A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage IIIb/c or Stage IV Melanoma in Subjects Who Are at High Risk for Recurrence (CheckMate 238: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 238)
Phase: PHASE3
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CA209238
IND Number:
115,195
Ex-US
Non-IND
EUDRACT Number
2014-002351-26
Date:
11-Nov-2014
Revised Date
14-Oct-2020
CLINICAL PROTOCOL CA209238
A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy with Nivolumab 
versus Ipilimumab after Complete Resection of Stage IIIb/c or Stage IV Melanoma in Subjects 
who are at High Risk for Recurrence
(CheckMate 238: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 2238)
Revised Protocol Number: 06
Incorporates Administrative Letters 2 and 3
Medical Monitoring Contact Information
Anila Qureshi, MD, MPH 
Medical Monitor
 
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, 
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Revised Protocol No: 06
Date:  14-Oct-2020
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disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person 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).
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Revised Protocol No: 06
Date:  14-Oct-2020
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 06
14-Oct-2020
The primary purpose of Revised Protocol 06 is to extend the collection of 
Overall Survival (OS) data for approximately 5 additional years. In 
addition, data associated with the primary, secondary, and exploratory 
efficacy outcomes (eg, melanoma recurrence data, data on development 
of new primary melanomas and non-melanoma cancers, subsequent anti-
cancer therapies) will continue to be collected on Case Report Forms. 
Study drug-related serious adverse events (SAEs) will continue to be
collected, whereas follow-up surveillance imaging assessments, plasma 
biomarker samples, and the EQ-5D questionnaire will no longer be 
required during extended follow-up.
Administrative 
Letter 03
15-Feb-2019
The purpose of this administrative letter is to change the Study Director 
for this study.
Administrative 
Letter 02
19-Dec-2017
The purpose of this administrative letter is to confirm that a surveillance 
assessment is required at the month 24 time point (relative to the first 
dose of study treatment).
Revised 
Protocol 05
26-Jan-2017
Incorporates Amendment(s) 18
Amendment 18
26-Jan-2017
The main purpose of this global amendment is to:
•
Add an interim analysis of RFS after all subjects have a minimum of 
18 months of follow-up (approximately 350 RFS events are 
anticipated at this analysis). 
•
Change the name and coordinates of the new Medical Monitor
•
Add the Mechanism for Action for Ipilimumab 
•
Confirm that also blood samples from subjects receiving Ipilimumab 
will also be evaluated for development of Anti-Drug Antibody 
(ADA).  
Revised 
Protocol 04
04-Aug-2016
Incorporates Amendment(s) 17
Amendment 17
04-Aug-2016
The main purpose of this global amendment is to:
•
Addition of Adrenocorticotropic hormone (ACTH) test at Week 45 
in subjects receiving ipilimumab/ipilimumab-placebo at Week 48  
(Note: All subjects will have completed 36 weeks of treatment prior 
to implementation of this amendment.)
•
Clarify that the minimum time between dosing visits is 12 days 
between Nivolumab administrations
•
Add information on surveillance scan requirements in case the 
patient discontinues and starts new systemic therapy. 
•
Update the contraception section
•
Updates in the treatment algorithms
Revised 
Protocol 03
24-Feb-2016
Incorporates Amendment(s) 16
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Revised Protocol No: 06
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Document
Date of Issue
Summary of Change
Amendment 16
24-Feb-2016
The main purpose of this global amendment is to:
1)
Increase the visit window from ± 2 days to ± 3 days for all dosing 
visits, except for Week 24, Week 36 and Week 48 where the visit 
window will increase from ± 2 days to ± 7 days.
2)
Clarify that the minimum time between dosing visits is 12 days
3)
Revise and clarify the Prohibited and /or Restricted Treatments
4)
Update the acceptable methods of contraception
Revised 
Protocol 02
06-Aug-2015
Incorporates Amendment(s) 15
Amendment 15
06-Aug-2015
The main purpose of this global amendment is to:
1)
Incorporate the definition of immune-mediated adverse events
2)
Incorporate the Adverse Event Management Algorithms for 
Immuno-oncology Agents as an appendix, and updated terminology 
to be consistent throughout document
3)
Clarify that follow-up of laboratory toxicities will continue until 
toxicities resolve, return to baseline, or are deemed irreversible 
based on on-site/local laboratory results.
4)
Clarify that follow-up of immune-mediated adverse drug reactions 
will continue until toxicities resolve, return to baseline, or are 
deemed irreversible
5)
Revise the discontinuation criteria to be consistent with the 
Nivolumab USPI
6)
Revise the definition of recurrence free survival to include new 
primary melanoma
7)
Add censoring rules for primary analysis of recurrence free survival
8)
Clarify that subjects will continue to be followed for recurrences 
(until local or regional recurrences for all subjects and until distant 
recurrence for Stage III subjects) and survival
Revised 
Protocol 01
02-Apr-2015
Incorporates Amendment(s) 09 and Administrative Letter 01
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Document
Date of Issue
Summary of Change
Amendment 09
02-Apr-2015
1)
The main purpose of this global amendment is to clarify the age 
requirement to participate in the study as the inclusion of 
adolescents may not be appropriate per local regulations.
2)
Additional clarifications have been made to other 
inclusion/exclusion criteria.
3)
There is also a new requirement regarding additional sample 
collection (serum, and biopsy of affected organ) for biomarker 
analysis. This collection will be done upon occurrence of ≥Grade 3 
drug-related AE and lab abnormalities regarded as a drug related 
SAE when clinically safe and feasible
4)
This amendment will also be used to implement recent changes in 
the program level protocol template as well as changes to the 
standard protocol model document
5)
This amendment applies to all subjects
Administrative 
Letter 01
21-Jan-2015
1)
IND Number 115,195
2)
The title of Section 3.3.1, Item 2 should read “Target Population”
3)
First survival follow-up visit will take place 3 months after Follow-up 
2
Original 
Protocol
11-Nov-2014
Not applicable
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SYNOPSIS
Clinical Protocol CA209238
Protocol Title:  A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy with Nivolumab versus 
Ipilimumab after Complete Resection of Stage IIIb/c or Stage IV Melanoma in Subjects who are at High Risk for 
Recurrence.
(CheckMate 238: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 238)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):
Ipilimumab 10 mg/kg/dose IV q3 weeks x 4 doses, then 10 mg/kg/dose IV q12 weeks starting at week 24 or
Nivolumab 3 mg/kg/dose IV q2 weeks 
Treat subjects until disease recurrence, unacceptable toxicity or subject withdrawal of consent, with a maximum of 
1 year of treatment.
Study Phase:  3
Research Hypothesis:  Treatment with nivolumab will improve recurrence-free survival as compared to ipilimumab 
in subjects with completely resected Stage IIIb/c or Stage IV no evidence of disease (NED) melanoma who are at high 
risk for recurrence.
Objectives: 
Primary: 
•
To compare the efficacy, as measured by recurrence free survival (RFS), provided by nivolumab versus 
ipilimumab in subjects with completely resected Stage IIIb/c or Stage IV NED melanoma who are at high-risk 
for recurrence.
Secondary:
•
To compare the overall survival of nivolumab vs ipilimumab in subjects with completely resected Stage IIIb/c or 
Stage IV NED melanoma who are at high risk for recurrence;
•
To assess the overall safety and tolerability of nivolumab and ipilimumab in subjects with completely resected 
Stage IIIb/c or Stage IV NED melanoma who are at high risk for recurrence;
•
To evaluate whether PD-L1 expression is a predictive biomarker for RFS;
•
To evaluate the Health Related Quality of Life (HRQoL) as assessed by European Organisation for Research and 
Treatment of Cancer (EORTC) QLQ-C30.
Revised Protocol No: 06
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Study Design:  
This is a Phase 3, randomized, double-blinded study of nivolumab versus ipilimumab in subjects (≥15 years) with 
complete resection Stage IIIb/c or Stage IV NED melanoma at high risk for recurrence. 
Approximately 800 subjects will be randomized 1:1 and stratified by PD-L1 status (positive vs negative/indeterminate) 
and American Joint Committee on Cancer (AJCC) stage.
Dose reductions will not be allowed.
Subjects will be treated with one of the following: 
Arm A: ipilimumab: 10 mg/kg IV q3 weeks for 4 doses, then q12 weeks starting at Week 24 with nivolumab 
placebo IV q2 weeks 
Arm B: nivolumab 3mg/kg IV q2 weeks with ipilimumab placebo IV q3weeks for 4 doses, then q12 weeks starting at 
Week 24
All subjects will be treated until recurrence of disease, unacceptable toxicity, or subject withdrawal of consent with a 
maximum of 1 year of treatment.
Note: As of Dec-2016, all subjects in both treatment groups were off study treatment.
Study Population:  High risk, completely resected Stage IIIb/c and IV melanoma subjects.
Key Inclusion Criteria:
•
At least 15 years of age
•
Except: where local regulations and/or institutional policies do not allow for subjects < 18 years of age (pediatric 
population) to participate. For those sites, the eligible subject population is ≥ 18 years of age.
•
All subjects must be either Stage IIIb/c or Stage IV AJCC (7th edition) and have histologically confirmed 
melanoma that is completely surgically resected in order to be eligible. Subjects must have been surgically 
rendered free of disease with negative margins on resected specimens. Please refer to Appendix 1 for description 
of AJCC 7th editions of TNM and staging.
•
If Stage III melanoma (whether Stage IIIb or IIIc) the subjects usually have clinically detectable lymph nodes that 
are confirmed as malignant on the pathology report and/or ulcerated primary lesions. Subjects who are “N2c” 
classification with 2-3 metastatic nodes and in transit metastases/satellites without metastatic nodes, or, 
“N3”classification with any “T” and 4+ metastatic nodes, or matted nodes, or in transit metastases/satellites with 
metastatic nodes are eligible. The pathology report for both Stage IIIb and IIIc must be reviewed, signed and 
dated by the investigator; this process will be confirmed during the IVRS randomization call. Clinically detectable 
lymph nodes are defined as:
1)
a palpable node (confirmed as malignant by pathology)
High Risk, 
completely 
resected
Stage IIIb/c 
Stage  IV 
NED melanoma
Randomize 1:1
Stratify by
• Stage
• PD-L1 status
Arm A (n = 400)
Ipilimumab 10 mg/kg IV q3 wks for 4 doses
then q12 wks starting at Wk 24
and
Nivolumab placebo IV q2 wks
Arm B (n = 400)
Nivolumab 3 mg/kg IV q2 wks
and
Ipilimumab placebo IV q3 wks for 4 doses
Then q12 wks starting at Wk 24
Follow-up
Secondary
endpoint OS
For both arms, the treatment duration is maximum one year.
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2)
a non-palpable but enlarged lymph node by CT scan (at least 15 mm in short axis) and confirmed as malignant 
by pathology
3)
a PET scan positive lymph node of any size confirmed by pathology
4)
evidence of pathologically macrometastatic disease in one or more lymph nodes defined by one or more foci 
of melanoma at least 1cm in diameter
If Stage IV melanoma, the pathology report confirming negative margins must be reviewed, dated, and signed by 
the investigator prior to randomization.
•
Complete resection of Stage III disease that is documented on the surgical and pathology reports or complete 
resection of Stage IV disease with margins negative for disease that is documented on the pathology report.
•
Complete resection must be performed within 12 weeks prior to randomization
•
All subjects must have disease-free status documented by a complete physical examination and imaging studies 
within 4 weeks prior to randomization. Imaging studies must include a CT scan of the neck, chest, abdomen, 
pelvis and all known sites of resected disease in the setting of Stage IIIb/c or Stage IV disease, and brain magnetic 
resonance (MRI) or CT (brain CT allowable if MRI is contraindicated or if there is no known history of resected 
brain lesions). 
•
Tumor tissue from the resected site of disease must be provided for biomarker analyses. In order to be randomized, 
a subject must have a PD-L1 expression classification (positive, negative/or indeterminate) as determined by a 
central lab.
Key Exclusion Criteria: 
•
History of ocular/uveal melanoma
•
Subjects with active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, residual 
hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as 
vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.
•
Subjects with previous non-melanoma malignancies are excluded unless a complete remission was achieved at 
least 3 years prior to study entry and no additional therapy is required or anticipated to be required during the 
study period (exceptions include but are not limited to, non-melanoma skin cancers; in situ bladder cancer, in situ 
gastric cancer, in situ colon cancers; in situ cervical cancers/dysplasia; or breast carcinoma in situ)
•
Subjects with a condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or
equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or 
topical steroids are permitted in the absence of active autoimmune disease.
•
Prior therapy for melanoma except surgery for the melanoma lesion(s) and/or except for adjuvant radiation 
therapy (RT) after neurosurgical resection for central nervous system (CNS) lesions and except for prior adjuvant 
interferon (see qualifier below). Specifically subjects who received prior therapy with interferon, anti-PD-1, anti-
PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug 
specifically targeting T cell co-stimulation or checkpoint pathways) are not eligible.
i) Prior treatment with adjuvant interferon is allowed if completed ≥6 months prior to randomization.
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Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209238
Medication 
Potency 
IP/Non-IP 
BMS-936558-01
(Nivolumab) Solution for
Injection
100 mg (10 mg/mL)
IP
Ipilimumab Solution for
Injection
200 mg (5 mg/mL)
IP
0.9% Sodium Chloride for 
Injection
N/A
IP
5% Dextrose for Injection
N/A
IP
Study Assessments: Recurrence-free survival is the primary endpoint of the trial. It is defined as the date between 
the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary 
melanoma, or death (whatever the cause), whichever occurs first. Subjects will be assessed for recurrence (until local, 
regional, or distant recurrence (whichever comes first) for Stage IV subjects and until distant recurrence for Stage III 
subjects) by CT or MRI as follows:
•
Screening. 
•
Treatment Period: Every 12 weeks (± 7 days) from first dose of study drug through 12 months (relative to the 
first dose of study drug)  
•
Follow-up Period: 
−
Every 12 weeks (± 7 days) through 12 months for subjects who discontinued early from treatment (relative 
to the first dose of study drug)  
−
Every 12 weeks (± 14 days) if > 12 months through 24 months (relative to the first dose of study drug)  
−
Every 6 months (± 4 weeks) if > 24 months through and up to Year 5 (relative to the first dose of study drug).
Although surveillance assessments will not be conducted beyond Year 5, data on recurrence of melanoma 
(loco-regional and distant), as well as development of new primary melanomas and non-melanoma cancers 
will continue to be collected in the respective Case Report Forms for an additional 5 years, for a total study 
duration of approximately 10 years.
Statistical Considerations: 
Sample Size: The sample size is calculated to compare RFS between subjects randomized to receive 
nivolumab vs ipilimumab. Approximately 900 subjects have been randomized to the two treatment arms in a 1:1 ratio. 
The final analysis for RFS will take place after all subjects have a minimum of 36 months of follow-up and will take 
approximately 43.5 months from the start of the study. At 43.5 months, approximately 450 events are anticipated
ensuring at least 85% power to detect a hazard ratio of 0.75 with an overall type I error of 0.05 (two-sided).
Endpoints:  
Primary Endpoint: Recurrence Free Survival in all randomized subjects is the primary endpoint for this study.
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Secondary Endpoint: Overall survival is a key secondary endpoint. If RFS superiority is demonstrated, OS will be 
tested hierarchically.  
Analyses:  The primary analysis of RFS in all randomized subjects will be conducted using a two-sided log-
rank test stratified by PD-L1 status and stage. The hazard ratio and corresponding two-sided (1-adjusted α)% 
confidence interval (CI) will be estimated using a Cox proportional hazards model, with treatment arm as a covariate, 
stratified by the above factors. RFS medians with 95% CIs and RFS rates at 6, 12, 18, 24, and 36 months with 95% 
CIs will be estimated using Kaplan-Meier methodology.
An interim analysis of RFS will be conducted after all subjects have a minimum of 18 months of follow-up.
Approximately 350 RFS events are anticipated at this analysis. The stopping boundaries at the interim and final 
analyses will be derived based on the exact number of RFS events using Lan-DeMets alpha spending function with 
O’Brien-Fleming boundaries. No interim analysis of OS will be performed at this time.
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
 
