Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination With Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination With Ipilimumab 3 mg/kg in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma
Phase: PHASE3
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CA209511
IND Number:
104,225
Ex-US
non-IND
EUDRACT Number
2015-004920-67
Date:
25-Nov-2015
Revised Date
20-Feb-2018
Clinical Protocol CA209511
Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination with 
Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination with Ipilimumab 3 mg/kg in 
Subjects with Previously Untreated, Unresectable or Metastatic Melanoma
(CheckMate 511: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 511)
Revised Protocol Number: 04
Study Director/Medical Monitor
Sheena Demelo, MD
 
 
 
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 
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expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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SYNOPSIS
Clinical Protocol CA209511
Protocol Title: Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination with 
Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination with Ipilimumab 3 mg/kg in Subjects with Previously 
Untreated, Unresectable or Metastatic Melanoma
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):

Arm A: nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg (N3I1) IV every 3 weeks for 4 doses then 
flat dose nivolumab 480 mg every 4 weeks 

Arm B: nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg (N1I3) IV every 3 weeks for 4 doses then flat 
dose nivolumab 480 mg every 4 weeks.
Study Phase:  IIIb/IV
Research Hypothesis: Treatment with N3I1 will show a reduced rate of drug-related Grade 3 - 5 adverse events 
compared with N1I3 and have similar efficacy in patients with previously untreated, unresectable or metastatic 
melanoma.
Objectives: 

The primary objective is to compare the incidence of drug-related Grade 3 - 5 AEs of nivolumab 3 mg/kg 
combined with ipilimumab 1 mg/kg to nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg in treatment-naive 
subjects with unresectable or metastatic melanoma.
Key secondary objectives include:

To evaluate the objective response rate (ORR), as determined by investigators, of nivolumab 3 mg/kg combined 
with ipilimumab 1 mg/kg and nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg in treatment-naive subjects 
with unresectable or metastatic melanoma.

To evaluate progression free survival (PFS) of nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg and 
nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg in treatment-naive subjects with unresectable or 
metastatic melanoma.

To assess overall survival (OS)

To assess Health Related Quality of Life (HRQoL) using the European Organisation for Research and Treatment 
of Cancer (EORTC QLQ-C30). 
Study Design:
This is a Phase IIIb/IV, randomized, double blinded, study of nivolumab 3 mg/kg in combination with ipilimumab 
1 mg/kg vs nivolumab 1 mg/kg ipilimumab in combination with 3 mg/kg in adult subjects with previously untreated, 
unresectable or metastatic melanoma.
The study will consist of 3 phases: screening, treatment, and follow-up.
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Subjects will be randomized 1:1 and stratified by programmed cell death receptor-ligand 1 (PD-L1) expression (5% 
tumor cell surface expression vs < 5% tumor cell surface expression/indeterminate), and American Joint Commission 
on Cancer (AJCC) M stage (M0/M1a/M1b vs M1c). Record of BRAF V600 status (mutant vs wildtype) must be 
provided (by local institutional standard), but not used for stratification.  
On-treatment phase consists of Parts 1 and 2:
During Part 1, subjects will be treated every 3 weeks with the combination of nivolumab and ipilimumab for 4 cycles.
A cycle will be defined as 3 weeks during Part 1.  
During Part 2, subjects will be treated by nivolumab, flat dose 480 mg every four weeks, beginning 6 weeks after the 
last combination dose. A cycle will be defined as 4 weeks during Part 2.  
Treatment will continue until progression or unacceptable toxicity in both arms, up to a maximum of 2 years treatment
Study Population:
Key Inclusion Criteria: (see Protocol Section 3.3.1 for full list of criteria)

Adult subjects (18 years) with histologically confirmed unresectable Stage III or Stage IV Melanoma as per 
AJCC staging system. 

Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

No prior systemic anticancer therapy for unresectable or metastatic melanoma.  Prior adjuvant or neoadjuvant 
melanoma therapy is permitted if it was completed at least 6 weeks prior to date of first dose, and all related 
adverse events have either returned to baseline or stabilized.

Measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) criteria

Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. In order 
to be randomized, a subject must be classified as PD-L1 positive, PD-L1 negative, or PD-L1 indeterminate. If an 
insufficient amount of tumor tissue from an unresectable or metastatic site is available prior to the start of the 
Previously
Untreated
Unresectable
Stage III -IV
Melanoma
Arm A (n = 173)
nivolumab 3 mg/kg IV
+ ipilimumab 1 mg/kg IV
every
3 weeks for 4 doses
Arm B (n = 173)
nivolumab
1 mg/kg IV
+ ipilimumab 3 mg/kg IV
every
3 weeks for 4 doses
Nivolumab
Flat Dose 480 mg 
Every 4 weeks
Nivolumab
Flat Dose 480 mg 
Every 4 weeks
Treat until progression* or unacceptable
toxicity
*Treatment
beyond initial investigator -assessed
RECIST 1.1 -defined progression will be
considered in subjects experiencing investigator -
assessed clinical benefit and tolerating study
therapy .  Such subjects must discontinue therapy
when further progression is documented .
Part 1
Part 2
Double -blinded
Open -label
Randomize
(N = 346)
1:1
Stratify by 
• PD-L1 
expression
• M  stage
6 weeks
#
#
#
#
# Treatment with Nivolumab will be limited to 2 years
maximum duration 
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screening phase, subjects must consent to allow the acquisition of additional tumor tissue for performance of 
biomarker analyses. 

Known BRAF V600 mutation status as determined by local institutional standard or subject to consent to BRAF 
V600 mutation testing per local institutional standards during the Screening Period, the results of which must be 
reported within 3 months of randomization. All BRAF statuses (BRAF wild-type or BRAF 600 mutation positive)
are eligible.
Key Exclusion Criteria:

Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have 
been treated and there is no evidence of progression via magnetic resonance imaging (MRI, except where 
contraindicated in which CT scan is acceptable) for at least 8 weeks after treatment is complete and within 28 days 
prior to first dose of study drug administration. There must also be no requirement for high doses of systemic
corticosteroids that could result in immunosuppression (> 10 mg/day prednisone equivalents) for at least 2 weeks 
prior to study drug administration.

Ocular melanoma

Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not 
requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted 
to enroll.
Subjects must also meet the study criteria including exclusion for medical history, positive hepatitis B/C, HIV and 
pregnancy tests, and the laboratory criteria described in Section 3.3.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209511
Medication 
Potency 
IP
Nivolumab BMS-936558-01 
Solution for Injection
100 mg (10 mg/mL)
10 mL per vial
Ipilimumab
200 mg (5 mg/mL)
40 mL per vial
Study Assessments: 
Adverse events will be collected to determine the incidence of drug-related adverse events between the two cohorts.
Subjects will be observed for tumor response (ORR and PFS).
Subjects will be assessed by computed tomography (CT) or magnetic resonance imaging (MRI) beginning Week 12 
(1 week) from randomization and continuing every 8 weeks (1 week) for the first 12 months and then every 
12 weeks (2 weeks) until disease progression.
Subjects will be followed for Overall survival (OS) after disease progression or after drug-discontinuation.
Patient reported outcomes will be collected using the EQ-5D and EORTC QLQ-30
Statistical Considerations:
Sample Size: Approximately 346 subjects will be randomized to the 2 treatment arms in a 1:1 ratio in order to target 
340 treated subjects (170 per arm). Given a two-sided alpha of 0.05, this number of treated subjects provides 80% 
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power to show a statistically significant difference in the rate of drug-related Grade 3 - 5 AEs between the two 
treatment arms, assuming a rate of 40% in Arm A and a rate of 55% in Arm B.
Endpoints: The primary endpoint is the incidence of drug-related Grade 3 - 5 AEs. 
The secondary endpoints of the study are investigator determined ORR, PFS, OS, and HRQoL.
Analyses:  For the primary analysis, we will report the drug-related Grade 3 - 5 AE rate by treatment arm, the 
difference in rates between arms, and the corresponding 95% confidence intervals. Two-sided CMH test, stratified by 
PD-L1 expression and M stage at screening, will be performed to compare the rate of drug-related Grade 3 - 5 AE rate 
between the two treatment arms.
ORRs and corresponding 95% exact Confidence Interval (CI)s will be calculated using the Clopper Pearson method 
for each of the treatment arms. BOR will be tabulated for each treatment group. The 2 treatment arms will be compared 
using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by PD-L1 expression and M stage at screening. 
Associated odds ratios and 95% CIs for Arm A relative to Arm B will be calculated, and a p-value will be presented 
for descriptive purposes. An estimate of the difference in ORRs and corresponding 95% CI will be calculated using 
CMH methodology.
PFS curves for each treatment group will be estimated using the Kaplan-Meier product limit method. Median PFS and 
corresponding two-sided, 95% confidence intervals will be computed. Descriptive Hazard Ratio and corresponding 
two sided 95% CIs for Arm A relative to Arm B will be estimated using a Cox proportional hazards model, with 
treatment group as a single covariate stratified by PD-L1 expression and M Stage at screening. PFS rates at 6 months 
with 95% CIs will be estimated using KM methodology. 
OS will be summarized descriptively using Kaplan-Meier methodology. Median values, along with two-sided 95% 
CIs will be calculated. EORTC QLQ-C30 scale data will be summarized by timepoint using descriptive statistics for 
each treatment group. 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
 
 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04............................ 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
........................ 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
 
 
.. 
 
