was evaluated in an exploratory post hoc analysis in the BMS-sponsored first line NSCLC 
study, CheckMate 026, which represents the first phase 3 study to demonstrate the impact of 
TMB on efficacy of a PD-1/L1 inhibitor.47 This 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 
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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.47
Interestingly, 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.48
Recently, the ongoing phase 3 CheckMate 227 study tested the combination of nivolumab
3mg/kg Q2W + ipilimumab 1mg/kg Q6W versus platinum-doublet chemotherapy in patients 
with previously-untreated metastatic or recurrent NSCLC. In the pre-specified analysis of 
patients with high tumor mutational burden at a prospective cutoff of ≥ 10 mutations/MB,
progression-free survival was significantly longer in the group treated nivolumab plus
ipilimumab compared to chemotherapy, demonstrating a median PFS of 7.2 months vs 5.5 
months, respectively (HR 0.58; 97.5% CI 0.41, 0.81). The treatment effect was consistent in a 
pre-specified multi-variate analysis when adjusted for PD-L1 expression, histology, and other 
clinical factors. The ORR was also significantly greater for the nivolumab plus ipilimumab group 
(45.3% vs. 26.9%; treatment difference 18.4%; 95% CI (7.6, 28.8), and the responses appeared 
durable with 68% of responses ongoing after 1 year and the DOR not reached (95% CI 12.2, NR) 
compared to 5.4 months (95% CI 4.2,6.9) for chemotherapy. Among the patients with low TMB 
(<10 mutations/MB), no PFS benefit was observed for nivolumab plus ipilimumab compared to 
chemotherapy (HR 1.07; 95% CI 0.84, 1.35; mPFS 3.2mo vs 5.5mo), suggesting the use of a 
TMB cutoff of ≥ 10 mutations/MB was an effective biomarker.49
The available data to date suggest that, in addition to and independently from PD-L1 expression, 
TMB is also a biomarker of clinical efficacy to IO therapy. 
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 
Institutional 
Review 
Board 
(IRB)/Independent Ethics Committee (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.
2) Type of Participant and Target Disease Characteristics
a) Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1. (Please see 
Special Population inclusion criteria in Section 6.1.1)
b) Cohort A, A1, and C (first-line NSCLC):
i)
Participants with histologically confirmed Stage IV or recurrent NSCLC (per the 7th 
International Association for the Study of Lung Cancer classification [IASLC])50
squamous or non-squamous histology, with no prior systemic anticancer therapy 
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nivolumab / ipilimumab
(including EGFR, ALK inhibitors, or other immuno-oncology agents) given as 
primary therapy for advanced or metastatic disease.
(1).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.
(2).Prior definitive 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.
c) Cohort B (second-line NSCLC)
i)
Participants with histologically- or cytologically-documented squamous or non-
squamous NSCLC who present with Stage IIIB/ Stage IV disease (per IASLC), or 
with recurrent or progressive disease following multimodal therapy (radiation 
therapy, surgical resection or definitive chemoradiation therapy for locally advanced 
disease). 
ii) Participants must have experienced disease recurrence or progression during or after 
one prior platinum doublet-based chemotherapy regimen for advanced or metastatic 
disease.
(1).Maintenance therapy following platinum doublet-based chemotherapy is not 
considered as a separate regimen of therapy
(2).Participants who received platinum-containing adjuvant, neoadjuvant or definitive 
chemoradiation therapy given for locally advanced disease, and developed 
recurrent (local or metastatic) disease within 6 months of completing therapy are 
eligible.
(3).Participants with recurrent disease > 6 months after platinum-containing adjuvant, 
neoadjuvant or definitive chemoradiation therapy given for locally advanced 
disease, who also subsequently progressed during or after a platinum doublet-
based regimen given to treat the recurrence, are eligible.
d) Evaluable disease by computed tomography (CT) or magnetic resonance imaging (MRI); 
radiographic tumor assessment performed within 28 days of start of study treatment.
e) Cohorts A,
A1, and B: Participants must have tissue submitted for PD-L1 
immunohistochemical (IHC) testing prior to the treatment assignment. If PD-L1 results 
are available from another BMS study, or a commercially available complementary 
diagnostic using an acceptable antibody (ie, 28-8, 22-C3, SP263), these results are 
acceptable. PD-L1 results obtained using antibody SP142 are not acceptable.
i)
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor 
tissue sections, with an associated pathology report, must be submitted for biomarker 
evaluation prior to treatment assignment. The tumor tissue sample may be fresh or 
archival if obtained within 12 months prior to enrollment (6 months for slides). 
ii) Tissue must be a core needle biopsy, excisional or incisional biopsy. Fine needle 
biopsies or drainage of pleural effusions with cytospins are not considered adequate 
for biomarker review. Biopsies of bone lesions that do not have a soft tissue 
component or decalcified bone tumor samples are also not acceptable.
(1).Samples collected via other procedures, including, but not limited to, 
endobronchial ultrasound (EBUS) guided biopsy, transbronchial lung biopsy 
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(TBLB) may be approved by the BMS medical monitor (MM)/study director (SD) 
on a case by case basis.
iii) Sufficient tissue (10-15 unstained slides) must be available.
f)
Prior palliative radiotherapy to non-central nervous system (CNS) lesions must have been 
completed at least 2 weeks prior to the treatment assignment. Participants with 
symptomatic tumor lesions at baseline that may require palliative radiotherapy within 
4 weeks of the treatment assignment are strongly encouraged to receive palliative 
radiotherapy prior to starting study therapy. Lesions which have received or are 
anticipated to receive palliative RT may not be designated as target or non-target lesions 
in the baseline tumor assessment.
g) Cohort C Tissue requirements: Sufficient tissue (10 unstained slides ≤ 3 months old) 
must be available for prospective TMB testing. Previously generated TMB results from 
the Foundation Medicine TMB test confirming ≥10 mutations/MB are acceptable. TMB 
testing results are required for enrollment. Five additional unstained slides for must also 
be available for PD-L1 testing. However, if PD-L1 results are available from another 
BMS study, or a commercially available Dako 28-8 complementary diagnostic using an 
acceptable antibody (ie, 28-8, 22-C3, SP263), these results are acceptable. PD-L1 results 
obtained using antibody SP142 are not acceptable. EGFR mutation and ALK 
translocation status will be assessed locally.
3) Age and Reproductive Status
a) Males and Females, ages 18 (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 human chorionic 
gonadotropin [HCG]) within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding.
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) 
nivolumab and ipilimumab plus 5 half-lives of study treatment plus 30 days (duration of 
ovulatory cycle) for a total of 5 months post-treatment completion
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 with study 
treatment(s) nivolumab and ipilimumab plus 5 half-lives of the study treatment plus 
90 days (duration of sperm turnover) for a total of 7 months post-treatment completion. 
In addition, male participants must be willing to refrain from sperm donation during this 
time. 
f)
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.
g) Post-menopausal females under age 55 must have serum FSH levels > 40 mIU (see 
Appendix 4)
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 
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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.
6.1.1
Inclusion Criteria for Cohort A1 Special Population 
4) Participants may be included in the 1L NSCLC special population cohort of the study 
with one of the following criteria. All other inclusion and exclusion criteria apply.
a) ECOG PS 0 and 1 participants with untreated, asymptomatic brain metastases
i)
Participants with untreated brain metastases must not require corticosteroids or 
anticonvulsant therapy.
b) ECOG PS 0 and 1 participants with hepatic impairment, defined as follows:
i)
Total bilirubin = 1.5-3.0 x ULN, and/or;
ii) AST/ALT = 3-5 x ULN
c) ECOG PS 0 and 1 participants with renal impairment, defined as follows:
i)
Creatinine clearance 20-39 mL/min (Cockcroft-Gault formula)
d) ECOG PS 0 and 1 participants with HIV
i)
Participants who are HIV positive must meet the following criteria:
(1). Acute or Chronic HIV infection. HIV-1 infection as documented by HIV rapid 
test performed in conjunction with screening (or ELISA, test kit, and confirmed 
by Western blot or other approved test). HIV plasma HIV-1 RNA below detected 
limit (limit of detection: 75) within 4 weeks prior to registration, without 
confirmed viral breakthrough for at least 6 months.
(2).HIV plasma HIV-1 RNA below detected limit (limit of detection: 75) within 4 
weeks prior to registration, without confirmed viral breakthrough for at least 6 
months.
(3).Participants with Chronic HIV must be asymptomatic/clinically latent, with CD4+ 
count of > 200 cells/mm3 obtained within 2 weeks prior to enrollment.
(4).Participants with a diagnosis of AIDS are excluded.
e) Participants with ECOG PS 2 who, in the opinion of the investigator, are expected to be 
able to tolerate study treatment.
6.2
Exclusion Criteria
1) Target Disease Exceptions
a) Participants 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 participants with non-squamous histology must 
have been tested for EGFR mutation status, with the exception of participants with 
known KRAS mutations. Use of an FDA-approved EGFR test is strongly encouraged. 
Participants with non-squamous histology and unknown or indeterminate EGFR status 
are excluded.
b) Participants 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. Participants with unknown or indeterminate ALK status may be enrolled.
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2) Medical Conditions
a) Participants with untreated CNS metastases are excluded.
i)
Participants are eligible if CNS metastases are adequately treated and participants are 
neurologically returned to baseline (except for residual signs or symptoms related to 
the CNS treatment) for at least 2 weeks prior to treatment assignment. 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.
b) Participants with carcinomatous meningitis.
c) Participants must have recovered from the effects of major surgery or significant 
traumatic injury at least 14 days before treatment assignment.
d) Active malignancy requiring concurrent intervention.
e) Participants with an active, known or suspected autoimmune disease. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll.
f)
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. Inhaled or topical steroids, and adrenal replacement 
steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
g) Participants with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity.
h) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS)-with the exceptions noted for Cohort A1 
participants. See Appendix 9 
i)
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.
3) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways
b) Not applicable per Revised Protocol 04: Cohort B: Prior participation in a BMS study 
where participants were treated with nivolumab and/or ipilimumab, except when 
approved by Medical Monitor/Study Director
c) 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 randomization/treatment. 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
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4) Physical and Laboratory Test Findings for Cohorts A, B, and C
Please see Section 6.1.1 Inclusion Criteria for Cohort A1 Special Population for physical and 