 
 
 
SYNOPSIS .................................................................................................................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
 
 
 
 
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 ............................................................................... 
 
3.2 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..................................................................................... 
 
4.4 Method of Assigning Subject Identification ..................................................... 
 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
 
4.5.1 Dosing Schedule....................................................................................... 
 
4.5.2 Antiemetic Premedications ...................................................................... 
 
4.5.3 Dose Delay Criteria ................................................................................. 
 
4.5.4 Dose Omission Criteria for Nivolumab or Ipilimumab ........................... 
 
4.5.4.1 Adverse Event Management Algorithms for Immuno-Oncology 
Agents .................................................................................................... 
 
4.5.5 Dose Modifications .................................................................................. 
 
4.5.6 Criteria to Resume Treatment .................................................................. 
 
4.5.7 Discontinuation Criteria .......................................................................... 
 
4.5.8 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ...... 
 
4.6 Blinding/Unblinding ......................................................................................... 
 
4.7 Treatment Compliance ...................................................................................... 
 
4.8 Destruction of Study Drug ................................................................................ 
 
4.9 Return of Study Drug ........................................................................................ 
 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
 
5.2 Study Materials ................................................................................................. 
 
5.3 Safety Assessments ........................................................................................... 
 
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5.3.1 Imaging Assessment for the Study ........................................................... 
 
5.4 Efficacy Assessments ........................................................................................ 
 
5.4.1 Definitions ................................................................................................ 
 
5.4.2 Methods of measurements ........................................................................ 
 
5.4.3 Date of Recurrence .................................................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
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 Laboratory Test Result Abnormalities .............................................................. 
 
6.4 Pregnancy .......................................................................................................... 
 
6.5 Overdose ........................................................................................................... 
 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
 
6.7 Other Safety Considerations ............................................................................. 
 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
 
8 STATISTICAL CONSIDERATIONS....................................................................... 
 
8.1 Sample Size Determination ............................................................................... 
 
8.2 Populations for Analyses .................................................................................. 
 
8.3 Endpoints .......................................................................................................... 
 
8.3.1 Primary Endpoint(s) ................................................................................ 
 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
 
 
8.4 Analyses ............................................................................................................ 
 