 
 
 
 
 
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2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening Phase ....................................................................................... 
3.1.2 Treatment Phase ...................................................................................... 
3.1.3 Follow-Up Phase ..................................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
 
 
 
 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.3.1 Part 1 Study Drug Administration (Combination Portion) ..................... 
4.3.2 Part 2 Study Drug Administration (Maintenance)................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.4.1 Dose Delay Criteria ................................................................................. 
4.4.2 Dose Modifications .................................................................................. 
4.4.3 Criteria to Resume Treatment .................................................................. 
4.4.4 Discontinuation Criteria .......................................................................... 
4.4.5 Treatment Beyond Disease Progression .................................................. 
4.4.6 Management Algorithms for Immuno-Oncology Agents ......................... 
4.4.7 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ...... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
4.10 Retained Samples for Bioavailability / Bioequivalence ................................. 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening ..................................................................... 
5.2 Study Materials ................................................................................................. 
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5.3 Safety Assessments ........................................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.4.2.1 Measurable Lesions ........................................................................ 
5.4.2.2 Non-measurable Lesions ................................................................. 
5.4.2.3 Special Considerations Regarding Lesion Measurability .............. 
5.4.3 Specifications for Method of Measurement ............................................. 
5.4.3.1 Measurement of Lesions ................................................................. 
5.4.3.2 Method of Assessment ..................................................................... 
5.4.3.3 CT/MRI Scan ................................................................................... 
5.4.3.4 Chest X-Ray .................................................................................... 
5.4.3.5 Clinical Lesions .............................................................................. 
5.4.3.6 Ultrasound ...................................................................................... 
5.4.3.7 Endoscopy, Laparoscopy ................................................................ 
5.4.3.8 Tumor Markers ............................................................................... 
5.4.4 Baseline Documentation of "Target” and “Non-Target Lesions” .......... 
5.4.4.1 Target Lesions ................................................................................. 
5.4.4.2 Lymph Nodes ................................................................................... 
5.4.4.3 Non-target Lesions .......................................................................... 
5.4.5 Tumor Evaluation .................................................................................... 
5.4.5.1 Target Lesions that Become “Too Small to Measure” ................... 
5.4.5.2 Target Lesions that Split or Coalesce on Treatment ...................... 
5.4.5.3 Evaluation of Non-target Lesions ................................................... 
5.4.5.4 Unequivocal Progression in Non-target Disease ........................... 
5.4.5.5 New Lesions .................................................................................... 
5.4.6 Response Criteria (RECIST 1.1) .............................................................. 
5.4.6.1 Missing Assessments and Not Evaluable Designation.................... 
5.4.6.2 Confirmation of Scan ...................................................................... 
5.4.6.3 Best Overall Response .................................................................... 
5.4.6.4 Duration of Objective Response ..................................................... 
5.5 Pharmacokinetic and Immunogenicity Assessments ........................................ 
5.5.1 Pharmacokinetic and Immunogenicity Sample Analyses ........................ 
5.6 
 .................................................................................... 
5.6.1 Tumor Tissue Specimen ........................................................................... 
 ............................................................... 
5.6.3 Peripheral Blood Mononuclear Cells (PBMCs) ...................................... 
5.6.4 Whole Blood for SNP Assessment ............................................................ 
5.6.5 Myeloid-Derived Suppressor cells ........................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Immune-mediated Adverse Events ................................................................... 
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6.4 Laboratory Test Result Abnormalities .............................................................. 
6.5 Pregnancy .......................................................................................................... 
6.6 Overdose ........................................................................................................... 
6.7 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.8 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Secondary Endpoints Methods ........................................................ 
8.4.3 Exploratory Endpoint Methods ................................................................ 
8.4.4 Safety Analyses......................................................................................... 
8.4.4.1 Primary Endpoints Methods ........................................................... 
8.4.4.2 Other Safety Analysis ...................................................................... 
....................................................................... 
8.4.6 Biomarker Analyses ................................................................................. 
8.4.7 Outcomes Research Analyses .................................................................. 
8.4.8 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 ADDITIONAL ETHICAL CONSIDERATIONS ................................ 
APPENDIX 2 PERFORMANCE STATUS SCALES ................................................. 
APPENDIX 3 MANAGEMENT ALGORITHMS ....................................................... 
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APPENDIX 4 AJCC MELANOMA STAGING .......................................................... 
APPENDIX 5 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
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1.2
Research Hypothesis 
Treatment with nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg (N3I1)-Arm A will show 
a reduced incidence of drug-related Grade 3 - 5 adverse events compared with nivolumab 1 mg/kg 
combined with ipilimumab 3 mg/kg (N1I3)-Arm B and have similar efficacy in patients with 
previously untreated, unresectable, or metastatic melanoma.
1.3
Objectives(s)
1.3.1
Primary Objectives
The primary objective is to compare the incidence of drug-related Grade 3 - 5 AEs of N3I1 to N1I3
in subjects with previously untreated, unresectable or metastatic melanoma.
1.3.2
Secondary Objectives

To evaluate the ORR, as determined by investigators, of N3I1 and N1I3 in subjects with
untreated, unresectable or metastatic melanoma.

To evaluate PFS of N3I1 and N1I3 in subjects with untreated, unresectable or metastatic 
melanoma.

To assess OS of N3I1 and N1I3 in subjects with untreated, unresectable or metastatic 
melanoma.

To evaluate Health Related Quality of Life (HRQoL) as assessed by the European Organization 
for Research and Treatment of Cancer (EORTC) QLQ-30.
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1.4
Product Development Background
 
 
 
 
 
 
 
by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system.
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 rejection in 
several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).22
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Bristol Myers Squibb (BMS) immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the study or 
the protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study.
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Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling
information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form and written information about the study in the language
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 

Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.

Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 

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 subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or her
informed consent during the study, consent must additionally be obtained from the subject.
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Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal guardian, 
of all pertinent aspects of the study and of any new information relevant to the subject's willingness 
to continue participation in the study. This communication should be documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed informed 
consent form (ICF) and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase IIIb/IV, randomized, double blind, 2-arm study of nivolumab 3 mg/kg combined 
with ipilimumab 1 mg/kg vs nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg, in adult 
(18 years) subjects with previously untreated, unresectable or metastatic melanoma. Subjects 
must have unresectable or metastatic Stage III or stage IV melanoma, as per the AJCC staging 
system, and must not have received prior systemic therapy for the treatment of unresectable or 
metastatic melanoma. 
Subjects will be randomized 1:1 and stratified by PD-L1 status and AJCC M stage as described 
below:

PD-L1 expression level

PD-L1 5% tumor cell surface expression (in a minimum of a hundred evaluable tumor 
cells) vs 

PD-L1 < 5% tumor cell surface expression (in a minimum of a hundred evaluable tumor 
cells)/indeterminate (tumor cell membrane scoring hampered by high cytoplasmic staining 
or melanin content)

AJCC M stage at screening (See Appendix 4)

M0/M1a/M1b vs

M1c
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
It is expected that 460 subjects will need to be enrolled in order to randomize 346, assuming a 
screen failure rate of 25%.
This study will consist of 3 phases: screening, treatment, and follow-up.
3.1.1
Screening Phase

Begins by establishing the subject’s initial eligibility and signing of the ICF.

Subject is enrolled using the IRT

Tumor tissue obtained in the metastatic setting or from an unresectable site of disease must be 
provided for biomarker analyses.  In order to be randomized, a subject must have quantifiable 
PD-L1 expression (5% or < 5% tumor cell membrane staining) or be classified as PD-L1 
indeterminate. If an insufficient amount of tumor tissue from an unresectable or metastatic site 
is available prior to the start of the screening phase, subjects must consent to the acquisition of 
additional tumor tissue for performance of biomarker analyses.
Previously
Untreated
Unresectable
Stage III -IV
Melanoma
Arm A (n = 173)
nivolumab 3 mg/kg IV
+ ipilimumab 1 mg/kg IV
every
3 weeks for 4 doses
Arm B (n = 173)
nivolumab
1 mg/kg IV
+ ipilimumab 3 mg/kg IV
every
3 weeks for 4 doses
Nivolumab
Flat Dose 480 mg 
Every 4 weeks
Nivolumab
Flat Dose 480 mg 
Every 4 weeks
Treat until progression* or unacceptable
toxicity
*Treatment
beyond initial investigator -assessed
RECIST 1.1 -defined progression will be
considered in subjects experiencing investigator -
assessed clinical benefit and tolerating study
therapy .  Such subjects must discontinue therapy
when further progression is documented .
Part 1
Part 2
Double -blinded
Open -label
Randomize
(N = 346)
1:1
Stratify by 
• PD-L1 
expression
• M  stage
6 weeks
#
#
#
#
# Treatment with Nivolumab will be limited to 2 years
maximum duration 
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3.1.2
Treatment Phase

Begins with the randomization call to the IRT. 

Subject will be randomized to:

Arm A (N3I1): nivolumab 3 mg/kg + ipilimumab 1 mg/kg administered every 3 weeks for 
4 doses or

Arm B (N1I3): nivolumab 1 mg/kg + ipilimumab 3 mg/kg ipilimumab are administered 
every 3 weeks for 4 doses.

After combination therapy, all subjects will receive a flat dose 480 mg nivolumab IV every 
4 weeks, beginning 6 weeks after the last combination dose, until progression or unacceptable 
toxicity.

Treatment with Nivolumab will be limited to 2 years maximum duration.

A negative pregnancy test should be documented within 24 hours prior to start of each dose of 
investigational product.

Within 3 days from randomization, the subject must receive the dose of study medication.

On study laboratory assessments should be drawn within 72 hours prior to dosing

PK samples and immunogenicity samples will be collected according to the schedule in Table 
5.1-2 and Table 5.1-3

Adverse event assessments should be documented at each clinic visit. 

Quality of Life will be assessed using European Organisation for Research and Treatment of 
Cancer Quality Of Life Questionnaire-core 30 (EORTC QLQ-C30) and European Quality of 
Life-5 Dimensions (EQ-5D) questionnaires, to be completed after randomization, prior to the 
first dose of study therapy and every 6 weeks for the first 6 months, and every 4 weeks until 
approximately week 40, according to the schedule in Table 5.1-2.

Study drug dose may be delayed for toxicity. See Section 4.4.1.

Treated subjects will be evaluated for response according to the RECIST 1.1 guidelines 
beginning 12 weeks (1 week) after randomization and continuing every 8 weeks (1 week) 
for the first 12 months, and then every 12 weeks (2 week) until disease progression or 
treatment discontinuation, whichever occurs later.

This phase ends when the subject is discontinued from study therapy. For a complete list of 
reasons for treatment discontinuation, see Section 3.5.
3.1.3
Follow-Up Phase

Begins when the decision to discontinue a subject from study therapy is made (no further 
treatment with study therapy).  Patients will be followed for efficacy and OS.

Subjects who discontinue treatment for reasons other than tumor progression will continue to 
have tumor assessments beginning 12 weeks (1 week) after randomization and continuing 
every 8 weeks (1 week) for the first 12 months from randomization, and every 12 weeks 
(2 weeks) thereafter until documented tumor progression.
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
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a minimum of 
100 days after last dose.