laboratory test findings
a) White blood cells (WBC) < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100*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)
f)
Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT): > 3.0 x ULN
g) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0x ULN)
h) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection.
5) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components.
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to 
continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is 
required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness
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 entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes date of consent, demography, screen failure 
details, eligibility criteria, and any serious AEs.
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6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / has 
not been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value).
The most current result prior to 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 assignment or treatment allocation. Study treatment includes both Investigational 
[Medicinal] Product (IP/IMP) and Non-investigational [Medicinal] Product (Non-IP/Non-IMP) 
and consist of the following:
•
Nivolumab
•
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 CA209817
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
240 mg kit or 
5 or 10 (100mg) vials per 
carton; Clear to opalescent, 
colorless to pale yellow 
liquid; Few particulates may 
be present.
Store at 2-8°C; 
Protect from 
light and 
freezing.
Ipilimumab 
Solution for Injection
5 mg/ml
IP
Open 
Label
4 vials per carton; Clear, 
colorless liquid. Few particles 
may be present.
Store at 2-8°C; 
Protect from 
light and 
freezing.
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
240 mg
Every 2 weeks
IV
Ipilimumab
1 mg/kg
Every 6 weeks
IV
Participants will receive treatment with nivolumab 240 mg as a 30 minute infusion every 2 
weeks and ipilimumab 1 mg/kg as a 30 minute infusion every 6 weeks, starting on Day 1, until 
progression, unacceptable toxicity, withdrawal of consent, 24 months from first dose, or the 
study ends, whichever occurs first. Participants should begin study treatment within 3 calendar 
days of treatment assignment.
When nivolumab and ipilimumab are to be administered on the same day, nivolumab is to be 
administered first. Nivolumab infusion must be promptly followed by a flush of diluent to clear 
the line of nivolumab before starting the ipilimumab infusion. The second infusion will always 
be the ipilimumab study treatment and will start after the infusion line has been flushed, filters 
changed and patient has been observed to ensure no infusion reaction has occurred.  
Nivolumab and ipilimumab may be diluted in 0.9% Sodium Chloride solution or 5% Dextrose 
solution. 
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 prior dose, 
the dose must be recalculated. All doses should be rounded to the nearest milligram. There will 
be no dose modifications allowed.  
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There are no premedications recommended.
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.
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending 
on how well the participant tolerates the treatment. For more details, see Sections 7.4.1 (dose 
delays), 7.4.3 (resuming treatment), and 8.1 (discontinuation).
7.2
Method of Treatment Assignment
All participants will be centrally assigned to treatment using an Interactive Response Technology 
(IRT). Before the study is initiated, each user will receive log in information and directions on 
how to access the IRT. Study treatment will be dispensed at the study visits as listed in Schedule 
of Activities (Section 2). 
7.3
Blinding
Not applicable. This is an open-label study, and therefore blinding procedures are not applicable.
7.4
Dosage Modification
7.4.1
Dose Delay Criteria for Cohorts A, B, and C
Nivolumab and ipilimumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, except for fatigue
•
Grade 3 skin, drug-related AE
•
Grade 2 drug-related creatinine, AST, ALT and/or total bilirubin abnormalities
•
Grade ≥3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require a dose delay
−
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 receiving ipilimumab in combination with nivolumab 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 4 amylase and lipase 
abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis 
and that are attributed to ipilimumab alone.)
Participants who require delay should be re-evaluated weekly or more frequently if clinically 
indicated and resume study medication dosing when re-treatment criteria are met.
Rescheduling:
•
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.
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•
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 and ipilimumab may be adjusted within the 
permitted ± 5 day 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 8.1.1.2.
7.4.1.1
Dose Delay Criteria for Special Population (Cohort A1)
All dose delay criteria listed in Section 7.4.1 apply to the special population cohort, with the 
following exceptions for participants with hepatic and renal impairment:
•
If a participant has Grade 2 baseline AST or ALT elevation (> 3.0-5.0 x ULN), delay dosing 
for a two-fold increase in AST or ALT or for AST or ALT values 8 x ULN.
•
If a participant has Grade 2 baseline total bilirubin (> 1.5-3.0 x ULN), delay dosing for drug-
related elevation > 5.0 x ULN.
•
If a participant has Grade 4 CrCl (CrCl < 15 ml/min), delay dosing/hold dose; participants 
may resume dosing with CrCl > 20 ml/min.
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 contain only human immunoglobulin protein sequences, they 
are unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the BMS Medical Monitor and reported 
as an SAE if criteria are met. Infusion reactions should be graded according to National Cancer 
Institute (NCI) common terminology criteria for adverse events (CTCAE) (Version 4) 
guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention 
not indicated)
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
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(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, intravenous {IV} fluids]; 
prophylactic medications indicated for ≤24 hours)
•
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline (or 
diluent), and treat the participant with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
participant closely. If symptoms recur, then no further nivolumab or ipilimumab will be 
administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and 
monitor the participant until resolution of symptoms. The amount of study drug infused must 
be recorded on the electronic case report form (eCRF).
•
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 infusions. If 
necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [eg, renal impairment, pulmonary infiltrates]. Grade 4: Life threatening; pressor 
or ventilatory support indicated)
•
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of 
normal saline (or diluent) and treat the participant as follows: Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 
mg of a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 
mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be 
monitored until the investigator is comfortable that the symptoms will not recur. Nivolumab 
or ipilimumab will be permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor 
participant until recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
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7.4.4
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered 
immuno-oncology agents in this protocol. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management Algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The above algorithms are found in both the nivolumab and ipilimumab Investigator Brochures, 
as well as in Appendix 7.
Additionally, rare cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with 
fatal outcome, have been reported with nivolumab or nivolumab in combination with 
ipilimumab. If a patient develops signs and symptoms of myotoxicity, close monitoring should 
be implemented, and the patient referred to a specialist for assessment and treatment without 
delay. Based on the severity of myotoxicity, nivolumab or nivolumab in combination with 
ipilimumab should be withheld or discontinued, and appropriate treatment instituted. For grade 3 
myocarditis, nivolumab or nivolumab in combination with ipilimumab should be permanently 
discontinued.
7.4.5
Criteria to Resume Dosing
7.4.5.1
Criteria to Resume Nivolumab for Cohorts A, B, and C
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, 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 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) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
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steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by 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 with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor 
(or designee). Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.
Dose delay of nivolumab which results in treatment interruption of > 6 weeks requires treatment 
discontinuation, with exceptions as noted in Section 8.1.1.
7.4.5.2
Criteria to Resume Ipilimumab for Cohorts A, B, and C
Participants may resume treatment with nivolumab and 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 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) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.
•
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.
•
Drug-related endocrinopathies (except Grade 3 or greater adrenal insufficiency) 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 8.1.1.2.
•
Ipilimumab may not be resumed sooner than 37 days 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.
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One exception to note is when ipilimumab and nivolumab doses are delayed due to drug-related 
Grade  4 amylase or lipase abnormalities not associated with symptoms or clinical manifestations 
of pancreatitis. If the investigator assesses the Grade 4 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 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 8 for treatment discontinuation criteria.
Please see Section 7.4.5.3 Criteria to Resume Nivolumab or Ipilimumab for Special Population.
7.4.5.3
Criteria to Resume Nivolumab and Ipilimumab for Special Population
(Cohort A1)
The criteria to resume nivolumab and ipilimumab dosing described in Section 7.4.5.1 and 
Section 7.4.5.2 apply to special population participants, with the following exceptions for hepatic 
impairment:
•
Participants with Grade 2 baseline AST or ALT elevation (> 3.0-5.0 x ULN), who require 
dose delays for reasons other than drug-related AST or ALT elevation > 8 x ULN, may 
resume dosing in the presence of AST or ALT elevation ≤8 x ULN.
•
Participants with Grade 2 baseline total bilirubin (> 1.5-3.0 x ULN), who require dose delays 
for reasons other than drug-related total bilirubin elevation > 5.0 x ULN, may resume dosing 
in the presence of total bilirubin elevation ≤5.0 x ULN.
Participants with combined AST/ALT and total bilirubin values meeting discontinuation 
parameters (Section 8.1) should have treatment permanently discontinued.
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites 
by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
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•
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.  
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not Applicable.
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. 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 14 days prior to study drug administration must be 
recorded on the CRF.
The following medications are prohibited during the study (unless utilized to treat a drug related 
AE):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.2)