8.4.1 Demographics and Baseline Characteristics........................................... 
 
8.4.2 Efficacy Analyses ..................................................................................... 
 
8.4.2.1 Primary Endpoint Methods ............................................................. 
 
8.4.2.2 Secondary Endpoint Methods ......................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
 
 
 
 
 
8.4.6 Outcomes Research Analyses .................................................................. 
 
8.5 Interim Analyses and Hierarchical Testing ....................................................... 
 
9 STUDY MANAGEMENT ........................................................................................ 
 
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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 .................................................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
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1
INTRODUCTION AND STUDY RATIONALE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
1.3
Objectives(s)
1.3.1
Primary Objectives
•
To compare the efficacy, as measured by RFS, provided by nivolumab versus ipilimumab in 
subjects with completely resected Stage IIIb/c or Stage IV NED melanoma who are at high 
risk for recurrence.
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1.3.2
Secondary Objectives
•
To compare the overall survival of nivolumab vs ipilimumab in subjects with completely 
resected Stage IIIb/c or Stage IV NED melanoma who are at high risk for recurrence.
•
To assess the overall safety and tolerability of nivolumab and ipilimumab in subjects with 
completely resected Stage IIIb/c or Stage IV NED melanoma who are at high risk for 
recurrence.
•
To evaluate whether PD-L1 expression is a predictive biomarker for RFS.
•
To evaluate the Health Related Quality of Life (HRQoL) as assessed by European Organisation 
for Research and Treatment of Cancer (EORTC) QLQ-C30.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have 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. 
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BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the informed consent form approved for 
the study prior to clinical study participation. The explicit wish of a minor, who is capable of 
forming an opinion and assessing this information to refuse participation in, or to be withdrawn 
from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
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3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
The subjects will be treated in both arms until disease recurrence, unacceptable toxicity, or subject
withdrawal of consent with a maximum of 1-year total duration of study medication.
Note: As of Dec-2016, all subjects in both treatment groups were off study treatment.
This study will consist of three phases: screening, treatment, and follow-up.
For a complete list of study required procedures, please refer to Section 5. 
Screening Phase:
•
Begins by establishing the subject’s initial eligibility and signing of the informed consent form 
(ICF).
•
Subject is enrolled using the IVRS. 
•
Subject is assessed for complete study eligibility within the required timeframe found in Table 
5.1-1.
•
A pregnancy test for WOCBP should be documented within 24 hours prior to the start of the 
first dose of study medication. 
•
Tumor tissue must be received at the Central Laboratory for PD-L1 IHC testing in order for 
the subject to be randomized. PD-L1 status will be used as a stratification factor. 
•
If Stage III, the pathology reports of clinically detectable node(s) confirming malignancy must 
be reviewed, dated, and signed by the investigator prior to randomization.
•
If Stage IV, the pathology report confirming negative margins must be reviewed, dated, and 
signed by the investigator prior to randomization.
High Risk, 
completely 
resected
Stage IIIb/c 
Stage  IV 
NED melanoma
Randomize 1:1
Stratify by
• Stage
• PD-L1 status
Arm A (n = 400)
Ipilimumab 10 mg/kg IV q3 wks for 4 doses
then q12 wks starting at Wk 24
and
Nivolumab placebo IV q2 wks
Arm B (n = 400)
Nivolumab 3 mg/kg IV q2 wks
and
Ipilimumab placebo IV q3 wks for 4 doses
Then q12 wks starting at Wk 24
Follow-up
Secondary
endpoint OS
For both arms, the treatment duration is maximum one year.
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Treatment Phase:
•
Following confirmation of the subject’s eligibility, the randomization call to the IVRS can be 
made. The subject is randomly assigned to the ipilimumab 10 mg/kg arm and placebo arm 
(Arm A), or the nivolumab 3 mg/kg arm and placebo arm (Arm B).
•
Within 3 business days from randomization the subject must receive the first dose of study 
medication (Day 1 of Week 1)
•
On-study laboratory assessments should be drawn within 72 hours prior to dosing
•
Adverse event assessments should be documented at each clinic visit and WOCBP must have 
a pregnancy test every four weeks ± 1 week.
•
PK samples and immunogenicity samples will be collected according to the schedule in Table 
5.5-1
•
Treated subjects will be evaluated for recurrence every 12 weeks ± 7 days 
•
Patient Reported Outcome (PRO) instruments must be completed after randomization, prior to 
the dose of study therapy and according to schedule in Table 5.1-2, Table 5.1-3, Table 5.1-4, 
and Table 5.1-6.
•
This phase ends when the subject is discontinued early from study therapy or at a maximum 
of 1 year of treatment. For a complete list of reasons for treatment discontinuation, see 
Section 3.5.
Follow- up Phase:
•
Begins after 1 year of treatment or when the decision is made to discontinue a subject from 
study therapy.
•
Follow-up visits (See Table 5.1-3) include collection of PK/immunogenicity samples.
•
After completion of the first two follow-up visits, subjects will be followed every 3 months for 
survival.
•
Subjects who discontinue treatment for reasons other than recurrence will continue to have 
surveillance assessments (until local, regional, or distant recurrence (whichever comes first)
recurrence for Stage IV subjects and until distant recurrence for Stage III subjects)
−
Surveillance assessments should occur every 12 weeks ± 7 days during the first year after 
randomization, every 12 weeks ± 14 days during the second year, every 
6 months ± 4 weeks between Year 3 and Year 5 with the last assessment at Year 5.
−
Study-specified surveillance imaging assessments will be discontinued beyond Year 5. 
Data on recurrence of melanoma (loco-regional and distant), as well as development of 
new primary melanomas and non-melanoma cancers after Year 5 will continue to be 
collected in the respective Case Report Forms.
•
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All toxicities will be documented for a minimum of 
100 days after the last dose of study medication.
•
PRO instruments will be completed according to the schedule in Table 5.1-6.
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The total duration of the study from start of randomization to the final survival follow-up visit is 
expected to be approximately 10 years.
The study will end once survival follow-up has concluded.
3.2
Post Study Access to Therapy
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol related procedures that are not part of normal subject care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, tumor biopsies, and other requirements of the study.
2) Target Population
a) All subjects must be either Stage IIIb/c or Stage IV American Joint Committee on Cancer 
(AJCC) Melanoma Staging (7th edition) and have histologically confirmed melanoma that 
is completely surgically resected in order to be eligible.  Subjects must have been surgically 
rendered free of disease with negative margins on resected specimens. Please refer to 
Appendix 1 or description of AJCC 7th editions of TNM and staging.
i)
If Stage III melanoma (whether Stage IIIb or IIIc) the subjects usually have clinically 
detectable lymph nodes that are confirmed as malignant on the pathology report and/or 
ulcerated primary lesions. Subjects who are “N2c” with 2-3 metastatic nodes and in 
transit metastases/satellites without metastatic nodes, or, “N3” classification with any 
“T” and 4+ metastatic nodes, or matted nodes, or in transit metastases/satellites with 
metastatic nodes are eligible. The pathology report for both Stage IIIb and IIIc must be 
reviewed, signed and dated by the investigator; this process will be confirmed during 
the IVRS randomization call.  Clinically detectable lymph nodes are defined as:
(1) A palpable node (confirmed as malignant by pathology)
(2) A non-palpable but enlarged lymph node by CT (at least 15 mm in short axis) and  
confirmed as malignant by pathology
(3) A PET positive lymph node of any size confirmed by pathology
(4) Evidence of pathologically macrometastatic disease in one or more lymph nodes 
defined by one or more foci of melanoma at least 1cm in diameter
ii) If Stage IV melanoma, the pathology report confirming negative margins must be 
reviewed, dated and signed by the investigator prior to randomization
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♦For CNS lesion(s), documentation, provided by a neurosurgeon, indicating that there 
has been complete resection of CNS lesion(s) will suffice as confirmation of negative 
margins  
b) All melanomas, except ocular/uveal melanoma, regardless of primary site of disease will 
be allowed; mucosal melanomas are eligible.
c) Complete resection of Stage III disease that is documented on the surgical and pathology 
reports or complete resection of Stage IV disease with margins negative that is documented 
on the pathology report.
d) The last intervention demonstrating that the subject is free of disease must be performed 
within 12 weeks prior to randomization.
e) Subjects must not have received anti-cancer treatment (for example but not limited to, 
systemic, local, radiation, radiopharmaceuticals) for their melanoma. 
3) Exceptions: Surgery for melanoma or/and post-resection brain RT if CNS metastases or/and 
prior treatment with adjuvant interferon under certain circumstances (as described in exclusion
criterion 2di)
a) All subjects must have disease-free status documented by a complete physical examination 
and imaging studies within 4 weeks prior to randomization.  Imaging studies must include 
CT scan of neck, chest, abdomen, pelvis, and all known sites of resected disease in the 
setting of Stage IIIb/c or Stage IV disease, and brain MRI (brain CT allowable if MRI is 
contraindicated or if there is no known history of resected brain lesions).
b) The complete set of baseline radiographic images must be available before randomization.
c) ECOG performance status score of 0 or 1 (Appendix 2)
d) Tumor tissue from the resected site of disease must be provided for biomarker analyses.  
In order to be randomized, a subject must have a PD-L1 expression classification (positive, 
negative, or indeterminate) as determined by the central lab. If insufficient tumor tissue 
content is provided for analysis, acquisition of additional archived tumor tissue (block and 
/or slides) for the biomarker analysis is required.   
e) Prior treated central nervous system (CNS) metastases must be without MRI evidence of 
recurrence for at least 4 weeks after treatment, subjects must be off immunosuppressive 
doses of systemic steroids (≥10 mg/day prednisone or equivalent) for at least 14 days prior 
to study drug administration, and must have returned to neurologic baseline 
post-operatively.
(1) The 4-week period of stability is measured after the completion of the neurologic 
interventions, ie surgery and/or radiation
f)
In addition to neurosurgery to treat CNS metastases, adjuvant radiation after the resection 
of CNS metastasis is allowed. Immunosuppressive doses of systemic steroids (doses 
≥10 mg/day prednisone or equivalent) must be discontinued at least 14 days before study 
drug administration
g) Prior surgery that required general anesthesia must be completed at least 4 weeks before 
study drug administration.  Surgery requiring local/epidural anesthesia must be completed 
at least 72 hours before study drug administration.  
h) All baseline laboratory requirements will be assessed and should be obtained within 
14 days of randomization. Screening laboratory values must meet the following criteria 
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i)
WBCs 
≥2000/μL
ii) Neutrophils 
≥1500/μL
iii) Platelets 
≥100 x 10³/μL
iv) Hemoglobin 
≥9.0 g/dL
v) Creatinine Serum creatinine ≤1.5 x upper limit of normal (ULN) or creatinine 
clearance > 40 mL/minute (using Cockcroft/Gault formula)
vi) AST 
≤3 x ULN 
vii)ALT 
≤3 x ULN
viii)
Total Bilirubin 
≤1.5 x ULN (except subjects with Gilbert Syndrome who 
must have total bilirubin < 3.0 mg/dL)
i)
Subject Re-enrollment:  This study permits the re-enrollment of a subject that has 
discontinued the study as a screen failure (ie, subject has not been randomized / has not 
been treated). If re-enrolled, the subject must be re-consented.
4) Age and Reproductive Status
a) Males and Females, ≥15 years of age
Except: where local regulations and/or institutional policies do not allow for subjects 
< 18 years of age (pediatric population) to participate. For those sites, the eligible subject 
population is ≥18 years of age
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
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug (s) plus 5 half-lives of study drug plus 30 days (duration of 
ovulatory cycle). The half-life of nivolumab and ipilimumab is up to 25 days and 18 days, 
respectively. Given the blinded nature of this study, WOCBP should therefore use an 
adequate method to avoid pregnancy for a total of 5 months post-treatment completion
(Appendix 3).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s) plus 
5 half-lives of the study drug (s) plus 90 days (duration of sperm turnover). The half-life 
of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. Given the blinded 
nature of this study, men should therefore use an adequate method of contraception for a 
total of 7 months post-treatment completion (Appendix 3).
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements.  However, they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
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Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
use of highly effective methods of contraception. Highly effective methods of contraception have 
a failure rate of < 1% when used consistently and correctly. (Refer to Appendix 3.)
3.3.2
Exclusion Criteria
1) Target Disease Exceptions
a) Subjects with carcinomatosis meningitis
b) History of ocular/uveal melanoma
2) Medical History and Concurrent Diseases
a) Subjects with previous non-melanoma malignancies are excluded unless a complete 
remission was achieved at least 3 years prior to study entry and no additional therapy is 
required or anticipated to be required during the study period (exceptions include but are 
not limited to, non-melanoma skin cancers; in situ bladder cancer, in situ gastric cancer, or
in situ colon cancers; in situ cervical cancers/dysplasia; or breast carcinoma in situ)
b) Subjects with active, known, or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring 
hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment are permitted to enroll.  For any cases of uncertainty, it is recommended 
that a BMS medical monitor be consulted prior to signing informed consent.
c) Subjects with a condition requiring systemic treatment with either corticosteroids (≥10 mg 
daily prednisone or equivalent) or other immunosuppressive medications within 14 days 
of study drug administration. Inhaled or topical steroids are permitted in the absence of 
active autoimmune disease.
d) Prior therapy for melanoma except surgery for the melanoma lesion(s) and except   
adjuvant RT after neurosurgical resection for CNS lesions and except for prior adjuvant 
interferon (see qualifier below). Specifically subjects who received prior therapy with anti-
PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including 
ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or 
checkpoint pathways) are not eligible.
i)
Prior treatment with adjuvant interferon is allowed if completed ≥6 months prior to 
randomization
e) Treatment directed against the resected melanoma (eg, chemotherapy, targeted agents, 
biotherapy, or limb perfusion) that is administered after the complete resection other than 
adjuvant radiation after neurosurgical resection.
f)
Any serious or uncontrolled medical disorder or active infection that, in the opinion of the 
investigator, may increase the risk associated with study participation, study drug
administration, or would impair the ability of the subject to receive protocol therapy.
3) Physical and Laboratory Test Findings
a) Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection.
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b) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).
4) Allergies and Adverse Drug Reaction
a) History of Grade ≥3 allergy to human monoclonal antibodies
5) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Pregnant or nursing women
d) Psychological, familial, sociological, or geographical conditions that potentially hamper 
compliance with the study protocol and follow-up schedule; those conditions should be 
discussed with the subject before registration in the trial
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 > 
40mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during 
the washout period, the woman can be considered postmenopausal:
−
1 week minimum for vaginal hormonal products (rings, creams, gels)
−
4 week minimum for transdermal products
−
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the treatment and follow-up phases (before 
recurrence) of the study (unless utilized to treat a drug-related adverse event):
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•
Immunosuppressive agents - only until treatment discontinuation
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 3.4.2) - only 
until treatment discontinuation
•
Any concurrent systemic anti-neoplastic therapy for the treatment of melanoma or a new 
malignancy (except as noted). Subjects who develop a new non-melanoma fully resectable 
malignancy (examples include but are not limited to: in situ bladder cancer, in situ gastric 
cancer, or in situ colon cancers; in situ cervical cancers/dysplasia; or breast carcinoma in situ; 
or prostate carcinoma) during the study may continue receiving study drugs if the only therapy 
required is hormonal therapy, surgery and/or radiation (and the surgery or radiation site does 
not overlap with a previous primary melanoma or melanoma metastasis location). Consultation 
with the medical monitor is required once a new malignancy is detected.
3.4.2
Permitted Therapy
Subjects are permitted the use of topical, ocular, intra-articular, intranasal and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted even if > 10 mg daily prednisone (or equivalent). A brief course of 
corticosteroids for prophylaxis (eg, for contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Intravitreal injections of vascular endothelial growth (VEGF) inhibitors are permitted if used 
according to the approved ocular indication, such as macular degeneration.
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
•
Recurrence (local, regional or distant)
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject
•
Termination of the study by Bristol Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Unblinding a subject for any reason (emergency or non-emergency)
•