After completion of the first two follow-up visits, subjects will be followed every 3 months for 
survival.
BMS may request that survival data be collected on all randomized subjects outside of the protocol 
defined window as detailed in the Time and Events Table 5.1-4 Follow-up Assessments 
(CA209511). At the time of this request, each subject will be contacted to determine their survival 
status unless the subject has withdrawn consent for all contact.
The total duration of the study from start of randomization to primary analysis of the study is 
expected to be approximately 13 months (7 months of accrual + 6 months of follow-up after last 
subject has been dosed ), assuming an accrual rate of 58 subjects per month. Additional survival 
follow-up may continue for up to 5 years from the primary analysis. The study will end once 
survival follow-up has concluded.  
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug up to the maximum treatment duration of 2 years. 
Study drug will be provided via an extension of the study, a rollover study requiring approval by 
responsible health authority and ethics committee or through another mechanism at the discretion 
of BMS. BMS reserves the right to terminate access to BMS supplied study drug if any of the 
following occur: a) the marketing application is rejected by responsible health authority; b) the 
study is terminated due to safety concerns; c) the subject can obtain medication from a government 
sponsored or private health program; or d) therapeutic alternatives become available in the local 
market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol related procedures that are not part of normal subject care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests including the completion of quality of life questionnaires and other 
requirements of the study.
2. Target Population
a) Histologically confirmed melanoma (per AJCC staging system) that is unresectable or 
metastatic (Refer to Appendix 4)
b) ECOG Performance Status 1 (Refer to Appendix 2)
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c) Treatment naïve subjects (ie, no prior systemic anticancer therapy for unresectable or 
metastatic melanoma). Note that prior adjuvant or neoadjuvant melanoma therapy is 
permitted if it was completed at least 6 weeks prior to randomization, and all related 
adverse events have either returned to baseline or stabilized.
d) Measurable disease by CT or MRI per RECIST 1.1 criteria Section 5.4.2.1.
e) Archival or recently acquired tumor tissue from an unresectable or metastatic site of disease 
must be provided for biomarker analyses. In order to be randomized, a subject must be 
classified as PD-L1 expression (5% or < 5% tumor cell membrane staining) or be 
classified as PD-L1 indeterminate. If an insufficient amount of tumor tissue from an 
unresectable or metastatic site is available prior to the start of the screening phase, subjects 
must consent to allow the acquisition of additional tumor tissue for performance of 
biomarker analyses.”
f)
Subjects with known BRAF V600 mutation status or consent to BRAF V600 mutation 
testing per local institutional standards during the Screening Period, the results of which 
must be reported within 3 months of randomization. All BRAF statuses (BRAF wild-type 
or BRAF 600 mutation positive) are eligible.
g) Prior radiotherapy must have been completed at least 2 weeks prior to study drug 
administration.
h) Screening laboratory values must meet the following criteria (using CTCAE v4):
i)
WBC
2000/uL
ii) Neutrophils
1500/uL
iii) Platelets
100x103/uL
iv) Hemoglobin
9.0 g/dL
v) Serum creatinine 1.5 x upper limit of normal (ULN) or calculated creatinine 
clearance > 40 mL/min (using the Cockcroft Gault formula): 
Female CrCl = (140- age in years) x weight in kg x 0.85
        72 x serum creatinine in mg/ dL
Male CrCl = (140- age in years) x weight in kg x 1.00
         72 x serum creatinine in mg/ dL
vi) AST
≤3.0 x ULN 
vii)ALT
≤3.0 x ULN 
viii)
Total Bilirubin ≤1.5 x ULN (except subjects with Gilbert Syndrome who must 
have a total bilirubin level of < 3.0x ULN).
3. Age and Reproductive Status
a) Males and Females, ages 18 years.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug.
c) Women must not be breastfeeding
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d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception, as indicated in the informed consent form, for a period of 
30 days (duration of ovulatory cycle) plus the time required for the investigational drug to 
undergo approximately five half lives. WOCBP should therefore use an adequate method 
to avoid pregnancy for 5 months after the last dose of investigational drug (combination or 
monotherapy). Refer to Appendix 5.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception, as indicated in the informed consent form, for a period of 
90 days plus the time required for the investigational drug to undergo approximately five 
half lives. Men who are sexually active with WOCBP must continue contraception for
7 months (90 days plus the time required for nivolumab to undergo approximately 5 half 
lives) after the last dose of investigational drug (combination or monotherapy). In addition, 
male subjects must be willing to refrain from sperm donation during this time.
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.  
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, which have a 
failure rate of < 1% when used consistently and correctly. (Refer to Appendix 5.)
The methods of contraception are also indicated in the informed consent form.  
At a minimum, subjects must agree to the use one highly effective method of contraception.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are 
eligible if these have been treated and there is no magnetic resonance imaging (MRI -
except where contraindicated in which computed tomography (CT) scan is acceptable) 
evidence of progression for at least 8 weeks after treatment is complete and within 28 days 
prior to first dose of study drug administration. There must also be no requirement for 
immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone 
equivalents) for at least 2 weeks prior to study drug administration.
b) Ocular melanoma. 
2. Medical History and Concurrent Disease
a) Prior active malignancy within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast
b) Subjects with an active, known or suspected autoimmune disease. Subjects with Type I
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
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c) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
d) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD37, anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell costimulation or 
immune checkpoint pathways.  This includes utilization of these agents in the adjuvant, 
neo-adjuvant, and metastatic melanoma setting.  
e) Subjects with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity
f)
Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS)
g) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances, a person who has been imprisoned may be included or permitted to continue 
as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
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.
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Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels.

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is >40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
3.4
Concomitant Treatments
 
 
alliative radiation therapy, or standard or investigational agents for treatment 
of cancer).
 
 
 
 
 
 
 
 
 
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3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the opinion 
of the investigator, indicates that continued participation in the study is not in the best interest 
of the subject

Termination of the study by 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

Unblinding a subject for any reason (emergency or non-emergency)

Pregnancy.
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 subject becomes pregnant 
during a clinical trial, the study drug must be discontinued immediately. In most cases, the study 
drug will be permanently discontinued in an appropriate manner (eg, dose tapering if necessary 
for subject 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 drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
Please also refer to Discontinuation Criteria in Section 4.4.4.
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If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
In this study, overall survival is a key endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects who 
discontinue study drug must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 5 until death or the conclusion of the study.
BMS may request that survival data be collected on all treated/randomized subjects outside of the 
protocol defined window (Table 5.1-1). At the time of this request, each subject will be contacted 
to determine their survival status unless the subject has withdrawn consent for all contacts or is 
lost to follow-up.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In the 
event that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
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4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for CA209511
Product Description / 
Class and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Packaging/
Appearance
Storage Conditions
(per label)
Nivolumab Solution for 
Injectiona
100 mg (10 mg/mL)
10 mL per vial
5 or 10 vials per carton/ 
Open-label
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
2° to 8C. Protect from 
light and freezing
Ipilimumab
200 mg (5 mg/mL)
40 mL per vial/Open-
label
4 vials per
carton/Open-label
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
2° to 8C. Protect from 
light and freezing
a Nivolumab is labeled as BMS-936558-01 Solution for Injection.
Pre-medications or medications used to treat in infusion reactions should be sourced by the investigative sites if available and 
permitted by local regulations. 
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational products are:

Nivolumab

Ipilimumab
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
4.3.1
Part 1 Study Drug Administration (Combination Portion)
In the nivolumab plus ipilimumab combination portion, nivolumab is to be administered first.
Subjects should receive nivolumab at a dose of 3 mg/kg (Arm A) or 1 mg/kg (Arm B) as a 
30-minute IV infusion, on Day 1 of each treatment cycle every 3 weeks for 4 doses or until 
progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs 
first. 
The nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab 
before starting the next infusion.
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The second infusion in the combination cohort will always be ipilimumab, and will start 
approximately 30 minutes after completion of the nivolumab infusion and the infusion line has 
been flushed, filters changed and the patient has been observed to ensure no infusion reaction has 
occured.
Subjects should receive ipilimumab at a dose of 1 mg/kg (Arm A) or at a dose of 3 mg/kg (Arm B) 
as a 30-minute IV infusion, on Day 1 of each treatment cycle every 3 weeks (within 3 calendar 
days of scheduled date) for 4 doses or until progression, unacceptable toxicity, withdrawal of 
consent, or the study ends, whichever occurs first. 
The risk/benefit profile for nivolumab has primarily been investigated using a 60-minute infusion 
and for ipilimumab a 90-minute infusion. Long infusion times place a burden on patients and 
treatment centers. Establishing that these agents can be safely administered using shorter infusion 
times will diminish some of this burden.  Previous clinical studies of nivolumab have used 
60-minute infusion duration and for ipilimumab 90-minute. Both nivolumab and ipilimumab have 
been administered safely at doses ranging up to 10 mg/kg over these treatment durations. Overall, 
infusion reactions including high-grade hypersensitivity reactions have been uncommon across 
multiple clinical studies, and all have been managed by following the safety algorithms. Infusion 
duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not 
expected to present any safety concerns compared with the prior experience at 10 mg/kg nivolumab 
dose infused over the 60-minute duration.  Similarly, shortened infusion duration of 30 minutes 
for ipilimumab is not expected to present additional safety concerns.24
Both agents given as single agent is uncommonly associated with infusion reactions, incidence 
less than 1% for ipilimumab (YervoyFDA Label) and for nivolumab 3%.9  In the CA209069
study, hypersensitivity/infusion reactions were listed as 3.2% for the combination and 2.2% for 
ipilimumab.  No Grade 3 or Grade 4 hypersensitivity/infusion reactions were observed in either 
the combination or single agent ipilimumab treatment groups.25  
Subjects should be carefully monitored for infusion reactions during nivolumab/ipilimumab 
administration. If an acute infusion reaction is noted, subjects should be managed according to 
Section 4.4.
The pharmacy manual includes detailed instructions for study medication preparation.  
Dosing calculations should be based on the body weight assessed at screening. It is not necessary 
to re-calculate subsequent doses if the subject weight is within 10% of the weight used to calculate 
the previous dose. All doses should be rounded to the nearest milligram. 
During Part 1, subjects may be dosed no less than 19 days between doses. If dosing is delayed, 
both nivolumab and ipilimumab must be delayed together. If dosing is resumed after a delay, both 
nivolumab and ipilimumab must be resumed on the same day.
Detailed instructions for dilution and infusion of nivolumab/ipilimumab injection may be provided 
in the pharmacy binder, pharmacy reference sheet or current investigator brochure.23,26 Care must 
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be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. 
4.3.2
Part 2 Study Drug Administration (Maintenance)
Starting 6 weeks after the last co-administered dose in Part 1, subjects will be administered a flat 
dose 480 mg nivolumab IV as a 30-minute IV infusion every 4 weeks (Q4W) (3 days) until 
unacceptable toxicity or disease progression, up to a maximum of 2 years treatment.
Subjects may be dosed up to 3 days after the scheduled date if necessary. Subsequent dosing should 
be based on the actual date of administration of the previous dose of drug. Every effort should be 
made to adhere to protocol treatment schedule of administration of nivolumab every 4 weeks in 
the maintenance phase.  In extenuating circumstances in which the patient cannot make the dosing 
schedule within the 3-day window, BMS Monitor should be contacted.
For details on prepared drug storage, preparation, and administration, please refer to the 
BMS-936558 (nivolumab) IB, the ipilimumab IB and/or pharmacy reference sheets.
4.4
Method of Assigning Subject Identification
CA209511 is a randomized, double-blind study. After the subject’s initial eligibility is established 
and informed consent has been obtained, the subject must be enrolled into the study by accessing 
an Interactive Response Technologies web-based system (IRT) to obtain the subject number. Every 
subject that signs the informed consent form must be assigned a subject number in IRT. Specific 
instructions for using IRT will be provided to the investigational site in a separate document. The 
investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:

Date that informed consent was obtained

Date of birth

Gender at birth.
Once enrolled in IRT, enrolled subjects that have met all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for subject randomization:

Subject number

Date of birth

PD-L1 expression level (PD-L1 5% expression vs PD-L1 < 5% expression/indeterminate) 
entered by vendor

M Stage at screening (See Appendix 4).
Subjects meeting all eligibility criteria will randomize 1:1 ratio to Arm A (N3I1) or Arm B (N1I3) 
and stratified by the following factors:

PD-L1 expression 

M stage.
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The randomization procedures will be carried out via permuted blocks within each stratum. The 
exact procedures for using the IRT will be detailed in the IRT manual.
4.4.1
Dose Delay Criteria
Regardless of whether or not the event is attributed to nivolumab, ipilimumab, or both, all study 
drugs must be delayed until treatment can resume (See Section 4.4.3). Tumor assessments for all
subjects should continue as per protocol even if dosing is delayed.
Nivolumab and ipilimumab administration should be delayed for the following:

Grade 2 non-skin, drug-related adverse event, with the exception of fatigue or laboratory 
abnormalities that do not require a treatment delay.