•
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 7.7.2.1.
•
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.
Any concomitant therapies taken at any time during the study must be recorded on the CRF.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring
systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days 
of treatment assignment are excluded. Inhaled or topical steroids, and adrenal replacement 
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steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
7.7.2.1
Palliative Radiotherapy (All Cohorts)
On study palliative radiotherapy is not allowed on target lesions used to assess disease response 
and designated as such in the eCRF. Non-target bone lesions not so designated and that do not 
include lung tissue in the planned radiation field may be treated with palliative radiotherapy at 
any time while participants remain on study treatment. In addition, palliative radiotherapy to a 
single metastatic site, other than bone, is permitted in participants who do not require immediate 
initiation of second line systemic anti-cancer therapy. Such radiotherapy to non-bone lesions 
must not be given within 2 weeks of initiation of study therapy and such lesions are not 
permitted to be designated as baseline target lesions in the eCRF. Details of palliative 
radiotherapy should be documented in the source records and CRF. Details in the source records 
should include: dates of treatment, anatomical site, dose administered and fractionation schedule, 
and AEs.
Participants requiring palliative radiotherapy to designated target lesions must be discontinued 
from study therapy.  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.
7.7.3
Permitted Therapy 
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief(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.
7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should 
ensure that the participant receives appropriate standard of care to treat the condition under 
study.
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.
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8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant 
to provide this information
•
Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
The assessment for discontinuation of nivolumab should be made separately from the 
assessment made for discontinuation of ipilimumab. Although there is overlap among the 
discontinuation criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, 
treatment with nivolumab may continue if ipilimumab is discontinued.
If a participant in any of the nivolumab/ipilimumab combination arms meets criteria for 
discontinuation and investigator is unable to determine whether the event is related to both or 
one study drug, the participant should discontinue both nivolumab and ipilimumab and be taken 
off the treatment phase of the study.
8.1.1
Study Drug Discontinuation
8.1.1.1
Nivolumab Discontinuation for Cohorts A, B, and C
Nivolumab treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, myocarditis, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation
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−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation:
o
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
*In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently 
discontinued. 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.
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 
hours of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
•
Any event that leads to delay in dosing lasting > 6 weeks for nivolumab from the previous 
dose requires discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. 
−
Dosing delays lasting > 6 weeks for nivolumab from the previous dose that occur for 
non-drug-related reasons may be allowed if approved by the BMS Medical Monitor (or 
designee). 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the BMS 
Medical Monitor (or designee) must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
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should also continue every 6 weeks or more frequently if clinically indicated during such dosing 
delays.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing.
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.
8.1.1.2
Ipilimumab Dose Discontinuation for Cohorts A, B, and C
Ipilimumab must be permanently discontinued if any of the following criteria are met:
•
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within 2 weeks OR requires 
systemic treatment;
•
Any Grade ≥3 bronchospasm or other hypersensitivity reaction;
•
Any other Grade 3 non-skin, drug-related adverse event with the following exceptions for 
laboratory abnormalities, grade 3 nausea and vomiting, grade 3 neutropenia and 
thrombocytopenia, and symptomatic endocrinopathies (except for adrenal insufficiency) 
which resolved (with or without hormone substitution);
•
Any drug-related LFT abnormality that meets the following criteria require discontinuation:
•
AST or ALT > 8x ULN
•
Total bilirubin > 5 x ULN
•
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any Grade 4 drug-related AE or laboratory abnormality, except for the following events, 
which do not require discontinuation:
•
Grade 4 neutropenia ≤7 days
•
Grade 4 lymphopenia or leukopenia
•
Isolated Grade 4 amylase or lipase abnormalities which are not associated with symptoms or 
clinical manifestations of pancreatitis. The BMS Medical Monitor should be consulted for 
Grade 4 amylase or lipase abnormalities.
•
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 AEs such as hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
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replacement (corticosteroids, thyroid hormones) or glucose controlling agents, respectively, 
may not require discontinuation after discussion with and approval from the BMS Medical 
Monitor.
•
Any treatment delay resulting in no ipilimumab dosing for > 12 weeks with the following 
exceptions: Dosing delays to manage drug-related AEs, such as prolonged steroid tapers, are 
allowed. Prior to re-initiating treatment in a participant with a dosing delay lasting 
> 12 weeks, the BMS medical monitor must be consulted. Tumor assessments should 
continue as per protocol even if dosing is delayed.
•
Dosing delays resulting in no ipilimumab dosing for > 12 weeks that occur for non-drug-
related reasons may be allowed if approved by the BMS medical monitor. Prior to re-
initiating treatment in a participant with a dosing delay lasting > 12 weeks, the BMS medical 
monitor must be consulted. Tumor assessments should continue as per protocol even if 
dosing is delayed.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued ipilimumab 
dosing.
8.1.1.3
Nivolumab and Ipilimumab Dose Discontinuation for Special Population
(Cohort A1)
The dose discontinuation criteria described in Section 8.1.1.1 and Section 8.1.1.2 apply to special 
population participants, with the following exceptions for hepatic impairment:
•
Any liver function test (LFT) abnormality that meets the following criteria require 
discontinuation (also see Hepatic Adverse Event Management Algorithm):
−
AST or ALT > 10 x ULN for > 2 weeks
−
AST or ALT > 15 x ULN
−
Total bilirubin > 8 x ULN
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 5 x ULN
•
Any drug-related renal dysfunction
Participants requiring renal transplant must be discontinued from study therapy. In some cases, 
participants requiring dialysis may be permitted to continue study therapy; however, these cases 
must be reviewed and approved by the BMS Medical Monitor.
8.1.2
Disease Progression
In general, study treatment must be discontinued at the time of disease progression per Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. However, accumulating evidence 
indicates a minority of participants treated with immunotherapy may derive clinical benefit 
despite initial evidence of progressive disease.36
Participants may be permitted to continue study treatment with nivolumab (with or without 
ipilimumab) beyond initial RECIST 1.1 defined progressive disease, assessed by the investigator
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up to a maximum of 24 months from date of first dose, 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 drug
•
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.
A radiographic assessment/ scan should be performed within 6 weeks of initial 
investigator-assessed progression to determine whether there has been a decrease in the tumor 
size or continued progressive disease. 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 nivolumab participant continues to achieve clinical benefit by 
continuing treatment, the participant should remain on the trial and continue to receive 
monitoring according to the Schedule of Activities in Section 2.
For the participants who continue nivolumab study therapy beyond progression, further 
progression is defined as an additional 10% increase in tumor burden with a minimum 5 mm 
absolute increase from time of initial progressive disease. 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 progressive disease. Nivolumab treatment should be discontinued permanently 
upon documentation of further progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
8.1.3
Additional Guidance on Treatment Discontinuation
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 7.4.1 OR 
Appendix 7 or if the investigator believes that it is in best interest of the participant. 
Discontinuation is required if the participants meets one of the conditions described in 
Section 8.1.
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Refer to the Schedule of Activities for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes 
pregnant during a clinical trial, the study treatment must be discontinued immediately. In most 
cases, the study treatment will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24 
hours of awareness of the pregnancy. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study treatment, a discussion between the 
investigator and the BMS Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-
up procedures as outlined in Section 2. The only exception to this requirement is when a 
participant withdraws consent for all study procedures including post-treatment study follow-up 
or loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records and entered on 
the appropriate case report form (CRF) page.
8.1.4
Post Study Treatment Study Follow-up
In this study, overall survival is a key secondary endpoint of the study. Post study follow-up is of 
critical importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed for collection of 
outcome and/or survival follow-up data as required and in line with Section 5 until death or the 
conclusion of the study.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures. The only exception to this 
is when a participant specifically withdraws consent for any further contact with him/her or 
persons previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
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•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their 
ongoing status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical 
records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the 
study has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date 
as determined by the investigator should be reported and documented in the participant’s 
medical records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities (Section 2). 
•
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 (eg, blood 
count) and obtained before signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities.
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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 AEs, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure and Appendix 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 the study. Every effort will be made to 
collect survival data on all participants including participants withdrawn from treatment for any 