Additional protocol specified reasons for discontinuation (see Section 4.5.7).
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
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All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
In this study, RFS and OS are key endpoints. 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 randomized subjects outside of the protocol 
defined window (Table 5.1-7). 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. 
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 
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representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for CA209238
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging/ 
Appearance
Storage Conditions
(per label)
BMS-936558-01 
(Nivolumab) Solution for 
Injection
100 mg (10 mg/mL)
IP
Open Labela
10 mL/vial (5 or 
10 vials/carton)
Store at 2° - 8°C.   
Protect from light and 
freezing.
Ipilimumab Solution for 
Injection
200 mg (5 mg/mL)
IP
Open Labela
40 mL/vial 
(4 vials/carton)
Store at 2° - 8°C.   
Protect from light and 
freezing.
0.9% Sodium Chloride 
for Injection
N/A
IP
Open Label
Various (local 
commercial product)
As per active IP
5%  Dextrose for 
Injection
N/A
IP
Open Label
Various (local 
commercial product)
As per active IP
a The term “open label” refers to the medication as it is upon receipt at the pharmacy.  The trial will be conducted in a double-blinded fashion.
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and 
permitted by local regulations. Solutions used as diluent or placebo (ie, 0.9% Sodium Chloride Injection or 5% Dextrose Injection) 
should also be sourced by investigative sites if available and permitted by local regulations.
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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, nivolumab placebo (0.9% 
sodium chloride injection or 5% dextrose injection), and ipilimumab placebo (0.9% sodium 
chloride injection or 5% dextrose injection).
4.2
Non-investigational Product
Not applicable.
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.
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).
For study drugs not provided by BMS and obtained commercially by the site, storage should be in 
accordance with the product label
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection, 5% dextrose 
injection) will not be supplied by the sponsor and should be purchased locally if permitted by local 
regulations.
Please refer to the current version of the Investigator Brochure (IB) and/or pharmacy reference 
sheets for complete storage, handling, dispensing, and infusion information for nivolumab and 
ipilimumab.
The unblinded pharmacist will obtain treatment assignment by IVRS and prepare blinded drug.
The infusion duration of nivolumab is 60 minutes and for ipilimumab 90 minutes. 
4.4
Method of Assigning Subject Identification
After the subject̓s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by calling an IVRS to obtain the subject number. Every 
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subject that signs the informed consent form must be assigned a subject number in IVRS. Specific 
instructions for using IVRS 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 IVRS, enrolled subjects that have met all eligibility criteria (the required tumor 
tissue received and result obtained by the central laboratory and the pathology report approved by 
the investigator) will be ready to be randomized through the IVRS. The randomization call will be 
performed by the unblinded pharmacy site staff. The following information is required for subject 
randomization:
•
Subject number
•
Date of birth
•
PD-L1 evaluable status
(Note that the result of PD-L1 positive vs PD-L1 
negative/indeterminate is entered by the central laboratory vendor and both the site and the 
BMS study team remain blinded to the result)
•
AJCC Stage and M classification
−
Stage IIIb/c
−
Stage IV M1a-M1b
−
Stage IV M1c.
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to Arm A ipilimumab + 
placebo or Arm B nivolumab + placebo stratified by the following factors: 
•
PD-L1 status
•
AJCC stage (M classification if Stage IV).
The exact procedures for using the IVRS will be detailed in the IVRS manual.
4.5
Selection and Timing of Dose for Each Subject
First dose must be administered within 3 business days following randomization. When study 
drugs (ipilimumab or nivolumab) or matched placebos are to be administered on the same day, 
separate infusion bags and filters must be used for each infusion. Nivolumab or nivolumab-placebo 
is to be administered first. The second infusion will always be the ipilimumab or ipilimumab-
placebo study drug, and will start no sooner than 30 minutes after completion of the nivolumab or 
nivolumab-placebo infusion.
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Subjects may be dosed up to ± 3 days before or after the scheduled date if necessary. There should 
be a minimum of 12 days between 2 nivolumab/nivolumab-placebo administrations. For dosing 
visits of Week 24, Week 36 and Week 48, subjects may be dosed up to ± 7 days.
4.5.1
Dosing Schedule
The Dosing schedule is described in Table 4.5.1-1 and Table 4.5.1-2. Weight should be used to 
calculate the dose and if the weight differs ≥10% from baseline, the dose should be recalculated. 
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Table 4.5.1-1:
Dosing Schedule 
Day 1 
Week 1
Day 1 
Week 3
Day 1 
Week 4
Day 1 
Week 5
Day 1 
Week 7
Day 1 
Week 9
Day 1 
Week 10
Day 1 
Week 11
Day 1 
Week 13
Arm A 
Ipilimumab  
+ 
Nivolumab
Placebo
3mg /kg 
Nivolumab-
Placebo 
3 mg/kg 
Nivolumab-
Placebo
10 mg/kg 
Ipilimumab
3 mg/kg 
Nivolumab-
Placebo
3mg /kg 
Nivolumab-
Placebo 
3 mg/kg 
Nivolumab-
Placebo
Ipi 10 mg/kg 
Ipilimumab
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
10 mg/kg
Ipilimumab
10 mg/kg 
Ipilimumab
Arm B 
Nivolumab 
+ 
Ipilimumab 
Placebo
3 mg/kg
Nivolumab
3 mg/kg 
Nivolumab
10 mg/kg
Ipilimumab-
Placebo
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
10 mg/kg
Ipilimumab-
Placebo
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
10 mg/kg
Ipilimumab-
Placebo
10 mg/kg
Ipilimumab-
Placebo
Day 1 
Week 15
Day 1 
Week 17
Day 1 
Week 19
Day 1 
Week 21
Day 1 
Week 23
Day 1 
Week 24
Day 1 
Week 25
Day 1 
Week 27
Day 1 
Week 29
Arm A 
Ipilimumab  
+ 
Nivolumab
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
10 mg/kg 
Ipilimumab
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
Arm B 
Nivolumab 
+ 
Ipilimumab 
Placebo
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
10 mg/kg
Ipilimumab-
Placebo
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
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Table 4.5.1-2:
Dosing Schedule 
Day 1 
Week 31
Day 1 
Week 33
Day 1 
Week 35
Day 1 
Week 36
Day 1 
Week 37
Day 1 
Week 39
Day 1 
Week 41
Day 1 
Week 43
Day 1 
Week 45
Arm A 
Ipilimumab
  + 
Nivolumab
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
10 mg/kg 
Ipilimumab
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
Arm B 
Nivolumab 
+ 
Ipilimumab 
Placebo
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
10 mg/kg
Ipilimumab-
Placebo
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
Day 1 
Week 47
Day 1 
Week 48
Day 1 
Week 49
Day 1 
Week 51
Arm A 
Ipilimumab  
+ 
Nivolumab
Placebo
3 mg/kg 
Nivolumab-
Placebo
10 mg/kg 
Ipilimumab
3 mg/kg 
Nivolumab-
Placebo
3 mg/kg 
Nivolumab-
Placebo
Arm B 
Nivolumab 
+ 
Ipilimumab 
Placebo
3 mg/kg 
Nivolumab
10 mg/kg
Ipilimumab-
Placebo
3 mg/kg 
Nivolumab
3 mg/kg 
Nivolumab
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If a subject cannot receive a dose within 3 days (or 7 days for dosing visits of Week 24, Week 36 
and Week 48) of its scheduled administration date, the dose should be completely omitted. There 
should be a minimum of 12 days between 2 nivolumab/nivolumab-placebo administrations. When 
the subject is able to re-initiate treatment, dosing should resume at the time of the next scheduled 
dose. Missed doses will not be replaced. 
4.5.2
Antiemetic Premedications
Antiemetic premedications should not be routinely administered prior to dosing of drugs. See 
Section 4.5.7 for premedication recommendations following a nivolumab or ipilimumab related 
infusion reaction.
4.5.3
Dose Delay Criteria
Dose delays will not be allowed.
4.5.4
Dose Omission Criteria for Nivolumab or Ipilimumab
Doses of nivolumab or ipilimumab should be omitted (not delayed) if any of the following criteria 
are met:
•
Any Grade 2 non-skin, drug-related adverse event, with the following exceptions:
−
Grade 2 drug-related fatigue or laboratory abnormalities do not require dose omission
−
Please note that endocrine abnormalities, eg, TSH depression, are not considered isolated 
laboratory abnormalities since they involve symptoms at Grade 2.  Therefore, endocrine 
adverse events of Grade 2 should lead to dose omission
•
Any Grade 3 skin, drug-related adverse event 
•
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, or total bilirubin: 
−
Grade 3 lymphopenia or leukopenia does not require dose omission
−
If a subject has baseline AST, ALT, or total bilirubin that is within normal limits, omit 
dosing for drug-related Grade ≥2 toxicity
−
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
omit dosing for drug-related Grade ≥3 toxicity
−
Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis do not require a dose omission. It is recommended that the 
BMS medical monitor be consulted for Grade 3 amylase or lipase abnormalities. 
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants omitting the dose of study medication.
If the criteria to resume treatment (specified in Section 4.5.6) are met within the dosing window 
(Day 1, Week X ± 3 days, Week 24, Week 36 and Week 48 ± 7 days), then the dose may be given.
Note: per BMS standards, the term “interruption” is reserved for interruption of the actual IV 
infusion during administration. The terms omission and interruption should not be used 
synonymously when completing the CRF forms.
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4.5.4.1
Adverse Event Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab and ipilimumab are 
considered immuno-oncology agents in this protocol. Early recognition and management of 
adverse events associated with immuno-oncology agents may mitigate severe toxicity. 
Management algorithms have been developed to assist investigators in assessing and managing 
the following groups of adverse events: gastrointestinal, renal, pulmonary, hepatic, 
endocrinopathies, skin and neurological. The management algorithms can be found in Appendix 4, 
and the nivolumab investigator brochure.
While the ipilimumab investigator brochure contains management algorithms for similar adverse 
events, the recommendations are to follow the adverse event management algorithms for I-O
agents in Appendix 4 and the nivolumab investigator brochure in order to standardize the safety 
management across the blinded treatment arms. 
For subjects expected to require more than 4 weeks of corticosteroids or other immunosuppressants 
to manage an adverse event, consider recommendations provided in Appendix 4 and in the 
nivolumab investigator brochure - Adverse Event Management Algorithms for I-O agents.
Immune-mediated AEs are specific events occurring within 100 days of the last dose (which 
includes pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, and endocrine 
abnormalities [adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes 
mellitus, and hypophysitis]), regardless of causality, for
which subjects received 
immunosuppressive medication for treatment of the event.  The exception to the 
immunosuppressive 
medication 
criteria 
for 
IMAEs 
is 
endocrine 
events 
(hypothyroidism/thyroiditis, 
hyperthyroidism, 
hypophysitis, 
diabetes 
mellitus, 
adrenal 
insufficiency), which are included regardless of treatment since these events are often managed 
without immunosuppression.
4.5.5
Dose Modifications
Dose reductions or dose escalations are not permitted.
All dose modification rules apply to both arms given the blinded nature of this study.
4.5.6
Criteria to Resume Treatment
All criteria to resume treatment for nivolumab and ipilimumab also apply for the placebo version 
of each agent, given the blinded nature of this study.
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 
or baseline value, 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 
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•
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose omissions for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the 
presence of Grade 2 AST/ALT OR Grade 2 total bilirubin
•
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 4.5.5) should have treatment permanently discontinued
•
Drug-related pulmonary toxicity, diarrhea, colitis, uveitis or neurological toxicity, must have 
resolved to baseline before treatment is resumed
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
timepoint per protocol. However, if the treatment is withheld past the window period of the next 
scheduled timepoint per protocol to ensure adequate recovery from the adverse event or tapering 
of immunosuppression, the dosing should continue to be withheld until the subsequent scheduled 
timepoint. 
If treatment is withheld > 6 weeks from the last dose, the subject must be permanently discontinued 
from study therapy, except as specified in Section 4.5.7.
4.5.7
Discontinuation Criteria
All discontinuation criteria for nivolumab and ipilimumab also apply for the placebo version of 
each agent, given the blinded nature of this study.
Treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within  3 weeks OR requires systemic 
treatment 
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic toxicity, hypersensitivity reactions, and infusion reactions:
−
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 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
AST or ALT > 8 x ULN
o
Total bilirubin > 5 x ULN
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
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•
Creatinine greater than 6 times ULN
•
Any severe or Grade 3 immune-mediated adverse reaction that recurs on reintroduction of 
nivolumab or ipilimumab, or an inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks
•
Persistent Grade 2 or 3 immune-mediated adverse drug reactions that do not recover to Grade 
1 or resolve within 12 weeks after the last dose of study drug
•
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:
−
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis. It is recommended to consult with the BMS Medical 
Monitor for Grade 4 amylase or lipase abnormalities.
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
•
Dosing that is withheld > 6 weeks from the last dose with the following exceptions:
−
Dosing omissions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing omission 
period lasting > 6 weeks from the last dose, the BMS medical monitor must be consulted. 
−
Dosing omissions > 6 weeks from the last 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 omission period lasting > 6 weeks from the last dose, the BMS 
medical monitor must be consulted. 
•
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 or 
ipilimumab dosing.
•
Tumor surveillance assessments, QoL questionnaires collection and biomarker sampling
should continue as per protocol even if dosing is omitted.
4.5.8
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, pruritis, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an SAE 
if criteria are met. Infusion reactions should be graded according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (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)
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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 paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before additional 
nivolumab or ipilimumab administrations.
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for ≤24 
hours).
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the infusion 
is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms resolve; 
if no further complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab or 
ipilimumab will be administered at that visit. Administer diphenhydramine 50 mg IV, and remain 
at bedside and monitor the subject until resolution of symptoms. The amount of study drug infused 
must be recorded on the electronic case report form (eCRF). The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 
and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 minutes 
before additional nivolumab or ipilimumab administrations. If necessary, corticosteroids 
(recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used.
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae [eg, 
renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; pressor or ventilatory support 
indicated). 
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg 
IV (or equivalent), as needed. Subject should be monitored until the investigator is comfortable 
that the symptoms will not recur. Nivolumab or ipilimumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. Remain 
at bedside and monitor subject until recovery from symptoms. In the case of late-occurring 
hypersensitivity symptoms (eg, appearance of a localized or generalized pruritis within 1 week 
after treatment), symptomatic treatment may be given (eg, oral antihistamine, or corticosteroids).
4.6
Blinding/Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. The management 
of adverse events for either nivolumab or ipilimumab is the same, according to the harmonized 
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adverse event management algorithms for I-O agents available in Appendix 4 and the nivolumab
investigator brochure. 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. 
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor. For example, for subjects that have recurrence and discontinue treatment the 
investigator may require knowledge of which treatment arm they were assigned to in order to 
appropriately select any post-recurrence subsequent therapy. See Section 1.4.8.5.
For this study, the method of unblinding is IVRS.
The Principal Investigator should only call in for unblinding AFTER the decision to discontinue 
the subject has been made.
For information on how to unblind for emergency, please consult the IVRS manual.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
In addition, designated staff of Bristol Myers Squibb Company 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 Company
(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.
To further minimize bias, the sponsor central study team and the investigative clinical site staff are 
blinded to results from PD-L1 analysis.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
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nivolumab
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s standard operating procedures (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. 
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CA209238
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nivolumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209238)
Procedure
Screening
Visit
(Day -28 till Day -1 prior to 
Randomization)
Notes
Eligibility Assessments
Informed Consent
x
Inclusion/Exclusion Criteria
x
All inclusion/exclusion criteria should be assessed during screening 
and confirmed prior to randomization.
Medical History
x
Review of pathology report
x
Stage III: The pathology report must be reviewed, signed and dated by 
the investigator prior to randomization.
Stage IV: The pathology report confirming negative margins must be 
reviewed, dated, and signed by the investigator prior to 
randomization.
 