Grade 2 drug-related creatinine, AST, ALT or Total Bilirubin abnormalities

Grade 3 skin, drug-related adverse event

Grade 3 drug-related laboratory abnormality, with the following exceptions :

Grade 3 lymphopenia does not require dose delay

If a subject has a baseline AST, ALT or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade 2 toxicity

Grade ≥3 AST, ALT, or total bilirubin will require discontinuation

Any Grade 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay. 

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Subjects requiring delay should be re-evaluated weekly or more frequently if clinically indicated 
and resume dosing when re-treatment criteria are met.
4.4.2
Dose Modifications
Dose reductions or dose escalations are not permitted. All dose modification rules apply to both 
Arms A and B given the blinded nature of this study.
4.4.3
Criteria to Resume Treatment 
Subjects should resume treatment with nivolumab and ipilimumab in both arms A and B given the 
blinded nature of the study when the drug-related AE(s) resolve(s) to Grade 1 or baseline, with 
the following exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue

Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity

Subjects with Grade 2 AST/ALT or total bilirubin may resume treatment when laboratory 
values return to baseline and management with corticoids, if needed, is completed.

Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 4.4.1) should have treatment permanently discontinued
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
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor.

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor. Adrenal 
insufficiency requires discontinuation regardless of control with hormone replacement.
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
time point per protocol. However, if the treatment is delayed past the next scheduled time point 
per protocol, the next scheduled time point will be delayed until dosing resumes.
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Section 4.4.1.
4.4.4
Discontinuation Criteria
All discontinuation criteria apply for nivolumab and ipilimumab in both Arms A and B (during 
Part 1) given the blinded nature of this study.
Treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment.

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
diarrhea, hypersensitivity reactions, infusion reactions and endocrinopathies:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation

Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation, regardless of control with hormone replacement.

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:

Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation

Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:
o
Grade 3 drug-related AST/ALT or Total Bilirubin abnormality
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN

In most cases of Grade 3 AST or ALT elevation, study drugs) will be permanently 
discontinued. If the investigator determines a possible favorable risk/benefit ratio that warrants 
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continuation of study drug(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.

Any Grade 4 drug-related adverse event or laboratory abnormality (including, but not limited 
to creatinine, AST, ALT, or total bilirubin), except for the following events which do not 
require discontinuation:

Grade 4 neutropenia 7 days

Grade 4 lymphopenia or leucopenia

Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis.

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 from the previous dose requires 
discontinuation, with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 

Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. 

Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 weeks, the BMS 
medical monitor must be consulted. Tumor assessments should continue as per protocol even 
if dosing is delayed. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such dosing delays.

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.
4.4.5
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of Progressive Disease (PD). 
Subjects will be permitted to continue treatment beyond initial RECIST 1.1 defined PD, up to a 
maximum of 2 years treatment, as long as they meet the following criteria:

Investigator-assessed clinical benefit, and 

Subject is tolerating study drug.

Stable performance status
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
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)

Subject provides written informed consent prior to receiving additional study medication, All 
other elements of the main informed consent including the 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 PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the subject is clinically deteriorating and unlikely to receive any benefit from continued 
treatment with nivolumab.
If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to 
the Time and Events Schedule on Section 5.
For the subjects who continue study therapy beyond progression, further progression is defined as 
an additional 10% increase in tumor burden with a minimum of 5 mm absolute increase from time 
of initial PD. This includes an increase in the sum of diameters of all target lesions and/ or the 
diameters of new measurable lesions compared to the time of initial PD. Treatment with study 
medication 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.
4.4.6
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 I-O
agents in this protocol. Early recognition and management of AEs associated with I-O agents may 
mitigate severe toxicity. Management Algorithms have been developed to assist investigators in 
assessing and managing the following groups of AEs:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathy
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
Skin

Neurological.
The above algorithms are found in Appendix 3.
4.4.7
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions
Since nivolumab and ipilimumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 
or 4 infusion reactions should be reported within 24 hours to the study medical monitor and 
reported as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI 
CTCAE (Version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated):

Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, non-steroidal antiinflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for 
24 hours):

Stop the study drug infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
and/or bronchodilator therapy may also be administered as appropriate. If the infusion is 
interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% 
of the original infusion rate. Monitor subject closely. If symptoms recur, then no further study 
medication will be administered at that visit.

For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab and/or ipilimumab infusions. If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
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For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (eg, renal impairment, 
pulmonary infiltrates). Grade 4: Life threatening; pressor or ventilatory support indicated):

Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and 
treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 
100 mg IV (or equivalent), as needed. Subject should be monitored until the Investigator is 
comfortable that the symptoms will not recur. Study drug will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor subject until recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
4.5
Selection and Timing of Dose for Each Subject
The dosing regimen and schedule for Parts 1 and 2 are detailed in Table 4.5-1 and Table 4.5-2,
respectively.
Note:  The first flat dose 480 mg nivolumab in Part 2 will be administered 6 weeks after the 
last combination dose in Part 1.
Table 4.5-1:
Dosing Schedule for Part 1  (Double-Blinded)
Every 3 weeks dosing
1 cycle = 3 weeks
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Arm A
Nivolumab 3 mg/kg
Ipilimumab 1 mg/kg
Nivolumab 3 mg/kg
Ipilimumab 1 mg/kg
Nivolumab 3 mg/kg
Ipilimumab 1 mg/kg
Nivolumab 3 mg/kg
Ipilimumab 1 mg/kg
Arm B
Nivolumab 1 mg/kg
Ipilimumab 3 mg/kg
Nivolumab 1 mg/kg
Ipilimumab 3 mg/kg
Nivolumab 1 mg/kg
Ipilimumab 3 mg/kg
Nivolumab 1 mg/kg
Ipilimumab 3 mg/kg
Table 4.5-2:
Dosing Schedule for Part 2  (Open Label) 
Every 4 weeks dosing
1 cycle = 4 weeks, Cycle 5 to begin 6 weeks after Cycle 4a
Cycle 5 and beyond
Arms A and B
Flat dose 480 mg nivolumab 
a Cycle X - Cycle 8, 9, etc until disease progression or unacceptable toxicity or a maximum treatment of 2 years.
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4.6
Blinding/Unblinding
The sponsor, subjects, investigator, and site staff will be blinded to the study drug administered 
during Part 1 (Combination Portion) of the study. Each investigative site must assign an unblinded 
pharmacist/designee, and an unblinded site monitor will be assigned by sponsor to provide 
oversight of drug supply and other unblinded study documentation.
During Part 2 (monotherapy portion), 480 mg nivolumab administered as a flat dose will be 
open-label. However, subject’s treatment assigned arm during Part 1 must not be revealed until 
end of study.
Blinding of treatment assignment is critical to the integrity of this clinical study. Hence, every 
effort should be made to maintain the blind. However, in the event of a medical emergency or 
pregnancy in an individual subject in which knowledge of the investigational product is critical to 
the subject's management, the blind for that subject may be broken by the investigator. The 
subject’s safety takes priority over any other considerations in determining if a treatment 
assignment should be unblinded.
Before breaking the blind of an individual subject's treatment, the investigator should determine
that the unblinded information is necessary, ie, that it will alter the subject's immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.

For this study, the method of unblinding for emergency purposes is through IRT. For 
information on how to unblind form emergency, please consult the IRT manual.

In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is 
made to preserve the blind.

Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
Designated staff of Bristol-Myers Squibb Research & Development may be unblinded prior to 
database lock to facilitate the bioanalytical analysis of pharmacokinetic samples and 
immunogenicity. A bioanalytical scientist in the Bioanalytical Sciences department of 
Bristol-Myers Squibb Research & Development (or a designee in the external central bioanalytical 
laboratory) will be unblinded to the randomized treatment assignments in order to minimize 
unnecessary bioanalytical analysis of samples. 
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and electronic case report form (eCRF).
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4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.10
Retained Samples for Bioavailability / Bioequivalence
Not Applicable. 
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Assessments (CA209511)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Prior to any screening procedures.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to 
randomization.
Medical History
X
Tumor Tissue Samples
X
Sufficient tumor tissue obtained in the metastatic setting or from an unresectable site (block 
or minimum of 10 slides, obtained from core biopsy, punch biopsy, excisional biopsy or 
surgical specimen) In order to be randomized, a subject must be have quantifiable PD-L1 
expression (5% or < 5% tumor cell membrane staining) or be classified as PD-L1 
indeterminate.
Safety Assessments
Physical Examination
X
Including pulmonary assessment
Vital Signs 
X
Including BP, HR, temperature. Obtain vital signs at the screening visit and within 
72 hours prior to first dose. (Section 5.3)
Physical Measurements (including 
performance status)
X
Height, Weight and ECOG Performance status
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose
Concomitant Medication Collection
X
Within 14 days prior to first dose
Laboratory Tests
X
CBC w/differential, Chemistry panel including: Albumin, LDH, AST, ALT, ALP, T.Bili, 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, Glucose, amylase, lipase, TSH, 
Free T4, Free T3, hepatitis B surface antigen (HBV sAg), and hepatitis C antibody (HCV 
Ab) or Hepatitis C RNA (HCV RNA), within 14 days prior to randomization
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Table 5.1-1:
Screening Assessments (CA209511)
Procedure
Screening
Visit
Notes
Pregnancy Test (WOCBP only)
X
Screening/Baseline Tumor Assessment
X
Chest, Abdomen, Pelvis, and Brain within 28 days prior to first dose. Head MRI is required 
in subjects with known history of brain metastases; subjects without known history of brain 
metastases may have head CT or MRI.
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Table 5.1-2:
On-Study Assessments Part 1 (CA209511)
Procedure
For Part 1, Study Drug Every 3 Weeks for 
4 Cycles
(Both Arm A and Arm B)
Notes
Cycle 1, 2, 3, 4
(Day 1)
Safety Assessments
Targeted Physical Examination
X
To be performed only as clinically indicated within 72 hours 
prior to dosing
Vital Signs
X
Including BP, HR, temperature. (Section 5.3)
Physical Measurements (including 
performance status)
X
Weight and ECOG Performance status within 72 hours prior to 
dosing
Adverse Events Assessment
Continuously
Review of Concomitant 
Medications
X
Laboratory Tests
X
Within 72 hrs prior to dosing to include CBC w/ differential, 
LFTs, BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, 
LDH, Glucose, amylase, lipase, TSH (+ reflex Free T4 and 
Free T3), albumin if clinically indicated).
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours prior to administration of first 
dose and every 3 weeks thereafter in Part 1 of the study.
Pharmacokinetic and 
Immunogenicity Assessments
Immunogenicity blood sample
See Section 5.5 for details regarding specific 
sample timing
PK Samples
See Section 5.5 for details regarding specific sample 
timing
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Table 5.1-2:
On-Study Assessments Part 1 (CA209511)
Procedure
For Part 1, Study Drug Every 3 Weeks for 
4 Cycles
(Both Arm A and Arm B)
Notes
Cycle 1, 2, 3, 4
(Day 1)
Exploratory Biomarker Testing
Exploratory Serum Biomarkers
X
To be collected pre-dose; before first 4 combination doses 
only.
Peripheral Blood Mononuclear 
Cells (PBMCs)
X
To be collected pre-dose; before first 4 combination doses 
only.
To be collected in USA and Canada only. 
Whole Blood Sample (DNA)
X
X = before first combination dose only.
Myeloid-Derived Suppressor Cell 
(MDSCs)
X
To be collected pre-dose; before the first and the third 
combination dose only
Efficacy Assessment
Tumor Assessment
See Notes
FIRST tumor assessment should be performed at 12 weeks (1 
wk) following randomization.
CT Chest, CT (or MRI) abdomen, pelvis and all known sites of 
disease. Use same imaging method as was used at 
screening/baseline.
Subjects with a history of brain metastasis should have 
surveillance MRI approximately every 12 weeks, or sooner if 
clinically indicated
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Table 5.1-2:
On-Study Assessments Part 1 (CA209511)
Procedure
For Part 1, Study Drug Every 3 Weeks for 
4 Cycles
(Both Arm A and Arm B)
Notes
Cycle 1, 2, 3, 4
(Day 1)
Outcomes Research Assessments
EORTC QLQ-C30 and EQ-5D
X
To be completed at the start of the clinic visit every 6 weeks. 
First questionnaire should be completed after IRT
randomization but before dosing.
(Cycle 1, 3)
Health Care Utilization
X
Health Care Utilization will be collected at each visit
Clinical Drug Supplies
IRT Drug Vial Assignment
X
Within 24 hours prior to dosing
Administer Study Treatment
X
First dose to be administered within 3 days following 
randomization. See Section 4.3.  
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Table 5.1-3:
On-Study Assessments - Part 2 (CA209511)
Procedure
For Part 2, Study Drug is 
Administered Every 4 Weeks
(Both Arm A and Arm B)
Notes
Cycle 5 will begin 6 weeks after Cycle 4
Cycle 5 and beyond
(Day 1)
Safety Assessments
Targeted Physical Examination
X
To be performed only if clinically indicated within 72 hours prior to dosing
Vital Signs
X
Including BP, HR, temperature (Section 5.3)
Physical Measurements (including 
performance status)
X
Weight and ECOG Performance status within 72 hours prior to dosing
Adverse Events Assessment
Continuously
Review of Concomitant 
Medications
X
Laboratory Tests
X
Beginning at Cycle 5 and every alternate dose thereafter (Cycle 7, 9, 11, 13, etc),  
on-study local laboratory assessments should be done within 72 hours prior to the 
first (Part 2) dose and include: CBC w/differential, LFTs (ALT, AST, total 
bilirubin, alkaline phosphatase), BUN or serum urea level, creatinine, Ca, Mg, 
Na, K, Cl, LDH, glucose, amylase, lipase, TSH with reflexive Free T4, Free T3. 
(Albumin if clinically indicated)
Beginning at Cycle 6 and every alternate dose thereafter (Cycle 8, 10, 12, 14,
etc), on-study local laboratory assessment should be done within 72 hours prior to 
the second (Part 2) dose and include: LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase) and creatinine. 
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours prior to first dose
and every 4 weeks thereafter in Part 2
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Table 5.1-3:
On-Study Assessments - Part 2 (CA209511)
Procedure
For Part 2, Study Drug is 
Administered Every 4 Weeks
(Both Arm A and Arm B)
Notes
Cycle 5 will begin 6 weeks after Cycle 4
Cycle 5 and beyond
(Day 1)
Outcomes Research Assessments
EORTC QLQ-C30 and EQ-5D
X
To be completed at the start of the clinic visit every 4 weeks from Cycles 5 to 11
Health Care Utilization
Health Care Utilization will be collected at each visit
Pharmacokinetic and 
Immunogenicity Assessments
Immunogenicity blood sample
See Section 5.5 for details 
regarding specific sample timing
PK Samples
See Section 5.5 for details 
regarding specific sample timing
Efficacy Assessment
Tumor Assessment
See Notes
First tumor assessment during Part 2 should occur after 8 weeks (± 1wk) relative 
to previous tumor assessment performed at week 12.
Subsequent tumor assessments should occur every 8 weeks (1 wk) for the first 
12 months from randomization.
From the second year from randomization, tumor assessments should occur every 
12 wks (2 wk) until disease progression.
CT Chest, CT (or MRI) abdomen, pelvis and all known sites of disease. Use same 
imaging method as was used at screening/baseline.
Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks, or sooner if clinically indicated.
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Table 5.1-3:
On-Study Assessments - Part 2 (CA209511)
Procedure
For Part 2, Study Drug is 
Administered Every 4 Weeks
(Both Arm A and Arm B)
Notes
Cycle 5 will begin 6 weeks after Cycle 4
Cycle 5 and beyond
(Day 1)
Clinical Drug Supplies
IRT Drug Vial Assignment
X
Administer Study Treatment
X
See Section 4.3.
Note: Within 3 days from vial assignment, the subject must receive the dose of 
study medication.
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Table 5.1-4:
Follow-up Assessments (CA209511)
Procedure
Follow Up,a
Visits X1 and 
X2
Survival,b
Follow-up Y 
Visits
Notes
Safety Assessments
Targeted Physical Examination
X
To assess for potential late emergent study drug related issues
Adverse Event Assessments
X
X
Laboratory Tests
X
On site/local CBC w/differential, LFTs, BUN, creatinine, amylase, lipase 
and TSH (+ reflex Free T4 and Free T3) for X1, repeat at X2 if study drug 
related toxicity persists.
Pregnancy Test (WOCBP Only)
X
Serum or urine
Review of Concomitant Medications
X
Pharmacokinetic Samples and
Immunogenicity Assessments
PK Samples
X
See Section 5.5 for schedule of assessments
Immunogenicity blood sample
X
Refer to Section 5.5 for details regarding specific sample timing
Survival Status
Subject Status
X
X
Every 3 months, Survival Follow up Visits may be accomplished by visit or 
phone contact, to include subsequent anti-cancer therapy
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Table 5.1-4:
Follow-up Assessments (CA209511)
Procedure
Follow Up,a
Visits X1 and 
X2
Survival,b
Follow-up Y 
Visits
Notes
Efficacy Assessments
Tumor Assessments
See Notes
Only for subjects without progression on study therapy.
FIRST tumor assessment should first be performed at 12 weeks (1 wk) 
following randomization
SUBSEQUENT tumor assessments should occur every 8 weeks (1 wk) 
thereafter for the first 12 months, then every 12 wks (2 wk) until disease 
progression 
CT Chest, CT (or MRI) abdomen, pelvis and all known sites of disease. Use 
same imaging method as was used at screening/baseline.
Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks, or sooner if clinically indicated
Exploratory Biomarker Testing
Tumor Tissue Biopsy
X
X
Optional; collection upon progression
a X visits occur as follows - X1 = 30 days from the last dose (7 days) or coincide with the date of discontinuation (7 days) if date of discontinuation is greater 
than 37 days after last dose, X2 = 84 days (7 days) from follow-up visit 1. Follow up visits X1 and X2 will occur only after patient completes all study 
treatment.
b Y Survival visits = every 3 months from X2 (7 days).
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5.1.1
Retesting During Screening 
Any new result will override the previous result (i.e., the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
5.2
Study Materials

NCI CTCAE version 4.0 

BMS-936558 (nivolumab) IB

Ipilimumab IB

Pharmacy Information Sheets

Laboratory manuals for collection and handling of blood (including biomarker and
immunogenicity) and tissue specimens