reason, who are eligible to participate in the study and who have not withdrawn consent for 
survival data collection. 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.
Study evaluations will take place in accordance with the Schedule of Activities (Section 2), 
according to RECIST 1.1 criteria.51 CT with oral/IV contrast or contrast-enhanced MRI is the 
preferred imaging modalities for assessing radiographic tumor response. If a participant has a 
known allergy to contrast material, please use local prophylaxis standards to obtain the 
assessment with contrast if at all possible, or use the alternate modality. In cases where contrast 
is strictly contraindicated, a non-contrast scan will suffice. Screening assessments should be 
performed within 42 days of start of study treatment. Brain MRI is the preferred imaging method 
for evaluating CNS metastasis, and assessment is required during screening in participants with a 
known history of treated brain metastases. All known or suspected sites of disease (including 
CNS) should be assessed at screening and at subsequent assessments using the same imaging 
method and technique. If more than one method is used at screening, then the most accurate 
method according to RECIST 1.1 should be used when recording data, and should again be used 
for all subsequent assessments. Bone scan, positron emission tomography (PET) scan, or 
ultrasound are not adequate for assessment of RECIST response. In selected circumstances 
where such modalities are the sole modality used to assess certain non-target organs, those non-
target organs may be evaluated less frequently. For example, bone scans may need to be repeated 
only when complete response is identified in target disease or when progression in bone is 
suspected. Previously treated CNS metastases are not considered measurable lesions for purposes 
of RECIST determined response. Participants with a history of brain metastasis should have 
surveillance MRI approximately every 12 weeks, or sooner if clinically indicated.
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Radiographic tumor assessments will be conducted until disease progression (or until 
discontinuation of study therapy in participants receiving study drug beyond progression), lost to 
follow-up, or withdrawal of study consent. Tumor assessments for all participants should 
continue as per protocol even if dosing is interrupted. Tumor measurements should be made by 
the same investigator or radiologist for each assessment whenever possible. Changes in tumor 
measurements and tumor responses to guide ongoing study treatment decisions will be assessed 
by the investigator using RECIST 1.1 (Appendix 6).
9.1.1
Imaging Assessment for the Study
At the Sponsor’s discretion, de-identified scans and measurements may be collected and 
reviewed by independent radiologists using RECIST 1.1 criteria at a later date, or at any time 
during the study.
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
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which 
were exacerbated by the induction of autoimmunity. Information supporting the assessment will 
be collected on the participant’s case report form.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE information should begin at initiation of study treatment until 
100 days after the last dose of study therapy, at the timepoints specified in the Schedule of 
Activities (Section 2). Non-serious AE information should also be collected from the start of a 
placebo lead-in period or other observational period intended to establish a baseline status for the 
participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of SAEs for expedited reporting. Following the 
participant’s written consent to participate in the study, all SAEs, whether related or not related 
to study drug, must be collected, including those thought to be associated with protocol-specified 
procedures.
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All SAEs must be collected that occur during the screening period and within 100 days after 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the appropriate section of the eCRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this 
being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the 
study treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants 
should not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs
•
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious (see Appendix 3).
•
Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 All identified non-serious AEs must be recorded and described on the non-serious AE page 
of the CRF (paper or electronic). Completion of supplemental CRFs may be requested for 
AEs and/or laboratory abnormalities that are reported/identified during the course of the 
study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
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9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting AEs 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. All SAEs 
must be collected that occur during the screening period and within 100 days of the last dose of 
study treatment. For participants randomized/assigned to treatment and never treated with study 
drug, SAEs should be collected for 30 days from the date of treatment assignment.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please call the BMS Medical Monitor 
within 24 hours of awareness of the pregnancy.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE 
CRF page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a 
back-up option when the electronic system is not functioning.
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•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for 
reporting details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), AND;
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), AND;
3) No other immediately apparent possible causes of aminotransaminase (AT) elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a non-serious or SAE, as appropriate, and reported
accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2).
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.
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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 the 
Schedule of Activities.
9.4.1
Electrocardiograms
Refer to Schedule of Activities. A 12-lead ECG must be performed during the screening phase, 
preferably after eligibility has been confirmed. This will serve as a baseline assessment in the 
event of any on-study cardiac AEs. Vital signs should also be taken as per institutional standard 
of care prior to, during and after infusions.
9.4.2
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
•
All clinical safety laboratory assessments will be performed locally per the Schedule of 
Activities and Table 9.4.2-1.
Table 9.4.2-1:
Laboratory Assessment Panels
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Creatinine
Blood Urea Nitrogen (BUN) or Serum Urea Level
Glucose
Uric acid
Sodium
Potassium
Chloride
Calcium
Phosphate
Lipase
Amylase
TSH (reflex to free T3 and T4 if abnormal)
Creatinine clearance (CrCL) calculation using 
Cockcroft-Gault at screening only and every 6 weeks 
for participants with renal impairment.
Serology 
Serum for hepatitis C antibody or hepatitis C RNA, hepatitis B surface antigen (screening only)
When mandated locally, HIV testing must be performed. HIV testing is required for all participants in Germany 
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Table 9.4.2-1:
Laboratory Assessment Panels
(see Appendix 9). 
Other Analyses
Pregnancy test and FSH (WOCBP only, as described in Section 2).
9.4.3
Imaging Safety Assessment
Not Applicable.
9.5
Pharmacokinetic Assessment
Samples for PK and immunogenicity assessments will be collected for all participants receiving 
nivolumab and ipilimumab as described in Table 9.5.1-1. All time points are relative to the start 
of study drug administration. All on-treatment time points are intended to align with days on 
which study drug is administered, if dosing occurs on a different day, the PK and 
immunogenicity sampling should be adjusted accordingly. Further details of sample collection, 
processing, and shipment will be provided in the laboratory procedures manual.
9.5.1
Pharmacokinetic and Immunogenicity Collection and Processing: All 
Cohorts
A detailed schedule of PK and immunogenicity evaluations is provided in Table 9.5.1-1. PK 
samples will be analyzed for nivolumab/ipilimumab by a validated ligand binding assay. 
Immunogenicity samples will be analyzed for anti-nivolumab antibodies/anti-ipilimumab 
antibodies by a validated immunogenicity assay; samples may also be analyzed for neutralizing 
antibodies by a validated method. Serum samples may be analyzed by an exploratory method 
that measures anti-drug antibodies for technology exploration purposes; exploratory results will 
not be reported. Serum samples designated for PK or biomarker assessments may also be used 
for immunogenicity analysis if required (eg, insufficient volume for complete immunogenicity 
assessment or to follow up on suspected immunogenicity related AE).
Table 9.5.1-1:
Pharmacokinetic and Immunogenicity Sample Collection for 
Nivolumab and Ipilimumab (All Cohorts)
Study Daya
(1 Cycle = 6 weeks)
Event 
(Relative 
To Dosing)
Hour
Time 
(Relative 
To Dosing)
Hour: Min
PK Blood 
Sample for 
Nivolumab
IMG Blood 
Sample for 
Nivolumab
PK Blood 
Sample for 
Ipilimumab
IMG Blood 
Sample for 
Ipilimumab
C1D1
(Nivolumab + 
Ipilimumab dose 1)
Predoseb
00:00
X
X
X
X
C1D1
0.5 (EOI)c
00:30c
X
X
C1D15 d
(Nivolumab dose 2)
Predoseb
00:00
X
X
X
X
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Table 9.5.1-1:
Pharmacokinetic and Immunogenicity Sample Collection for 
Nivolumab and Ipilimumab (All Cohorts)
Study Daya
(1 Cycle = 6 weeks)
Event 
(Relative 
To Dosing)
Hour
Time 
(Relative 
To Dosing)
Hour: Min
PK Blood 
Sample for 
Nivolumab
IMG Blood 
Sample for 
Nivolumab
PK Blood 
Sample for 
Ipilimumab
IMG Blood 
Sample for 
Ipilimumab
C2D15 d
(Nivolumab dose 5)
Predoseb
00:00
X
X
X
X
C4D15 d (Nivolumab 
dose 11)
Predoseb
00:00
X
X
X
X
D15 of every 4th 
cycle after C4D15 
until discontinuation 
of study treatment or 
maximum up to 2 
years of treatment d
Predoseb
00:00
X
X
X
X
a If ipilimumab is discontinued and nivolumab continues, ipilimumab PK and ADA should be collected only for 
the next 2 time points (corresponding to nivolumab sample collection) according to the PK table.
b Predose samples should be collected just before the administration of the first drug (preferably within 30 
minutes). If it is known that a dose is going to be delayed, then the predose sample should be collected just prior 
to the delayed dose. However, if a predose sample is collected but the dose is subsequently delayed, an additional 
predose sample should not be collected.
c EOI: End of Infusion. This sample should be taken immediately prior to stopping the second drug infusion 
(preferably within 2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal 
infusion duration, the collection of this sample should also be delayed accordingly. EOI samples may not be 
collected from the same IV access as drug was administered.
d If the D15 PK collection is missed, PK can be collected at next visit, D29.
9.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7
Pharmacogenomics
Pharmacogenomic testing will not be performed in this study.
9.8
Biomarkers
9.8.1
Tumor Tissue Specimens
9.8.1.1
Cohorts A, A1,and B
Fresh or archival FFPE tumor tissue collected within 12 months (block) or within 6 months for 
sectioned slides) must be submitted for PD-L1 IHC testing prior to the treatment assignment for 
all cohorts. Previously generated PD-L1 results are also acceptable if generated using anti-PD-L1 
antibodies 28-8, 22-C3 or SP263. If results using approved antibodies are provided, then 
additional PD-L1 testing is not required. PD-L1 results generated using the SP142 antibody are 
not acceptable. If PD-L1 status is unknown then samples will be sent to a third party to stain and 
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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.
 