 
Safety Assessments
Physical Examination
x
Including height
Vital Signs 
x
Including weight, blood pressure (BP), heart rate (HR), temperature 
Oxygen saturation
x
By pulse oximetry at rest and after exertion
Performance Status (ECOG)
x
Within 14 days prior to randomization
Assessment of Signs and Symptoms
x
Within 14 days prior to randomization
Electrocardiogram (ECG)
x
Within 14 days prior to randomization
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CA209238
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209238)
Procedure
Screening
Visit
(Day -28 till Day -1 prior to 
Randomization)
Notes
Laboratory Tests
x
On site/local complete blood count (CBC) w/differential, Chemistry 
panel including: LDH, AST, ALT, ALP, T.Bili, amylase, lipase, blood 
urea nitrogen (BUN) or serum urea level, creatinine, Ca, Mg, Na, K, 
Cl, Glucose, endocrine panel (TSH, Free T4, Free T3) within 14 days 
prior to randomization.
Hep B/C (HBV sAG, HCV antibody or HCV RNA) within 28 days 
prior to randomization
Pregnancy Test 
x
WOCBP only
Efficacy assessment
Surveillance assessments
x
CT scan neck, chest, abdomen, pelvis and all known sites of resected 
disease in the setting of Stage IIIb/c and Stage IV and brain MRI (brain 
CT allowable if MRI is contraindicated or if there is no known history 
of resected brain lesions).
Other
IVRS call
x
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CA209238
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Assessments Week 1 - Week 9 (CA209238)
Procedure
Day 1 
Week 1
Day 1 
Week 3
Day 1 
Week 4
Day 1 
Week 5
Day 1 
Week 7
Day 1 
Week 9
Notes
Safety Assessments
Targeted Physical Examination
x
x
x
x
x
x
To be performed within 72 hours prior to 
dosing
Vital Signs
x
x
x
x
x
x
Including  BP, HR, temperature  
Oxygen saturation
x
x
x
x
x
x
By pulse oximetry at rest and after exertion 
prior to dosing
Weight and performance status
x
x
x
x
x
x
Within 72 hours prior to dosing
Adverse Events Assessment
Continuously
Laboratory Tests
x
x
x
Within 72 hrs prior to dosing to include CBC 
w/differential, AST, ALT, ALP, T. Bili, BUN 
or serum urea level, creatinine, Ca, Mg, Na, K, 
Cl, LDH, Glucose, amylase, lipase, TSH (with 
reflexive Free T4 and Free T3)
Note: Laboratory tests do not need to be 
repeated if performed within 14 days prior to 
first dose
Pregnancy Test 
x
x
x
Within 24 hours prior to the initial 
administration of study drug, then every 
4 weeks ± 1 week. Serum or Urine
 