Site manual for operation of IRT, including enrollment worksheets

Manual for entry of local laboratory data

Serious Adverse Events (or eSAE) case report form pages

Pregnancy surveillance forms

RECIST 1.1 pocket guide

Quality of Life questionnaires.
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, blood pressure 
(BP), heart rate (HR) and temperature should be performed within 28 days prior to randomization. 
Baseline signs and symptoms are those that are assessed within 14 days prior to first dose. 
Concomitant medications will be collected from within 14 days prior to the first dose through the 
study treatment period (see Table 5.1-1).
Baseline local laboratory assessments should be done within 14 days prior to the randomization
and include: CBC with differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN 
or serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH, 
Free T4, Free T3, and Hep B and C testing (HBV sAg and HCV RNA or Ab) (see Table 5.1-1). 
Pregnancy testing for WOCBP (done locally) must be performed within 24 hours prior to the initial 
administration of study drug at baseline and then every 3 weeks during Part 1, every 4 weeks 
during Part 2, and at the safety follow up visits (Follow up visits 1 and 2).
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments
will be continuous during the treatment phase. During the safety follow-up phase (Table 5.1-4),
toxicity assessments should be done in person. Once subjects reach the survival follow-up phase, 
either in-person visits or documented telephone calls to assess the subject’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
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On-study weight, ECOG performance status, and vital signs should be assessed at each on-study 
visit prior to nivolumab dosing. Vital signs should also be taken as per institutional standard of 
care prior to, during and after dosing. The start and stop time of the nivolumab infusion should be 
documented. Physical examinations are to be performed as clinically indicated (including a 
pulmonary assessment at screening). If there are any new or worsening clinically significant 
changes since the last exam, report changes on the appropriate non-serious or serious adverse event 
page.
During Part 1, on-study local laboratory assessments should be done within 72 hours prior to each 
dose and include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH with 
reflexive Free T4, Free T3 and albumin if clinically indicated.
During Part 2, on-study local laboratory assessments should be done within 72 hours prior to the 
first (Part 2) dose beginning at Cycle 5 (Week 18) and every alternate dose thereafter (Cycle 7, 9, 
11, 13, etc) and include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase), BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, 
lipase, TSH with reflexive Free T4, Free T3 and albumin if clinically indicated.
During Part 2, on-study local laboratory assessment should be done within 72 hours prior to the 
second (Part 2) dose (beginning at Cycle 6 and every alternate dose thereafter (Cycle 8, 10, 12, 14,
etc) and include: LFTs (ALT, AST, total bilirubin, alkaline phosphatase) and creatinine.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
inducted liver enzyme elevations) 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.
Some of the previously assessments referred to in this section may not be captured as data in the 
eCRF. They are intended to be used as safety monitoring by the treating physician. Additional 
testing or assessments may be performed as clinically necessary or where required by institutional 
or local regulations.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. Baseline 
assessments should be performed within 28 days prior to randomization utilizing CT or MRI. In 
addition to chest, abdomen, pelvis, and brain, all known sites of disease should be assessed at 
baseline. Subsequent assessments should include chest, abdomen, and pelvis, and all known sites 
of disease and should use the same imaging method as was used at baseline. Subjects will be 
evaluated for tumor response beginning 12 weeks (± 1 week) from randomization and continuing 
every 8 weeks (± 1 week) for the first 12 months and every 12 weeks (± 1 week) thereafter, until 
disease progression is documented or treatment is discontinued (whichever occurs later). Tumor 
assessments for ongoing study treatment decisions will be completed by the investigator using 
RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria.
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Radiographic images will be collected and sent to a centralized imaging core laboratory for storage 
and potential future central reading. 
5.4.1
Primary Efficacy Assessment 
Efficacy assessment is not a primary endpoint.  The primary endpoint is the incidence of
drug-related Grade 3 - 5 AEs. See Section 6 for a further description of adverse event reporting.
5.4.2
Secondary Efficacy Assessments
The secondary measure of efficacy will include the ORR and PFS.
The ORR, will be determined by the investigator using RECIST 1.1 criteria, in all treated subjects. 
ORR and is defined as the number of subjects with a BOR of complete response (CR) or partial 
response (PR) divided by the number of treated subjects. The investigator-determined ORR will 
be further characterized by the investigator-determined duration of response (DOR) and the 
magnitude of reduction in tumor volume
The other secondary efficacy measure will be to evaluate PFS in all treated patients.
Additional secondary endpoints include OS in all treated subjects.
Radiographic images will be collected and sent to a centralized imaging core laboratory for storage 
and potential future central reading. 
5.4.2.1
Measurable Lesions
Measurable lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:

10 mm by CT/MRI scan (CT/MRI scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured
with calipers should be recorded as nonmeasurable)

20 mm by chest x-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow up, only the short axis will be measured 
and followed.
5.4.2.2
Non-measurable Lesions 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes 
with 10 to < 15 mm short axis), as well as truly non-measurable lesions.

Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques.
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5.4.2.3
Special Considerations Regarding Lesion Measurability
Bone Lesions

Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.

Blastic bone lesions are non-measurable.
Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are by definition, simple 
cysts.
“Cystic lesions” thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same subject, these are preferred for selection as target lesions.
Non-measurable Lesions
Tumor lesions situated in a previously irradiated area, or in an area subjected to locoregional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion.
5.4.3
Specifications for Method of Measurement
5.4.3.1
Measurement of Lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 28 days before the 
beginning of treatment.
5.4.3.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
5.4.3.3
CT/MRI Scan 
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
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5.4.3.4
Chest X-Ray
Chest CT is preferred over chest x-ray, particularly when progression is an important endpoint
since CT is more sensitive than x-ray, particularly in identifying new lesions. However, lesions on 
chest x-ray may be considered measurable if they are clearly defined and surrounded by aerated 
lung.
5.4.3.5
Clinical Lesions
Clinical lesions will only be considered measurable when they are superficial and 10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated both by clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study. 
5.4.3.6
Ultrasound
Ultrasound is not useful in the assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
5.4.3.7
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
5.4.3.8
Tumor Markers
Tumor markers such as, but not limited to, LDH may be used for clinical management, but will 
not be included in the assessment of BOR.
5.4.4
Baseline Documentation of "Target” and “Non-Target Lesions”
5.4.4.1
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.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements.
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 below, 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.
Previously treated CNS metastases are not considered measurable lesions for purposes of 
RECIST 1.1 determined response. 
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5.4.4.2
Lymph Nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be
visible by imaging even if not involved by tumor. Pathological nodes which are defined as
measurable and may be identified as target lesions must meet the criterion of a short axis of
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum.
Nodes that have a short axis < 10 mm are considered non-pathological and should not be recorded 
or followed.
5.4.4.3
Non-target Lesions
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”. 
In addition, it is possible to record multiple non-target lesions involving the same organ as a single 
item on the case report form (eg, “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”).  
5.4.5
Tumor Evaluation
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.
5.4.5.1
Target Lesions that Become “Too Small to Measure”
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). If the radiologist is able 
to provide an actual measurement, that should be recorded, even if it is below 5 mm.
5.4.5.2
Target 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.
As lesions coalesce, a plane between them maybe maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly coalesced such that they 
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are no longer separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.
5.4.5.3
Evaluation 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 (< 10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) above the normal limits.
PD: Unequivocal progression of existing non-target lesions (Note: the appearance of one or more 
new lesions is also considered progression).
5.4.5.4
Unequivocal Progression in Non-target Disease
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.
5.4.5.5
New Lesions
The appearance of new malignant lesions denotes disease progression. 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 preexisting lesions. This is particularly important 
when the subject’s baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan reported as a “new” cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the subject 
who has visceral disease at baseline and while on study has a CT or MRI brain scan ordered which 
reveals metastases. The subject’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.
5.4.6
Response Criteria (RECIST 1.1)
For subjects who have measurable disease at baseline, Table 5.4.6-1 provides a summary of the 
overall response status calculation at each time point.
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Table 5.4.6-1:
Time Point Response - Subjects 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, NE=Not evaluable
5.4.6.1
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular time point, the subject is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned time-point 
response.
5.4.6.2
Confirmation of Scan 
Verification of Response: As per RECIST 1.1, confirmation of response is required for trials with 
response as a primary endpoint but is no longer required in randomized studies since the control 
arm serves as appropriate means of interpretation of data. Hence, confirmation is NOT required.27
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 not to have 
progressive disease per RECIST 1.1.
5.4.6.3
Best Overall Response
The BOR is determined once all the data for the subject is known. It is defined as the best response 
designation, as determined by the investigator, recorded between the date of randomization and 
the date of objectively documented progression per RECIST1.1 or the date of subsequent therapy, 
whichever occurs first. For subjects without documented progression or subsequent therapy, all 
available response designations will contribute to the BOR assessment. The subject’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.
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For the purpose of this study, the minimum scan time from baseline for determination of SD will 
be 12 weeks.
5.4.6.4
Duration of Objective Response
The duration of objective response is measured from the time measurement criteria are first met
for CR/PR (whichever is first recorded) until the first date that progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded on 
study). 
5.5
Pharmacokinetic and Immunogenicity Assessments
Samples for PK and immunogenicity assessments will be collected for all subjects receiving 
nivolumab and ipilimumab as described in Table 5.5.1-1. All timepoints are relative to the start of 
study drug administration. All on-treatment timepoints are intended to align with days on which 
study drug is administered. If it is known that a dose is going to be delayed, then the predose 
sample should be collected just prior to the delayed dose. However, if a predose sample is collected 
but the dose is subsequently delayed, an additional predose sample should not be collected. Further 
details of sample collection, processing, and shipment will be provided in the laboratory 
procedures manual.
Blood samples should be drawn from a site other than the infusion site (ie, contralateral arm) on 
days of infusion. All samples collected pre-dose should be taken just prior to the administration 
from the contralateral arm (ie, the arm not used for the infusion). If the infusion was interrupted,
the interruption details will also be documented on the CRF. Blood samples will be processed to 
collect serum and stored preferably at -70°C (samples may be stored at -20°C up to 2 months). 
Further details of pharmacokinetic sample collection and processing will be provided to the site in 
the lab manual.
Blood samples for immunogenicity analyses of nivolumab and/or ipilimumab will be collected 
according to the schedule given in Table 5.5.1-1. Samples collected from subjects will be evaluated 
for the development of Anti-Drug Antibody (ADA) for nivolumab and/or ipilimumab by validated 
immunoassays. Samples may also be analyzed for neutralizing ADA response to nivolumab and/or 
ipilimumab. Neutralizing ADA testing conditional upon assay availability.
5.5.1
Pharmacokinetic and Immunogenicity Sample Analyses
The serum samples will be analyzed for drug (nivolumab and ipilimumab) and ADA (anti-
nivolumab and anti- ipilimumab antibodies) by validated immunoassays. Samples with a positive 
ADA response may also be analyzed for neutralizing ADA response to nivolumab and/or 
ipilimumab. 
In addition, selected serum samples may be analyzed by an exploratory method that measures 
nivolumab and ipilimumab, or detect anti-drug antibodies for technology exploration purposes; 
exploratory results will not be reported. The corresponding serum samples designated for either 
PK, immunogenicity or biomarker assessments may also be used for any of those analyses, if 
required (eg, insufficient sample volume to complete testing or to follow up on suspected 
immunogenicity related AE).
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Table 5.5.1-1:
Pharmacokinetic and Immunogenicity Sample Collections (CA209511)
Parta
Study Dayb
( 1 Cycle = 3 weeks 
for Part 1
1 Cycle = 4 Weeks 
for Part 2)
Time (Event)
Time (Relative 
to Start of 
Nivolumab  
Infusion) 
Hours:Min
Pharmacokinetic 
Blood Sample for 
Nivolumab
Immunogenicity 
Blood Sample 
for Nivolumab
Pharmacokinetic 
Blood Sample for 
Ipilimumab
Immunogenic 
Blood Sample 
for Ipilimumab
1
C1D1
(Predose)c
00:00
X
X
X
X
1
C1D1
(EOI-nivo)d
00:90
X
1
C1D1
(EOI-ipi)d
00:30
X
1
C2D1
(Predose)c
00:00
X
X
X
X
1
C2D1
(EOI-nivo)d
00:90
X
1
C2D1
(EOI-ipi)d
00:30
X
1
C3D1
(Predose)c
00:00
X
X
X
X
1
C3D1
(EOI-nivo)d
00:90
X
1
C3D1
(EOI-ipi)d
00:30
X
2
C5D1
(Predose)c
00:00
X
X
X
X
2
C5D1
(EOI-nivo)d
00:30
X
2
C9D1
(Predose)
00:00
X
X
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Table 5.5.1-1:
Pharmacokinetic and Immunogenicity Sample Collections (CA209511)
Parta
Study Dayb
( 1 Cycle = 3 weeks 
for Part 1
1 Cycle = 4 Weeks 
for Part 2)
Time (Event)
Time (Relative 
to Start of 
Nivolumab  
Infusion) 
Hours:Min
Pharmacokinetic 
Blood Sample for 
Nivolumab
Immunogenicity 
Blood Sample 
for Nivolumab
Pharmacokinetic 
Blood Sample for 
Ipilimumab
Immunogenic 
Blood Sample 
for Ipilimumab
2
CXD1: Every 
16 weeks after C09 
(ie, C13D1, C17D1, 
etc.)
(Predose)
00:00
X
X
First 2 Follow-up 
Visits 
(Approximately up to 
100 Days from the 
Discontinuation of 
Study Drug)
NA
X
X
a Part 1 indicates first 12 weeks (or 4 cycles) of combination treatment (nivolumab + ipilimumab). Part 2 indicates nivolumab monotherapy period starting from 
Week 16 (or Cycle 5).
b If a subject discontinues study drug treatment during the sampling period, they will move to sampling at the follow-up visits.
c Predose: All predose samples for nivolumab and ipilimumab should be taken prior to the start of nivolumab infusion.
d EOI-nivo and EOI-ipi: End of Infusion samples for nivolumab and ipilimumab, respectively. For sequential dosing, both EOI samples should be collected 
immediately (preferably within 2 - 5 minutes) prior to the end of the ipilimumab infusion. If the end of infusion is delayed, the collection of the EOI 
samples should be delayed accordingly. EIO samples may not be collected from the same IV access as drug was administered, refer to the laboratory manual for 
additional instructions.
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5.6.1
Tumor Tissue Specimen 
Pre-treatment tumor tissue specimens in the form of a paraffin embedded block or a minimum of
10 unstained slides will be submitted for central PD-L1 immunohistochemistry (IHC) assessment
prior to randomization. These biopsy samples should be excisional, incisional, punch or core
needle. Fine needle aspirates or other cytology specimens are insufficient for downstream
biomarker analyses. PD-L1 stained tissue sections will be assessed by a pathologist and scored as
PD-L1 expression 5% or PD-L1 expression < 5% based on the frequency of tumor cell surface 
PD-L1 staining among a minimum of a hundred (100) evaluable tumor cells. Where membrane 
staining is obscured by high cytoplasmic staining or melanin content, but the tumor tissue sample 
contain the minimum number of evaluable tumor cells, samples will be deemed PD-L1 
indeterminate.
Tumor samples will be stained for PD-L1 by ICH and the stained tissue sections will be assessed 
by a pathologist for tumor and immune cell membrane expression of PD-L1. These tumor samples 
may also be assessed for the expression of other immune or melanoma related genes, RNAs and/or 
proteins, as well as, the presence of immune cell populations using a variety of methodologies 
inclusive of, but not limited to IHC, qRT-PCR, genetic mutation detection, fluorescent in-situ 
hybridization (FISH) and exome sequencing. Various molecular markers with potential predictive 
value for the treatment of melanoma with nivolumab, ipilimumab and other immunotherapies are 
currently under investigation and may be assessed in this study. These tumor tissue biomarkers 
include, but are not limited to PD-1, PD-L2, tumor infiltrating lymphocytes (TILs) or 
subpopulations of TILs and a Th1 immune mRNA expression signature. In addition, other methods 
of measuring tumor PD-L1 expression may also be assessed.
Tumor tissue samples may also be collected upon progression. This sample may be used for the 
assessment of markers implicated in resistance to immunotherapeutic agents, including but not 
limited to other T cell checkpoint receptors and ligands (eg, Lag-3, Tim-3) and intratumoral 
immune cell subsets, including but not limited to, T regulatory cells and myeloid derived 
suppressor cells. These samples may also be used to investigate the effect of 
nivolumab + ipilimumab on the expression of potentially relevant predictive and/or prognostic 
melanoma biomarkers, including, but not limited to PD-L1. Both the pre-treatment tumor sample 
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and the sample collected upon recurrence may be retrospectively assessed for BRAF mutation 
status, as well as for the expression of other immune or melanoma related genes.
 