 
 
 
 
 
 
 
 
9.8.1.2
Cohort C
Archival FFPE tumor tissue collected within 3 months or fresh tissue for sectioned slides must 
be submitted for TMB testing. Ten unstained tumor tissue sections are required for TMB testing 
by Foundation Medicine unless TMB previous results from Foundation Medicine are available. 
PD-L1 testing is required unless results available from another BMS study, or a commercially 
available complementary diagnostic using an acceptable antibody (ie, 28-8, 22-C3, SP263).
PD-L1 results obtained using antibody SP142 are not acceptable. Cohort C tissue will be 
assessed for biomarkers, as other cohorts.
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9.9
Healthcare Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
9.10
Patient Reported Outcomes
In this study, patient-reported outcomes (PRO) will be measured using the Functional 
Assessment of Cancer Therapy-Lung (FACT-L) Version 4, a quality of life questionnaire to 
assess various functional dimensions and includes the Lung Cancer Subscale (LCS) that 
specifically assesses the treatment impact on lung cancer-related symptoms. The FACT-L is 
provided in Appendix 8.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
In this study, approximately 400 participants will be treated in Cohort A and 400 participants 
will be treated in Cohort B. 
In general, for nivolumab combined with ipilimumab, the safety profile to date is similar across 
tumor types, while select treatment related AEs of high grade (Grade 3-4) are rather uncommon. 
Their incidence per category was ≤5% in the CA209012 trial that tested nivolumab 3 mg/kg 
every 2 weeks and ipilimumab 1 mg/kg every 6 weeks.13
An additional special population NSCLC cohort (Cohort A1) will include approximately 200 
treated participants with one or more of the following criteria: ECOG PS 2, or PS ≤ 1 
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asymptomatic untreated brain metastases, renal or hepatic dysfunction, and/or HIV. Descriptive 
safety and efficacy analysis based on this cohort (Cohort A1) will be performed.
 
 
Approximately 300 participants will be screened for TMB to achieve approximately 100 treated 
participants in Cohort C. 
 
 
 
 
 