 
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CA209238
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Assessments Week 1 - Week 9 (CA209238)
Procedure
Day 1 
Week 1
Day 1 
Week 3
Day 1 
Week 4
Day 1 
Week 5
Day 1 
Week 7
Day 1 
Week 9
Notes
 
 
 
 
Efficacy Assessments
Surveillance Assessments
Every 12 weeks (± 7 days) from first dose of study treatment 
through 12 months (until local, regional, or distant recurrence 
[whichever comes first] for Stage IV subjects and until distant 
recurrence for Stage III subjects)
CT scan neck, chest, abdomen, pelvis and all 
known sites of resected disease in the setting of 
Stage IIIb/c and Stage IV and brain MRI (brain 
CT allowable if MRI is contraindicated or if 
there is no known history of resected brain 
lesions). Use same imaging method as was 
used at screening/baseline.
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CA209238
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Assessments Week 1 - Week 9 (CA209238)
Procedure
Day 1 
Week 1
Day 1 
Week 3
Day 1 
Week 4
Day 1 
Week 5
Day 1 
Week 7
Day 1 
Week 9
Notes
Study Drug
IVRS Randomize
x
Dispense Study Treatment (Active 
drug or placebo - blinded)
x
x
x
x
x
x
First dose to be administered within 3 business
days of randomization. See Section 4.3. 
Subsequent doses may be administered within 
3 days before or after the scheduled date if 
necessary.
Outcome Research Assessments
EORTC-QLQ-C30
x
x
x
Prior to dosing. D1W1 should be completed 
after randomization but prior to dosing.
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CA209238
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Week 10 - Week 19 (CA209238)
Procedure
Day 1 
Week 10
Day 1 
Week 
11
Day 1 
Week 
13
Day 1 
Week 
15
Day 1 
Week 
17
Day 1 
Week 
19
Notes
Safety Assessments
Targeted Physical Examination
x
x
x
x
x
x
Within 72 hours prior to dosing
Vital Signs
x
x
x
x
x
x
Including  BP, HR, temperature
Oxygen saturation
x
x
x
x
x
x
By pulse oximetry at rest and after exertion 
prior to dosing
Weight and performance status
x
x
x
x
x
x
Within 72 hours prior to dosing
Adverse Events Assessment
Continuously
Laboratory Tests
x
x
Within 72 hrs prior to dosing to include CBC 
w/differential, AST, ALT, ALP, T. Bili, BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, 
LDH, Glucose, amylase, lipase, TSH (with 
reflexive Free T4 and Free T3)
Pregnancy Test
x
x
Every 4 weeks ± 1 week. Serum or Urine
 
 
 
 
 
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CA209238
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Week 10 - Week 19 (CA209238)
Procedure
Day 1 
Week 10
Day 1 
Week 
11
Day 1 
Week 
13
Day 1 
Week 
15
Day 1 
Week 
17
Day 1 
Week 
19
Notes
 
 
 