 
 
 
 
 
 
 
5.6.3
Peripheral Blood Mononuclear Cells (PBMCs)
Peripheral blood samples will be taken prior to initiation of study therapy and at designated 
timepoints on-treatment (see Section 5.1 for additional details on the blood sample collection 
schedule) for PBMC preparation, except at sites where the stability of the samples after shipment 
to the Central Laboratory cannot be guaranteed. Samples must be shipped within 48 hours to a 
BMS-designated central laboratory for processing.
These PBMC samples may be used for immunophenotyping or characterization of the immune 
cell subsets in the periphery, including, but not limited to, T cells, B cells, NK cells, or 
subpopulations of the aforementioned immune cell types. These samples may also be used to 
assess immune cell function or antigen specific T cell proliferation or activation pending emerging 
information from other nivolumab or ipilimumab studies. 
5.6.4
Whole Blood for SNP Assessment
Whole blood samples for exploratory pharmacogenetic assessment will be collected from all
subjects and put in frozen storage. Genomic DNA will be extracted and subsequently assessed for 
single nucleotide polymorphisms (SNPs) and other genetic variations in genes that may predispose 
subjects to nivolumab or ipilimumab benefit or adverse events (unless restricted by local 
requirements.) Such genes include, but are not limited to PD-1, PD-L1, PD-L2 and CTLA-4. 
Additional use of these data may include correlative analyses aimed at identifying genotypic 
associations with clinically-relevant biomarkers identified by other methodologies described in 
this section.
5.6.5
Myeloid-Derived Suppressor cells
Myeloid derived suppressor cells (MDSCs) are an immune cell population capable of suppressing 
T cell activation and proliferation. Low pre-treatment MDSC levels in peripheral blood may be 
associated with better overall survival in melanoma patients treated with the immunotherapeutic 
agent ipilimumab.28 MDSCs will be measured at baseline and on-treatment to assess 
pharmacodynamic changes or associations with outcome (see Section 5.6.3 for additional details 
on the blood sample collection schedule).
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5.7
Outcomes Research Assessments
HRQoL will be assessed using the EORTC QLQ-C30. The EORTC QLQ-C30 is the most 
commonly used QoL instrument in advanced melanoma clinical studies. It is a 30-item instrument 
that has gained wide acceptance in oncology clinical studies. The EORTC QLQ-C30 comprises 
6 functional scales (physical functioning, cognitive functioning, emotional functioning, social 
functioning and global quality of life) as well as nine symptom scales (fatigue, pain, 
nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). Except for the overall health status and global quality of life items, responses for all 
items are 4-point categorical scales ranging from 0 (Not at all) to 4 (Very much). The overall health 
status/quality of life responses are 7-point Likert scales.
General health status will be measured using the EQ-5D. The EQ-5D is a standardized instrument 
for use as a measure of self-reported health status. The EQ-5D comprises 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort and anxiety) and a visual analog rating scale (VAS). 
The utility data generated from the EQ-5D is recommended for and commonly used in cost 
effectiveness analysis.
The EQ-5D will be administered along with the EORTC QLQ-C30 during on-study phases (Parts
1 and 2) as outlined in Section 5.1, to all subjects. 
Healthcare resource utilization data (eg, hospitalizations, non-protocol specified medical visits, 
diagnostics, etc) will be collected for all randomized subjects. The resource utilization capture is 
specific to hospital admission utilization data and non-protocol specified visits related to study 
therapy. Resource utilization questions will be collected on-study phases (Parts 1 and 2) as outlined 
in Section 5.1, to all subjects.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.
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Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.7 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent
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
admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).

admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within
100 days of discontinuation of dosing. For subjects randomized and never treated with study drug, 
SAEs should be collected for 30 days from the date of randomization. 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. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF.  The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning.  
In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting.  In the event the electronic system is unavailable for transmission, 
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paper forms must be used and submitted immediately.  When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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. 
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug until 100 days 
from the last dose of study drug. Nonserious AE information should also be collected from the 
start of a placebo lead-in period or other observational period intended to establish a baseline status 
for the subjects.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on subject’s case report form.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Immune-mediated Adverse Events
Immune-mediated adverse events (IMAEs) are AEs consistent with an immune-mediated 
mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection 
or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology 
which were exacerbated by the induction of autoimmunity. Information supporting the assessment 
will be collected on the subject’s case report form.
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6.4
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic) as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted

Any laboratory test result abnormality that required the subject 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).
6.5
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half 
lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Section 6.1.1.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the blinded study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of blinded study drug(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur. Under no circumstances will dosing during pregnancy be allowed.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.6
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered of both excessive and specifically important.
All occurrences of overdose must be reported as SAEs (see Section 6.1.1 for reporting details).
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6.7
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 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable to this study.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Approximately 346 subjects will be randomized to the 2 treatment arms in a 1:1 ratio in order to 
target 340 treated subjects (170 per arm). Given a two-sided alpha of 0.05, this number of treated 
subjects provides 80% power to show a statistically significant difference in the rate of 
drug-related Grade 3 - 5 AEs between the two treatment arms, assuming a rate of 40% in Arm A 
and a rate of 55% in Arm B.
We assume that treatment with N3I1 (Arm A) will result in a 15% reduction in the rate of 
drug-related Grade 3 - 5 events when compared to treatment with N1I3 (Arm B). The difference 
of 15% is clinically meaningful and assumes a 40% event rate in Arm A and a 55% event rate in 
Arm B. The assumption of 55% in Arm B is based on observed rates of drug-related Grade 3 - 5 
AEs in the combination arm of studies CA209069 and CA209067, which enrolled the same patient 
population as the current study (previously untreated metastatic melanoma). The assumed 
reduction to 40% in Arm A corresponds to the same rate ratio (0.727) that was observed in Cohort 
2a relative to Cohort 2 in Study CA209004.
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Table 8.1-1 shows the precision that the sample size of 170 treated subjects per arm will provide 
for estimating adverse event rates (primary endpoint) or objective response rates (secondary 
endpoint), under different assumed observed rates. 
For example, if exactly 68 of 170 treated subjects (40%) experience a drug-related Grade 3 - 5 AE 
in Arm A and 94 of 170 treated subjects (55.3%) experience a drug-related Grade 3 - 5 AE in Arm 
B, then the exact 95% CI for the rate of drug-related Grade 3 - 5 AEs will be (32.6%, 47.8%) for 
Arm A and (47.5%, 62.9%) for Arm B. 
Furthermore, if exactly 102 of 170 treated subjects (60%) experience an objective response in a 
treatment arm, then the exact 95% CI for the ORR in that treatment arm will be (52.2%, 67.4%). 
If the observed ORR is exactly the same in each arm and equal to 60%, then the 95% CI for the 
difference in ORR between arms will be (-10.4%, 10.4%), and the 95% CI for the odds ratio will 
be (0.65, 1.54).
Table 8.1-1:
Exact 95% CI for Rates when Observed in 170 Subjects
Number Subjects with 
Event 
Observed Rate 
Lower limit Exact 
95% CI
Upper limit Exact 95% CI
68
40.0%
32.6%
47.8%
77
45.3%
37.7%
53.1%
85
50.0%
42.2%
57.8%
94
55.3%
47.5%
62.9%
102
60.0%
52.2%
67.4%
8.2
Populations for Analyses
Since the primary objective will be addressed by a safety endpoint, the primary endpoint analysis 
will be based on all treated subjects. For consistency, the secondary endpoints will use the same 
analysis population as the primary endpoint (ie, all treated subjects).