 
10.2
Populations for Analyses
Population
Description
Enrolled 
All participants who signed informed consent and were 
registered in IVRS
Treated 
All participants who take at least 1 dose of any study 
medication. 
Primary NSCLC cohorts 
treated participants
All treated participants in Cohort A and B. This is the primary 
cohort for safety and efficacy analyses
Special population NSCLC 
All treated participants in the special population cohort (A1). 
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Population
Description
cohort treated participants
Exploratory analysis will be conducted by special populations.
PK
All 
treated 
participants 
with 
available 
serum 
time-
concentration data.
Immunogenicity
All treated participants with available immunogenicity data.
10.3
Statistical Analyses
10.3.1
Efficacy Analyses
The primary efficacy analysis is scheduled to occur once all patients have initiated study therapy 
and have been followed for at least 9 months.
Endpoint
Statistical Analysis Methods
Secondary 
in Cohorts 
A, B, and C
Objective Response Rate (ORR) defined as the number and percentage of 
participants with a best overall response (BOR) of confirmed complete response 
(CR) or partial response (PR). Best overall response (BOR) is defined as the best 
response designation, recorded between the date of first dose and the date of the 
initial objectively documented tumor progression per RECIST v1.1 or the date 
of subsequent therapy, whichever occurs first. For participants without
documented progression or subsequent therapy, all available response 
designations will contribute to the BOR determination.
The ORR will be summarized by binomial response rates and their 
corresponding two-sided 95% exact CIs using the Clopper-Pearson method.
Secondary 
in Cohorts 
A, B and C
Progression-free survival (PFS) is defined as the time from first dosing date to 
the date of the first documented tumor progression, as determined by 
investigators (per RECIST v1.1), or death due to any cause, whichever occurs 
first. Participants who die without a reported prior progression will be 
considered to have progressed on the date of their death. Participants who did 
not progress or die will be censored on the date of their last evaluable tumor 
assessment. Participants who did not have any on study tumor assessments and 
did not die will be censored on the first dosing date. Participants who started any 
palliative local therapy or subsequent anti-cancer therapy without a prior 
reported progression will be censored on the date of their last evaluable tumor 
assessment prior to the initiation of the palliative local therapy or subsequent 
anti-cancer therapy, whichever procedure occurred first.
OS is defined as the time from first dosing date to the date of death. A 
participant who has not died will be censored at last known date alive.
OS and PFS will be summarized by Kaplan-Meier (KM) product-limit method 
for all treated participants. Median values of OS and PFS, along with two-sided 
95% CI using Brookmeyer and Crowley method, will be calculated. Survival 
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Endpoint
Statistical Analysis Methods
rates at fixed timepoints (eg, at 6 months) will also be estimated using KM 
estimates on the OS curve for all treated participants. Associated two-sided 95% 
CIs will be calculated using the Greenwood formula. 
Duration of objective response (DOR) is defined as the time between the date of 
first confirmed response to the date of the first documented tumor progression 
(per RECIST 1.1), or death due to any cause, whichever occurs first. 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 the subsequent anti-cancer 
therapy. DOR will be evaluated for responders (ie, participants with confirmed 
CR or PR) only.
Exploratory
Will be described in the statistical analysis plan finalized before database lock
10.3.2
Safety Analyses
The primary safety analysis is scheduled to occur once all patients have initiated study therapy 
and have been followed for at least 3 months.
Endpoint
Statistical Analysis Methods
Primary in 
Cohorts A,
B, and C
The number and percentage of participants who experience high grade (Grade 3-
4 and Grade 5) treatment related select and immune-mediated adverse events 
(imAEs) will be summarized for all treated participants. High grade (Grade 3-4 
and Grade 5) treatment related select AEs and imAEs will be tabulated using 
worst grade per NCI CTCAE v4 criteria by system organ class and Medical 
Dictionary for Regulatory Affairs (MedDRA) preferred term. The analysis is 
scheduled to occur once all patients have initiated study therapy and have been 
followed for at least 3 months.
The (select AEs consist of a list of preferred terms grouped by specific category 
(eg, pulmonary events, gastrointestinal events categories, etc). AEs that may
differ from or be more severe than AEs caused by non-immunotherapies and 
AEs whose early recognition and management may mitigate severe toxicity are 
included as select AEs. The select AEs and the categories are defined by the 
Sponsor and the list that is the most current at the time of analysis will be used. 
Changes may be made to this list with each new version of MedDRA prior to 
database lock. Only select AEs occurring within 30 days of the last dose are 
included in the analysis.
Immune-mediated AEs are specific events (or groups of preferred terms [PTs] 
describing specific events) that include pneumonitis, diarrhea/colitis, hepatitis, 
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Endpoint
Statistical Analysis Methods
nephritis/renal dysfunction, rash, and endocrine (adrenal insufficiency, 
hypothyroidism/thyroiditis, 
hyperthyroidism, 
diabetes 
mellitus, 
and 
hypophysitis). IMAE analyses included events, regardless of causality, occurring 
within 100 days of the last dose. These analyses will be limited to participants
who received immunosuppressive medication for treatment of the event, with
the exception of endocrine events (hypothyroidism/thyroiditis, hyperthyroidism, 
hypophysitis, diabetes mellitus, adrenal insufficiency), which were included in 
the analysis regardless of treatment since these events are often managed 
without immunosuppression.
Exploratory
Will be described in the statistical analysis plan finalized before database lock
10.3.3
Other Analyses
10.3.3.1
Patient Reported Outcomes
The analysis of FACT-L will be performed in all treated participants who have an assessment at 
screening/baseline and at least 1 follow-up assessment. The questionnaire completion rate for the 
FACT-L, defined as the proportion of questionnaires received out of the expected number (ie, the 
number of participants still on treatment in follow-up), will be calculated and summarized at 
each assessment point. 
The FACT-L, including its subscales (LCS and TOI), will be scored using a 5-point scale (0 = 
not at all; 1 = a little bit, 2 = somewhat; 3 = quite a bit; 4 = very much). The ranges of possible 
total scores are 0 - 136 for the FACT-L, 0 - 28 for the LCS and 0 - 84 for the TOI, with a higher 
score representing better quality of life, improved symptomatology and enhanced physical/ 
functional outcomes, respectively. According to Functional Assessment of Chronic Illness 
Therapy (FACIT) scoring guidelines, in the event of missing responses for some of the 
questions/items, scores will be prorated using the average of the other answers in that scale. 
Additional details around the analyses will be provided in the statistical analysis plan. 
The overall FACT-L (including the LCS and TOI) will be analyzed using descriptive statistics at 
each of the assessment time points. Summary statistics including the reporting of means, 
medians, ranges and standard deviation. Additional detail on methodology and analyses for the 
PRO secondary endpoint will be described in the statistical analysis plan.
10.3.3.2
Pharmacokinetic Analyses
The nivolumab and ipilimumab concentration data obtained in this study may be combined with 
data from other studies in the clinical development program to develop or refine a population PK 
model. This model may be used to evaluate the effects of intrinsic and extrinsic covariates on the 
PK of nivolumab and to determine measures of individual exposure (such as steady-state peak, 
trough, and time-averaged concentration). In addition, model determined exposures may be used 
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for exposure-response analyses. Results of population PK and exposure response-analyses will 
be reported separately.
Immunogenicity, pharmacodynamic, 
 exploratory analyses will be described in the 
statistical analysis plan finalized before database lock.
10.3.4
Interim Analyses 
There will be no formal interim analyses. Administrative interim analyses based on one single 
cohort or multiple cohorts may be performed at several times prior to completion of the study in 
order to support presentations or publications.
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11
REFERENCES
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14 Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
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17 Brambilla E, Travis WD, Colby TV, et al. The new World Health Organization classification 
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19 Schrump DS, Carter D, Kelsey CR, et al. Non-Small Cell Lung Cancer. Cancer: Principles 
and Practice of Oncology. 9th Edition. 2011. (Chapter 75).
20 www.cancer.org. Accessed 28-Jun-2016.
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22 Pujol JL, Barlesi F, Daures JP. Should chemotherapy combinations for advanced non-small 
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Cancer 2006; 51:335-45
23 NCCN Clinical Practice Guidelines in Oncology. Non-small Cell Lung Cancer. v.4.2016. 
www.nccn.org.
24 Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical 
Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin 
Oncol. 2009;27(36):6251–6266. 
25 NSCLC Meta-analyses Collaborative Group. Chemotherapy in addition to supportive care 
improves survival in advanced non–small cell lung cancer: a systematic review and meta-
analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol. 
2008;26:4617–4625.
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26 D’Addario G, Pintilie M, Leighl NB, et al. Platinum-based versus nonplatinum-based 
chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published 
literature. J Clin Oncol. 2005;23:2926–2936.
27 Gridelli C, Ardizzoni A, Ciardiello F, et al Second-line treatment of advanced non-small cell 
lung cancer. J Thorac Oncol 2008;3(4):430–440. 
28 Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for 
PD-L1–positive non–small-cell lung cancer. NEJM. published online on October 9, 2016 at 
NEJM.org.
29 Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-
stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. Epub 2008 May 
27.
30 Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing 
bevacizumab plus carboplatin and paclitaxel alone in previously untreated locally advanced 
or metastatic non-small-cell lung cancer. J Clin Oncol. 2004; 22: 2184-91.
31 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39.
32 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27.
33 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
34 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2004;23:515-48.
35 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45.
36 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.
37 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.
38 Spigel DR, Schwartzberg LS, Waterhouse DM. Is Nivolumab Safe and Effective in Elderly 
and ECOG PS Results of CheckMate 153. International Association for the Study of Lung 
Cancer 17th World Conference on Lung Cancer; December 4–7, 2016; Vienna, Austria
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39 Schadendorf D, Hodi FS, Robert C, Weber JS, 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.
40 5. Schadendorf D. 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.
41 2. Brahmer J, Horn L, Jackman D, 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.
42 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)
43 Caroline Robert 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
44 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
45 Snyder A, Makarov V, Merghoub T, et al. Genetic Basis for Clinical Response to CTLA-4 
Blockade in Melanoma. N Engl J Med 2014; 371:2189-2199
46 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.
47 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.
48 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. 
49 Hellmann MD, Ciuleanu TE, Pluzanski A et al. Nivolumab plus Ipilimumab in Lung Cancer 
with a High Tumor Mutational Burden. 2018. N Engl J Med. Epub ahead of print
50 Goldstraw P, Crowley J, Chansky K, Giroux DJ, et al. The IASLC Lung Cancer Staging 
Project: Proposals for the Revision of the TNM Stage Groupings in the Forthcoming 
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(Seventh) Edition of the TNM Classification of Malignant Tumours. J Thorac Oncol 2007; 
2:706-714.
51 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. (2009); 45:228-247.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ACTH
adrenocorticotropic hormone deficiency
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
APC
antigen presenting cell
AST
aspartate aminotransferase
AT
aminotransaminases
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BSC
best supportive care
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
CMV
cytomegalovirus
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CrCl
creatinine clearance
CRF
case report form, paper or electronic
CSR
clinical study report
CT
computed tomography
CTCAE
common terminology criteria for adverse events
CTLA-4
cytotoxic T lymphocyte-associated antigen 4
DILI
drug induced liver injury
DMC
data monitoring committee
DOR
duration of response
EBUS
endobronchial ultrasound
EC50
median effective concentration
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
ELISA
Enzyme-Linked Immunosorbent Assay
EU
European Union
FACIT
Functional Assessment of Chronic Illness Therapy
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Term
Definition
FACT-L
Functional Assessment of Cancer Therapy - Lung
FFPE
formalin-fixed paraffin-embedded
FDA
Food and Drug Administration
Hep B
hepatitis B
Hep C
hepatitis C
HBV sAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRQoL
Health Related Quality of Life
IASLC
International Association for the Study of Lung Cancer
IB
Investigator Brochure
IC50
50% inhibitory concentration
IEC
Independent Ethics Committee
IFN
interferon
Ig
immunoglobulin
IHC
immunohistochemical
IL
interleukin
imAE
immune-mediated adverse events
IMG
immunogenicity
IMP
investigational medicinal products
I-O
immuno-oncology
IP
investigational product
IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
IVRS
interactive voice response system
KM
Kaplan Meier
LCS
Lung Cancer Subscale
LDH
lactate dehydrogenase
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MLR
mixed lymphocyte reaction
MM
medical monitor
MRI
magnetic resonance imaging
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Term
Definition
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cells
PD-1
programmed death-1
PD-L1
programmed death-ligand 1
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PPK
population pharmacokinetic
PR
partial response
PRO
patient reported outcomes
PS
performance status
PT
preferred term
q
every
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RNA-seq
ribonucleic acid sequencing
ROS-1
proto-oncogene tyrosine-protein kinase 1
SAE
serious adverse event
SD
study director
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBLB
transbronchial lung biopsy
TKI
tyrosine kinase inhibitors
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the 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 (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
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 (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, 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).
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When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage 
area
•
amount currently in storage area
•
label identification number or batch 
number
•
amount dispensed to and returned by each 
participant, including unique participant 
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
non-study disposition (eg, lost, wasted) 
•
amount destroyed at study site, if 
applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence, if 
applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
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:
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If
Then
•
label identification number or batch 
number 
•
amount dispensed to and returned by each 
participant, including unique participant 
identifiers
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects 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 sub-investigator and who is delegated this task on the 
Delegation of Authority Form. Sub-investigators 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 
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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. 
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 (eg, cytotoxics or 
biologics).
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If
Then
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
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:
•
Participant recruitment (eg, among the top quartile of enrollers), and/or;
•
Involvement in trial design
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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).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.*
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
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Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
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
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
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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)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
1) 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 STATUS a
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 6
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ൒2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (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/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
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 non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
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.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above.
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
as the reference diameter. (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 
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small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
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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 lymphangitic disease from localized to widespread, or may be 
described 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.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
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
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Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 7
COUNTRY SPECIFIC AMENDMENTS
Germany HIV Testing requirement:
This amendment responds to the German Health Authority’s (PEI) request to:
•
Change eligibility to ensure that HIV positive participants are excluded from the study
•
Add HIV testing to screening laboratory tests for participants enrolled in Germany.
This amendment will be implemented at sites after IRB approval. These revisions apply to all 
participants in the future who enroll on the study, and where applicable, to all participants currently 
enrolled.
Changes to the Protocol:
Page
Protocol Section
Revised Protocol Text
Page 12 
Table 2-1 Screening Procedural 
Outline (CA2099LA)
Add “HIV testing” to list of laboratory tests.
Page 43
Section 6.2 Exclusion Criteria, 1) 
Medical Conditions j)
Replace “Known history of testing positive for human 
immunodeficiency 
virus 
(HIV) 
or 
known 
acquired 
immunodeficiency syndrome (AIDS). Testing for HIV must be 
performed at sites mandated by local requirements” with 
“Positive test for HIV”
Page 78
Section 9.4.3 Clinical Safety 
Laboratory Assessments
Replace “HIV testing (if mandated locally)” with “HIV testing”.
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APPENDIX 8
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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APPENDIX 9
FACT-L
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APPENDIX 10
COUNTRY SPECIFIC AMENDMENT 
This amendment is being produced in response to a request from the German Health Authority 
(PEI).
•
Adjust the exclusion criteria to ensure that HIV positive participants are excluded from the 
study.
•
Added “HIV” test to Laboratory Tests as screening for participants enrolled in Germany.
Timing: This amendment is to be implemented only after IRB approval at each site.
Scope: Revisions apply to future participants enrolled on the study, and where applicable, to all 
participants currently enrolled. 
Criteria for exclusion of HIV-positive Participants in Germany
Country-specific language
Section 2 Flow Chart/Time and Events
Schedule, Table 2-1: ScreeningAssessments-
LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 2h
“Known history of testing positive for human
immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS)”to be replaced with
“Positive test for HIV”.
Section 9.4 SafetyAssessments (baseline
laboratoryassessments)
Add “HIV” test to baseline local laboratory assessments
to be done within 14 days prior to first dose.
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Date: 02-Jul-2019
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8.0
Approved
930103349
7.0
v
Approved
1.0
v

Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
APPENDIX 11
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 05, 04-Jun-2018
The study protocol has been updated to include safety as the primary endpoint for Cohort C 
aligning with the primary objective of the study. Additional changes updated document to align 
with current program standards.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 05
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated study personnel
To update study personnel
Section 1 Synopsis
Table 4-1 Objectives and Endpoints
Figure 5.1-1 CA209817 Study Design 
Schema
Section 10.3.1 Efficacy Analyses and 
Section 10.3.2 Safety Analyses 
Modified objectives and 
endpoints for Cohort C
To include safety as the primary 
endpoint for Cohort C
Section 1 Synopsis
Figure 5.1-1 CA209817 Study Design 
Schema
Section 5.2.1 All Cohorts (NSCLC)
Section 10.1 Sample Size Determination 
Modified cohort size for Cohort 
C
To include safety as the primary 
endpoint for Cohort C
Table 2-1 Screening Procedural Outline
Section 6.2 Exclusion Criteria
Updated language for EGFR 
mutation and ALK testing 
requirements
To provide clarity for sites that 
test results from either local 
and/or central laboratories are 
acceptable
Table 2-1 Screening Procedural Outline
Table 2-2 Treatment Phase Assessments
Updated radiographic 
assessments for brain 
metastases
To clarify inconsistency in the 
MRI requirements versus 
preferred modality for the brain 
scans
Section 5.5.5 Rationale for Tumor 
Mutation Burden Testing
Modified document with 
updated CA209227 study 
results 
To update document with study 
results
Section 6.2 Exclusion Criteria 3)c
Section 7.7.1 Prohibited and/or Restricted 
Treatments
Allowed marijuana use by 
prescription or by local legal 
status
Allowed marijuana use for 
treatment of cancer/cancer 
treatment symptoms
Section 7.1 Treatments Administered
Updated treatment procedures 
To provide clarity on infusion 
steps
Revised Protocol No.: 06
Date: 02-Jul-2019
123
8.0
Approved
930103349
7.0
v
Approved
1.0
v

Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 05
Section Number & Title
Description of Change
Brief Rationale
Section 7.4.4 Management Algorithms for 
Immuno-Oncology Agents
Added monitoring for 
myotoxicity
 
Section 7.4.5.1 Criteria to Resume 
Treatment for Cohorts A, B, and C
Added language for study 
discontinuation for adrenal 
insufficiency 
To align criteria with 
Investigator Brochure for safety
Section 8.1.1.1 Nivolumab 
Discontinuation for Cohorts A, B, and C
Updated language study 
discontinuation language
To align criteria with internal 
program standards for safety
Overall Rationale for the Revised Protocol 04, 25, Oct-2017
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis: Rationale
Added new study cohort (Cohort C) of first-line 
NSCLC participants with high tumor mutation 
burden (TMB).
High TMB cohort added to 
evaluate response to immuno-
oncology (IO) therapy in this 
population.
Synopsis: Primary
Objectives and 
Endpoints
Primary objective (objective response rate 
[ORR]) added for Cohort C
ORR is the endpoint for the 
additional Cohort C
Synopsis: Secondary 
Objectives
Modified secondary objective information for the 
assessment of progression-free survival (PFS), 
overall survival (OS), and duration of response 
(DOR) across other cohorts. 
Updated PRO assessments to include all patients. 
Characterized the safety assessments for 
nivolumab.
Updated secondary objectives 
and information to align with 
study design and statistical 
analyses.
Synopsis: Exploratory 
Objectives and 
Endpoints
Added information to assess the screen failure 
rate as an exploratory endpoint for Cohort C
The screen failure rate is an 
endpoint to evaluate 
prospective testing for the 
Cohort C high TMB population.
Synopsis: Overall 
Design
Updated the study design and schema to include 
cohort C 
Added the maximum treatment duration of 2 
years
The description of study design 
includes the new study cohort 
C. The maximum treatment 
duration was added to align 
with current program 
characterization of nivolumab 
efficacy.
Synopsis: Number of 
Participants
Added anticipated participant numbers for Cohort 
C (screened, n = 1000 and enrolled n = 200)
Anticipated enrollment for high 
TMB population (Cohort C) 
added.
Revised Protocol No.: 06
Date: 02-Jul-2019
124
8.0
Approved
930103349
7.0
v
Approved
1.0
v

Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 2 Table 2-1: 
Screening Procedure 
Outline
Added tissue requirements for biomarker 
assessments for Cohort C (15 slides for PD-L1 
and TMB testing).
Information on biomarkers was 
added for Cohort C.
Section 2 Table 2-1:  
Screening Procedure 
Outline
Time window changed from ≤ 28 days to 
≤42 days. 
FSH level was added to the screening visit.
The screening visit was 
expanded to allow for TMB 
testing. 
The FSH level was added to test 
under 55 years of age female 
participants as per Appendix 4.
Section 2 Table 2-2: 
Treatment Phase 
Assessments
Changed the cycle window to ±5 days.
The cycle window was 
increased from 3 to 5 days to 
allow sites to complete 
procedures with addition of 
Cohort C
Section 3 Introduction
Added TMB information and definition.
Introductory information added 
regarding the description and 
definition of the TMB
Section 3.1.2: NSCLC 
Background
Descriptive information added on the NSCLC 
prognosis and recent scientific information. 
Removed information regarding major AEs 
related to platinum doublet chemotherapy 
regimens.
Removed other treatment options for non-
squamous histology NSCLC.
Updated the background section 
with current NSCLC 
information. Section was 
updated for clarity.
Section 4 Table 4-1: 
Objectives and 
Endpoints
Updated primary, secondary, and exploratory 
objectives to match synopsis
ORR is the endpoint for the 
additional Cohort C
Updated secondary objectives 
information to align with study 
design and statistical analyses
Anticipated enrollment for high 
TMB population (Cohort C) 
added.
Section 5.1: Overall 
Design
Added Cohort C information and updated study 
schematic
Information on Cohort C was 
added to the overall design 
section.
Section 5.1.1: Dosing
Added the new Cohort information and the 
maximum treatment duration.
This section was updated to 
incorporate Cohort C. The 
maximum treatment duration 
was added to align with current 
program characterization of 
nivolumab efficacy.
Revised Protocol No.: 06
Date: 02-Jul-2019
125
8.0
Approved
930103349
7.0
v
Approved
1.0
v

Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.2.1: All 
Cohorts (NSCLC)
Added description of Cohort C, including the 
number of participants.
This section describes Cohort C 
and cohort size.
Section 5.3: End of 
Study Definition
Removed information regarding the primary 
analysis scheduling.
The timing of primary analysis 
is described in the statistical 
section and removed from end 
of study definitions. 
Section 5.4: Scientific 
Rationale for Study 
Design
Added scientific rationale for inclusion of TMB 
assessments in Cohort C and Cohorts A, A1, and 
B. Added nivolumab monotherapy safety 
information for Cohort A1.
This section updated to include 
scientific rational information, 
historical rationale to be 
compliant with all new 
information.
Section 5.5.3: Rationale 
for Two Year Duration 
of Treatment
Updated maximum duration of 2 years of 
treatment and added scientific rationale.
The maximum treatment 
duration was added to align 
with current program 
characterization of nivolumab 
efficacy.
Section 5.5.4: 
Justification for 
Removing Retreatment
Language added to remove the retreatment 
option.
Discontinuation of retreatment
was added to align with current 
program characterization of 
nivolumab efficacy.
Section 5.5.5:  
Rationale for Tumor 
Mutation Burden 
Testing
Added information and justification for TMB 
testing.
Added to provide clarity of 
TMB testing rationale.
Section 6.1:  Inclusion 
Criteria
Added additional information to PD-L1 
immunohistochemical (IHC) testing, and 
removed allowing use of previous PD-L1 IHC 
test.
Updated to conform to study 
specific requirements 
surrounding PD-L1.
Section 6.1:  Inclusion 
Criteria
Added requirement about sufficient tissue 
requirements for Cohorts A, A1, (10-15 FFPE 
slides) and C (15 slides). Allows previous 
approved testing of TMB and PD-L1. 
Updated tissue requirements to 
allow for clarity in biomarker 
requirements and testing in 
protocol.
Section 6.1:  Inclusion 
Criteria
Added FSH testing to inclusion criteria
The FSH level was added to test 
under 55 years of age female 
participants as per Appendix 4.
Section 6.2:  Exclusion 
Criteria
Exceptions to HIV exclusion were added for 
Cohort A1 participants.
This information was added for 
clarity in the special population.
Section 6.2:  Exclusion 
Criteria
Added botanical preparations as an exclusion 
criterion within 2 weeks prior to randomization.
This exclusion criterion will 
limit potential effects of these 
concomitant treatments.
Section 6.2:  Exclusion 
Criteria
Changed limits for Physical and Laboratory Test 
Findings for Cohorts A, B, and C.
Updated to comply with 
program requirements for drug 
safety.
Revised Protocol No.: 06
Date: 02-Jul-2019
126
8.0
Approved
930103349
7.0
v
Approved
1.0
v

Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.1.1: Cohort A, 
Cohort A1 (optional), 
and Cohort B
Updated the timing of treatment infusion for 
participants who require small volumes and 
treatment windows.
Updated for study specific 
requirements.
Section 7.4.1: Dose 
Delay Criteria
Updated the dose delay criteria for multiple 
items.
Updated per program specific 
requirements for drug safety..
Section 7.7.1: 
Prohibited and/or 
Restricted Treatments
Added information on botanical preparations
This restriction will limit 
potential effects of these 
concomitant treatments.
Section 7.7.2.1: 
Palliative Radiotherapy 
(All Cohorts)
Added information about palliative radiotherapy 
exclusion
Added to align with study 
design
Section 7.7.3: Permitted 
Therapy
Added information on corticosteroids as a 
permitted therapy.
Added to comply with program 
standards on corticosteroid 
therapy
Section 8.1.1.1: 
Nivolumab Dose 
Discontinuation for 
Cohorts A, B, and C
Added discontinuation information regarding 
Grade 3 nonskin, drug-related AEs lasting >7 
days..
Added to comply with program 
specific standards for drug 
safety.
Section 9.8.1.1: Tumor 
Tissue Specimens
Updated tumor tissue requirements, timing, and 
PD-L1-specific language.
Updated tissue requirements to 
allow for clarity in biomarker 
requirements and testing in 
protocol.
Section 9.8.1.2: Cohort
C
Added tissue requirements for Cohort C
Added to provide tissue 
information for Cohort C
Section 10.1:  Sample 
Size Determination
Added sample size information for Cohort C
Information needed for Cohort 
C
Section 10.3:  Efficacy 
Analyses
Added statistical information for the updated 
primary and secondary objective
Complies with new statistical 
information for the updated 
primary and secondary 
objectives.
Section 10.3.4:  Interim 
Analyses
Information added to allow for the administrative 
interim analyses
Added to comply with program 
specific standards.
Revised Protocol No.: 06
Date: 02-Jul-2019
127
8.0
Approved
930103349
7.0
v
Approved
1.0
v

Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 10:  References
Added new references for the new information 
added to the protocol
New references added for new 
citations.
Appendix 10 Summary 
of Key Changes of 
Revised Protocol 04
Added Appendix 10 table
Incorporates previous Summary 
of Key Changes of Revised 
Protocol 04 keeping 
information in single document
OVERALL RATIONALE FOR THE REVISED PROTOCOL 03
 changes from protocol amendments and administrative 
letters were incorporated into a revised protocol.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number & Title
Description of 
Change
Brief Rationale
Title Page
Change in study personnel
Change in Medical 
Monitor as per 
Administrative Letter 03
Title Page
Change in title
Reflect secondary 
objectives and endpoints.
Synopsis; Secondary Objectives and Endpoints, 
Exploratory Objectives and Endpoints, Overall 
Design, Schema, Number of Participants, Study 
Treatment, Section 4.1 Overall Design, Section 
4.2.1 NSCLC Cohorts, Section 4.1.2 DMC, Section 
4.2 Number of participants, Section 4.4 Scientific 
Rationale for Study Design, Section 5.1.1 Inclusion 
Criteria For Cohort A1 Special Population, Section 
5.2 Exclusion Criteria 4), Section 6.4.1.1 Dose 
Delay Criteria for Special Population (Cohort A1), 
Section 6.4.5.3 Criteria to Resume Nivolumab and 
Ipilimumab for Special Population (Cohort A1), 
Section 5.2 Exclusion Criteria 3b), Section 8.5.1 
Pharmacokinetic And Immunogenicity Collection, 
Section 9.1 Sample Size Determination, Section 9.2 
Population for Analyses, 
Addition of special 
population (Cohort A1) 
and relevant language for 
data collection and 
analyses
Incorporation of additional 
language for special 
population (Cohort A1) 
from Site Specific 
Amendment 01
Table 2-2 On Study Assessments, Table 8.4.2-1 
Clinical Safety Laboratory Assessments
Language creatinine 
clearance assessment 
updated for participants 
with renal clearance 
Incorporation of additional 
language for participants 
with renal impairment 
from Site Specific 
Amendment 01
Section 5.2 Exclusion Criteria 
Prior treatment with 
nivolumab or ipilimumab 
requires Medical Monitor 
permission
Incorporation of additional 
language for special 
population (Cohort A1) 
from Site Specific 
Amendment 01
Revised Protocol No.: 06
Date: 02-Jul-2019
128
8.0
Approved
930103349
7.0
v
Approved
1.0
v

Clinical Protocol
CA209817
BMS-936558 / BMS-734016
nivolumab / ipilimumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number & Title
Description of 
Change
Brief Rationale
Schedule of Activities Table 2-1, Table 8.4.2-1 
Laboratory Assessment Panels
Added HIV testing for 
participants in Germany.
Incorporation of additional 
language for HIV testing 
from Site Specific 
Amendment 02
Section 5.5.3 Rationale for the Duration of 
Treatment with Nivolumab and Ipilimumab
Added immunotherapy 
treatment duration of 24 
months.
Added standard program 
language
Section 7.7.2 Other Restrictions and Precautions 
Allowed corticosteroid use 
was changed. 
New language provides 
greater clarity.
Section 8.1.1.3 Nivolumab and Ipilimumab Dose 
Discontinuation for Special Population (Cohort A1) 
Section added 
Incorporation of additional 
language for special 
population (Cohort A1) 
from Site Specific 
Amendment 01
Revised Protocol No.: 06
Date: 02-Jul-2019
129
8.0
Approved
930103349
7.0
v
Approved
1.0
v