 
Efficacy Assessments
Surveillance Assessments
Every 12 weeks (± 7 days) from first dose of study treatment 
through 12 months (until local, regional, or distant recurrence 
[whichever comes first] for Stage IV subjects; until distant 
recurrence for Stage III subjects)
CT scan neck, chest, abdomen, pelvis and all 
known sites of resected disease in the setting of 
Stage IIIb/c and Stage IV and brain MRI (brain 
CT allowable if MRI is contraindicated or if 
there is no known history of resected brain 
lesions). Use same imaging method as was used 
at screening/baseline.
Study Drug
Dispense Study Treatment (Active 
drug or placebo - blinded)
x
x
x
x
x
x
See Section 4.3. Subsequent doses may be 
administered within 3 days before or after the 
scheduled date if necessary.
Outcome Research Assessments
EORTC-QLQ-C30
x
x
Prior to dosing
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CA209238
BMS-936558
nivolumab
Table 5.1-4:
On-Treatment Assessments Week 21 - Week 29 (CA209238)
Procedure
Day 1 
Week 
21
Day 1 
Week 
23
Day 1 
Week 
24
Day 1 
Week 
25
Day 1 
Week 
27
Day 1 
Week 
29
Notes
Safety Assessments
Targeted Physical Examination
x
x
x
x
x
x
Within 72 hours prior to dosing
Vital Signs
x
x
x
x
x
x
Weight and  performance status
x
x
x
x
x
x
Within 72 hours prior to dosing
Oxygen saturation
x
x
x
x
x
x
By pulse oximetry at rest and after exertion prior 
to dosing
Adverse Events Assessment
Continuously
Laboratory Tests
x
x
x
Within 72 hrs prior to dosing to include CBC 
w/differential, AST, ALT, ALP, T. Bili, BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, 
LDH, Glucose, amylase, lipase, TSH (with 
reflexive Free T4 and Free T3)
Pregnancy Test
x
x
x
Every 4 weeks ± 1 week. Serum or Urine
 
 
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CA209238
BMS-936558
nivolumab
Table 5.1-4:
On-Treatment Assessments Week 21 - Week 29 (CA209238)
Procedure
Day 1 
Week 
21
Day 1 
Week 
23
Day 1 
Week 
24
Day 1 
Week 
25
Day 1 
Week 
27
Day 1 
Week 
29
Notes
 
 
 
Efficacy Assessments
Surveillance Assessments
Every 12 weeks (± 7 days) from first dose of study treatment 
through 12 months (until local, regional, or distant recurrence 
[whichever comes first] for Stage IV subjects and until distant 
recurrence for Stage III subjects)
CT scan neck, chest, abdomen, pelvis and all 
known sites of resected disease in the setting of 
Stage IIIb/c and Stage IV and brain MRI (brain 
CT allowable if MRI is contraindicated or if 
there is no known history of resected brain 
lesions). Use same imaging method as was used 
at screening/baseline.
Study Drug
Dispense Study Treatment (Active 
drug or placebo - blinded)
x
x
x
x
x
x
See Section 4.3. Subsequent doses may be 
administered within 3 days (7 days for Week 24)
before or after the scheduled date if necessary
Outcome Research Assessments
EORTC-QLQ-C30
x
Prior to dosing
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CA209238
BMS-936558
nivolumab
Table 5.1-5:
On-Treatment Assessments Week 31 - Week 39 (CA209238)
Procedure
Day 1 
Week 
31
Day 1 
Week 
33
Day 1 
Week 
35
Day 1 
Week 
36
Day 1 
Week 
37
Day 1 
Week 
39
Notes
Safety Assessments
Targeted Physical Examination
x
x
x
x
x
x
Within 72 hours prior to dosing
Vital Signs
x
x
x
x
x
x
Oxygen saturation
x
x
x
x
x
x
By pulse oximetry at rest and after exertion prior 
to dosing
Weight and performance status
x
x
x
x
x
x
Within 72 hours prior to dosing
Adverse Events Assessment
Continuously
Laboratory Tests
x
x
Within 72 hrs prior to dosing to include CBC 
w/differential, AST, ALT, ALP, T. Bili, BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, 
LDH, Glucose, amylase, lipase, TSH (with 
reflexive Free T4 and Free T3)
Pregnancy Test
x
x
Every 4 weeks ± 1 week. Serum or Urine
 
 
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CA209238
BMS-936558
nivolumab
Table 5.1-5:
On-Treatment Assessments Week 31 - Week 39 (CA209238)
Procedure
Day 1 
Week 
31
Day 1 
Week 
33
Day 1 
Week 
35
Day 1 
Week 
36
Day 1 
Week 
37
Day 1 
Week 
39
Notes
 
 
Efficacy Assessments
Surveillance Assessments
Every 12 weeks (± 7 days) from first dose of study treatment 
through 12 months (until local, regional, or distant recurrence 
[whichever comes first] for Stage IV subjects and until distant 
recurrence for Stage III subjects)
CT scan neck, chest, abdomen, pelvis and all 
known sites of resected disease in the setting of 
Stage IIIb/c and Stage IV, and brain MRI (brain 
CT allowable if MRI is contraindicated or if 
there is no known history of resected brain 
lesions). Use same imaging method as was used 
at screening/baseline.
Study Drug
Dispense Study Treatment (Active 
drug or placebo - blinded)
x
x
x
x
x
x
See Section 4.3. Subsequent doses may be 
administered within 3 days (7 days for Week 36) 
before or after the scheduled date if necessary.
Outcome Research Assessments
EORTC-QLQ-C30
x
Prior to dosing
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CA209238
BMS-936558
nivolumab
Table 5.1-6:
On-Treatment Assessments Week 41 - Week 51 (CA209238)
Procedure
Day 1 
Week 
41
Day 1 
Week 
43
Day 1 
Week 
45
Day 1 
Week 
47
Day 1 
Week 
48
Day 1 
Week 
49
Day 1 
Week 
51
Notes
Safety Assessments
Targeted Physical Examination
x
x
x
x
x
x
x
Within 72 hours prior to dosing
Vital Signs
x
x
x
x
x
x
x
Weight and  performance status
x
x
x
x
x
x
x
Within 72 hours prior to dosing
Oxygen saturation
x
x
x
x
x
x
x
By pulse oximetry at rest and after exertion prior 
to dosing
Adverse Events Assessment
Continuously
 
x
x
x
x
x
Laboratory Tests
x
x
x
Within 72 hrs prior to dosing to include CBC 
w/differential, AST, ALT, ALP, T. Bili, BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, 
LDH, Glucose, amylase, lipase, TSH (with 
reflexive Free T4 and Free T3)
ACTH at Week 45 in subjects receiving 
ipilimumab/ ipilimumab-placebo at Week 48
(note that all subjects will have completed 36
weeks at the time of implementation)
Pregnancy Test
x
x
x
Every 4 weeks ± 1 week. Serum or Urine.
 
 
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CA209238
BMS-936558
nivolumab
Table 5.1-6:
On-Treatment Assessments Week 41 - Week 51 (CA209238)
Procedure
Day 1 
Week 
41
Day 1 
Week 
43
Day 1 
Week 
45
Day 1 
Week 
47
Day 1 
Week 
48
Day 1 
Week 
49
Day 1 
Week 
51
Notes
 
 
 
 
 
Efficacy Assessments
Surveillance Assessments
Every 12 weeks (± 7 days) from first dose of study 
treatment through 12 months (until local, regional, or 
distant recurrence [whichever comes first] for Stage IV
subjects and until distant recurrence for Stage III subjects)
CT scan neck, chest, abdomen, pelvis and all 
known sites of resected disease in the setting of 
Stage IIIb/c and Stage IV and brain MRI (brain 
CT allowable if MRI is contraindicated or if there 
is no known history of resected brain lesions). 
Use same imaging method as was used at 
screening/baseline.
Study Drug
Dispense Study Treatment 
(Active drug or placebo - blinded)
x
x
x
x
x
x
x
See Section 4.3. Subsequent doses may be 
administered within 3 days (7 days for Week 48)
before or after the scheduled date if necessary.
Note: As of Dec-2016, all subjects in both 
treatment groups were off study treatment.
Outcome Research Assessments
EORTC-QLQ-C30
x
Prior to dosing
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CA209238
BMS-936558
nivolumab
Table 5.1-6:
On-Treatment Assessments Week 41 - Week 51 (CA209238)
Procedure
Day 1 
Week 
41
Day 1 
Week 
43
Day 1 
Week 
45
Day 1 
Week 
47
Day 1 
Week 
48
Day 1 
Week 
49
Day 1 
Week 
51
Notes
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Date: 14-Oct-2020
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CA209238
BMS-936558
nivolumab
Table 5.1-7:
Follow-Up Procedural Outline (CA209238)
Procedure
Follow-up, 
Visits 1 and 2a
Survival, Follow up Visitsb
Notes
Safety Assessments
Targeted Physical Examination
x
Adverse Events Assessment
x
x
See Section 6.2.1. Immune-mediated adverse reactions should 
be followed until stabilization.
Nonimmune-mediated adverse reactions should be followed 
until resolution or stabilization.
Laboratory Tests
x
Laboratory toxicities (eg, suspected drug induced liver enzyme 
elevations) will be monitored during the follow-up phase, based 
on results from on-site/local labs, until all study drug related 
toxicities resolve, return to baseline, or are deemed irreversible.
Pregnancy Test
x
Serum or urine
 