All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IRT.

All Randomized Subjects: All subjects who were randomized to any treatment group. This is 
the primary dataset for efficacy listings

All Treated Subjects: All subjects who received at least one dose of any study medication. This 
is the primary dataset for analysis of study conduct, study population, efficacy (including 
secondary endpoints), exposure, and safety (including primary endpoint).

PK Subjects: All treated subjects with available serum time-concentration data.

Immunogenicity Subjects: All treated subjects with available ADA data.

Biomarker Subjects: All treated subjects with available biomarker data.
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8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary endpoint of the study is the rate of drug-related Grade 3 - 5 AEs. The drug-related 
Grade 3 - 5 AE rate is defined as number of subjects who experienced at least 1 AE of Grade 3 or 
higher, judged to be related to study drug by the investigator, and with onset on or after the first 
dose of study treatment and within 30 days of the last dose of study treatment, divided by number 
of treated subjects. AE grade will be defined using National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria.
The analysis of the primary endpoint will occur when all subjects who are still on-treatment have 
had at least 2 post-baseline tumor assessments.
8.3.2
Secondary Endpoint(s)
Descriptive analyses of secondary endpoints will be performed to evaluate the hypothesis of 
similar efficacy between the treatment arms.
The first secondary endpoint is ORR as determined by investigators. The ORR is defined as the 
number of subjects with a BOR of CR or PR divided by the number of treated subjects for each 
treatment group. The BOR is defined as the best response designation, as determined by the 
investigator, recorded between the date of randomization and the date of objectively documented 
progression per RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first. 
For subjects without documented progression or subsequent therapy, all available response 
designations will contribute to the BOR assessment. Tumor assessments are scheduled to be 
performed at Week 12 following randomization, every 8 weeks for the first 12 months and then 
every 12 weeks until disease progression.
The second secondary endpoint is PFS. PFS is defined as the time between the date of 
randomization and the first date of documented progression, as determined by the investigator, or 
death due to any cause, whichever occurs first. Subjects who die without a reported progression 
will be considered to have progressed on the date of their death. Subjects who did not progress or 
die will be censored on the date of their last evaluable tumor assessment. Subjects who did not 
have any on study tumor assessments and did not die will be censored on their date of 
randomization. Subjects who started 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 subsequent 
anti-cancer therapy.
The third secondary endpoint is OS. OS is defined as the time between the date of randomization
and the date of death due to any cause. A subject who has not died will be censored at the last 
known alive date. OS will be followed continuously while subjects are on the study drug and every 
3 months via in-person or phone contact after subjects discontinue the study drug.
The fourth secondary objective (to evaluate HRQoL) will be measured by mean changes from 
baseline in the EORTC-QLQ-C30 global health status/QoL composite scale and by mean changes 
from baseline in the remaining EORTC QLQ-C30 scales. HRQoL will be evaluated per Section
5.7.
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Secondary endpoints will be analyzed at the time of the primary endpoint analysis.
 
 
 
 
 
 
 
 
 
 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized in all treated subjects by treatment 
group, as treated, using descriptive statistics.
8.4.2
Efficacy Analyses
The primary endpoint is related to safety and there are no primary efficacy endpoints. Analysis 
methods for the primary safety endpoint are described in Section 8.4.4.1.
8.4.2.1
Secondary Endpoints Methods
Descriptive analyses of secondary endpoints will be performed to evaluate the hypothesis of 
similar efficacy between the treatment arms.
ORRs and corresponding 95% exact CIs will be calculated using the Clopper Pearson method for 
each of the treatment arms. BOR will be tabulated for each treatment group. The 2 treatment arms 
will be compared using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by PD-L1 
expression and M stage at screening. Associated odds ratios and 95% CIs for Arm A relative to 
Arm B will be calculated, and a p-value will be presented for descriptive purposes. An estimate of 
the difference in ORRs and corresponding 95% CI will be calculated using CMH methodology, 
adjusting for the stratification factors PD-L1 expression and M stage at screening. 
PFS curves for each treatment group will be estimated using the Kaplan-Meier (KM) product limit 
method. Median PFS and corresponding two-sided, 95% confidence intervals will be computed. 
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Descriptive HRs and corresponding two sided 95% CIs for Arm A relative to Arm B will be 
estimated using a Cox proportional hazards model, with treatment group as a single covariate, 
stratified by PD-L1 status and M Stage at screening. A p-value from a 2-sided log-rank test 
stratified by PD-L1 expression and M stage at screening will be presented for descriptive purposes.
PFS rates at 6 months with 95% CIs will be estimated using KM methodology.
OS will be summarized descriptively using Kaplan-Meier methodology. Median values, along 
with two-sided 95% CIs will be calculated.  Additional survival analysis may be conducted for up 
to 5 years beyond analysis of the primary endpoint.
 
 
 
 
 
8.4.4
Safety Analyses
8.4.4.1
Primary Endpoints Methods
For the primary analysis, we will report the drug-related Grade 3 - 5 AE rate by treatment arm, the 
difference in rates between arms, and the corresponding 95% CIs. Two sided CMH test stratified 
by PD-L1 status and M Stage at screening will be performed to compare the drug-related 
Grade 3 - 5 AE rate between the two treatment arms. 
An additional descriptive summary of drug-related AEs will be performed including only those 
events with onset during the combination portion (Part 1) of the regimen.
8.4.4.2
Other Safety Analysis
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 by treatment group. All on-study AEs, drug-related AEs, AEs leading 
to discontinuation, SAEs, and drug-related SAEs will be tabulated using worst grade per NCI 
CTCAE v 4.0 criteria by system organ class and preferred term. On-study lab parameters and 
changes from baseline including hematology, chemistry, liver function, and renal function will be 
summarized using worst grade NCI CTCAE v 4.0 criteria
8.4.5
Pharmacokinetic Analyses
 
 
 
 
 
 
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8.4.6
Biomarker Analyses
Methodology for exploratory biomarker analyses is described in the statistical analysis plan.
8.4.7
Outcomes Research Analyses
Analysis of EORTC QLQ-C30 will be performed in all patients who have an assessment at 
baseline and at least one follow-up assessment. All scales and single items are scored on a 
categorical scale and linearly transformed to 0-to-100 scales with higher scores for a functional 
scale representing higher levels of functioning, higher scores for the global health status/quality of 
life representing higher levels of global health/quality of life and higher scores for a symptom scale 
representing higher level of symptoms. EORTC QLQ-C30 scale data will be summarized by 
timepoint using descriptive statistics for each treatment group
8.4.8
Other Analyses 
Methodology for other analyses including immunogenicity, other HRQoL questionnaires, and 
healthcare resource utilization is described in the statistical analysis plan.
8.5
Interim Analyses
Not Applicable.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
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If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
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9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product and 
the following non-investigational product(s). Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
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For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
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 BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. For electronic CRFs, review and approval/signature is completed 
electronically through the BMS electronic data capture tool. The investigator must retain a copy 
of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study 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 BMS 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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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete Abstinence is defined as complete avoidance of 
heterosexual intercourse and is an acceptable form of 
contraception for all study drugs. This also means that 
abstinence is the preferred and usual lifestyle of the patient. 
This does not mean periodic abstinence (e.g., calendar, 
ovulation, symptothermal, profession of abstinence for entry 
into a clinical trial, post-ovulation methods) and withdrawal, 
which are not acceptable methods of contraception. Women
must continue to have pregnancy tests. Acceptable alternate 
methods of highly contraception’s must be discussed in the 
event that the subject chooses to forego complete abstinence.
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11
LIST OF ABBREVIATIONS
Term
Definition
ADA
Anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
AJCC
American Joint Committee on Cancer 
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AT
aminotransaminases
-HCG
beta-human chorionic gonadotrophin
BMS
Bristol-Myers Squibb
BOR
Best overall response
BORR
best overall response rate 
BP
blood pressure
BRt
Total amount recovered in bile
%BRt
Total percent of administered dose recovered in bile
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CR
Complete response
CRC
Colorectal Cancer
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Term
Definition
CRF
Case Report Form, paper or electronic
CT
Computerized tomography
CTLA-4
Cytotoxic T lymphocyte-associated antigen 4
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
dL
deciliter
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli grata (for example)
EMA
European Medicines Agency
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality Of 
Life Questionnaire-core 30 
EQ-5D
European Quality of Life-5 Dimensions
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
ICC
investigator’s choice of chemotherapy
ie
id est (that is)
IEC
Independent Ethics Committee
IL
interleukin
IMAE
Immune-mediated adverse event
IMP
investigational medicinal products
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Term
Definition
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IRT
Interactive Response Technologies web-based system
IU
International Unit
IV
intravenous
K+
potassium
kg
kilogram
L
liter
LDH
lactate dehydrogenase
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mRCC
Metastatic renal cell carcinoma
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
NCI CTCAE
National Cancer Institute Common Terminology Criteria for AE
NE
Not evaluable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer 
ORR
Objective Response Rate
OS
Overall survival
PD
pharmacodynamics
PD
Progressive disease
PD-1
Programmed death-1
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Term
Definition
PD-L1
Programmed cell death- ligand 1
PD-L2
Programmed cell death- ligand 2
PFS
Progression free survival
PK
pharmacokinetics
PPK
population pharmacokinetic
PR
Partial response
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SD
Stable disease
SNP
Single nucleotide polymorphism
SOP
Standard Operating Procedures
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TCR
T-cell receptor
Tmax, TMAX
time of maximum observed concentration
TTR
Time to response
ULN
Upper limit of normal
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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