Outcome Research Assessments
EORTC-QLQ-C30
x
 
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Date: 14-Oct-2020
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CA209238
BMS-936558
nivolumab
Table 5.1-7:
Follow-Up Procedural Outline (CA209238)
Procedure
Follow-up, 
Visits 1 and 2a
Survival, Follow up Visitsb
Notes
Efficacy Assessments
Surveillance Assessment
•
Every 12 weeks (± 7 days) < 12 months
•
Every 12 weeks (± 14 days) > 12 months 
through 24 months
•
Every 6 months (± 4 weeks) > 24 months 
through and up to Year 5
Until local, regional, or distant recurrence 
(whichever comes first) for Stage IV
subjects and until distant recurrence for 
Stage III subjects.
All time points are relative to the first dose 
of study treatment.
CT scan neck, chest, abdomen, pelvis and all known sites of 
resected disease in the setting of Stage IIIb/c and Stage IV and 
brain MRI (brain CT allowable if MRI is contraindicated or if 
there is no known history of resected brain lesions). Use same 
imaging method as was used at screening/baseline.
Note: If a subject starts systemic therapy for melanoma 
recurrence after study drug discontinuation, follow-up scans 
should be discontinued. If a subject starts systemic therapy for a 
new non-melanoma tumor after study drug discontinuation, 
follow-up scans can be done as per standard of care.
Effective Revised Protocol 06: Although study-specified
surveillance assessments will not be conducted beyond Year 5, 
data on recurrence of melanoma (loco-regional and distant), as 
well as development of new primary melanomas and non-
melanoma cancers will continue to be collected in the respective 
Case Report Forms. Subjects will be queried for this data during 
the routine survival status follow-up. This data will also be 
collected retrospectively to account for any time interval 
between the subject's Year 5 time point and approval of Revised 
Protocol 06 by ECs/IRBs.
Survival status
Survival status
x
x
Every 3 months (± 14 days), maybe accomplished by visit or 
phone contact,c to include subsequent anti-cancer therapy. The 
frequency and mode of contact applies to the extended follow-up 
period as well. This data will be collected retrospectively to 
Revised Protocol No: 06
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CA209238
BMS-936558
nivolumab
Table 5.1-7:
Follow-Up Procedural Outline (CA209238)
Procedure
Follow-up, 
Visits 1 and 2a
Survival, Follow up Visitsb
Notes
account for any time interval between the subject's Year 5 time 
point and approval of Revised Protocol 06 by ECs/IRBs.
 
 
 
 
 
 
 
 
 
a Follow-up visit 1 (FU1) = 30 days (± 7 days) from the last dose or coincide with the date of discontinuation (± 7days) if date of discontinuation is greater than 
37 days after last dose, Follow-up visit 2 (FU2) = 84 days (± 7 days) from follow-up visit 1
b First Survival Follow-up visit 3 months (± 14 days) after FU2
c Phone contacts during the survival follow-up visits are only allowed at time periods between surveillance assessment visits.
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CA209238
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nivolumab
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening will be 
permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, 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. 
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultation with 
the Medical Monitor may be needed to identify whether repeat testing of any particular parameter 
is clinically relevant.
5.2
Study Materials
•
NCI CTCAE version 4.0
•
Nivolumab Investigator Brochure
•
Ipilimumab Investigator Brochure
•
Pharmacy binder
•
Laboratory manuals for collection and handling of blood (including biomarker and 
immunogenicity) and tissue specimens
•
Site manual for operation of IVRS, including enrollment/randomization worksheets
•
Manual for entry of local laboratory data
•
Pregnancy Surveillance Forms
•
PRO instruments.
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, BP, HR, 
temperature and oxygen saturation by pulse oximetry at rest and after exertion and should be 
performed as noted in Table 5.1-1 Notes. Baseline signs and symptoms are those that are assessed 
within 14 days prior to randomization. Concomitant medications will be collected from within 
14 days prior to randomization through the study treatment period and follow-up visits 1 and 2. 
(See Tables from Section 5.1.) During the Survival Follow-up visits subsequent only anti-cancer 
therapy will be collected.
Baseline local laboratory assessments should be done within 14 days prior to randomization to 
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, Free T4, 
Free T3; Hep B and C testing (HBV sAg, HCV RNA, HCV antibodies) should be assessed within 
28 days prior to randomization (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 4 weeks (± 1 week) during the treatment phase. 
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Date: 14-Oct-2020
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CA209238
BMS-936558
nivolumab
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 5.1-7, 
toxicity assessments should be done in person. Once subjects reach the survival follow-up phase 
either in person or documented telephone calls (telephone calls are only allowed during times 
where no surveillance assessments are to be done) to assess the subject’s status are acceptable. 
Adverse events and laboratory values will be graded according to the NCI CTCAE version 4.0.
On-study weight and ECOG Performance status and vital signs should be assessed on at each 
on-study visit .Vital signs should also be taken as per institutional standard of care prior to, during 
and after dosing. Oxygen saturation by pulse oximetry at rest and after exertion should be assessed 
at each on study visit prior to dosing. The start and stop time of the blinded infusions should be 
documented. Physical examinations are to be performed as clinically indicated. 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.
On study local laboratory assessments should be done within 72 hours prior to dosing (laboratory 
tests should not be repeated if performed within 14 days prior to the first dose) to 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. Adrenocorticotropic hormone (ACTH) will be assessed at Week 45 prior to 
ipilimumab/ ipilimumab placebo administration at Week 48, since all subjects will be past the 
36 weeks’ timepoint. 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. 
Oxygen saturation by pulse oximetry should be obtained prior to each dosing and at any time a 
subject has any new or worsening respiratory symptoms. Accurate recording and documentation 
of oxygen saturation at two different activity levels is important because drug-related pulmonary 
toxicity can present initially as lower than baseline oxygen saturation.  A reading at rest and on 
exertion should be obtained at each time point. The extent of the exertion should be based on the 
judgment of the investigator, but should remain consistent for each individual subject throughout 
the study. If the subject’s status changes, the investigator can alter the extent of exertion based on 
their medical judgment. If a subject shows changes on pulse oximetry or other pulmonary related 
signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, fever) consistent with possible pulmonary 
adverse events, the subject should be immediately evaluated to rule out pulmonary toxicity. An 
algorithm for the management of suspected pulmonary toxicity can be found in Appendix 4 or the 
nivolumab investigator brochure.
Some of the previously referred to assessments 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.
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5.3.1
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.  Baseline disease 
assessments should be performed within 28 days prior to the first dose utilizing CT or MRI.  This 
includes a CT scan of neck, chest, abdomen, pelvis and all known sites of resected disease in the 
setting of Stage IIIb/c and Stage IV, and brain MRI (brain CT allowable if MRI is contraindicated 
or if there is no known history of resected brain lesions). Subjects will be evaluated for presence 
or continued lack of tumor until local, regional, or distant recurrence (whichever comes first) for 
Stage IV subjects and until distant recurrence for Stage III subjects beginning 12 weeks (± 7 days) 
relative to the first dose of study treatment, and will continue to have surveillance assessment every 
12 weeks (± 7 days) for the first 12 months. From > 12 months to 24 months after randomization, 
efficacy assessments should be every 12 weeks (± 14 days). From > 24 months until Year 5 after 
first dose of study treatment, efficacy assessments should be performed every 6 months (± 4 
weeks).  
If a subject starts systemic therapy for melanoma recurrence after study drug discontinuation, 
follow-up scans should be discontinued. If a subject starts systemic therapy for a new non-
melanoma tumor after study drug discontinuation, follow-up scans can be done as per standard of 
care.
5.4.1
Definitions 
Recurrence is defined as the appearance of one or more new melanoma lesions, which can be local, 
regional, or distant in location from the primary resected site.  
Local Cutaneous Recurrence:
Local cutaneous recurrence after adequate excision of the primary melanoma is associated with 
aggressive tumor biologic features and is frequently a harbinger of metastases.
Regional Lymphatic and Nodal Recurrences:
The neoplastic nature of the regional recurrences should be attempted and confirmed by 
histology/cytology.
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•
In Transit Metastases: In transit metastases represents the clinical manifestations of small 
tumor emboli trapped within the dermis and subdermal lymphatics between the site of the 
primary tumor and the regional lymph node drainage basin(s).  In extremities, in transit 
metastases can also occur distal to the site of the primary lesion as a result of reversed 
lymphatic flow.  In transit metastases occur in 10% to 15% in patients with Stage III disease.  
Although previous staging systems distinguished between the small satellitosis (within 2 cm 
of the primary tumor), pathophysiologically these two events represent different points on a 
continuum of the same biologic process.  When present, in transit metastases are usually 
multiple, evolve over time, and, as previously stated, are often the harbinger of subsequent 
systemic disease.
•
Regional Node Recurrences: Regional node failure in a previously dissected basin is usually 
found at the periphery of the prior surgical procedure.
Patterns of Metastases:
Melanoma is well known for its ability to metastasize to virtually any organ or tissue.  The most 
common initial sites of distance metastases are the non-visceral (skin, subcutaneous tissue, and 
lymph nodes), which are recurrence sites for 42% to 59% of subjects in various studies.  Visceral 
locations are the lung, brain, liver, gastrointestinal tract, and bone; the visceral sites are the initial 
sites of relapse in approximately 25% of all melanoma patients who experience recurrence.
Measurable Disease per RECIST 1.1:
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 examination (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable)
•
20 mm by chest x-ray.
Malignant lymph nodes: to be considered pathologically enlarged and measurable per 
RECIST 1.1, 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).  
If the measurable disease is restricted to a solitary lesion (visceral or nodal), its neoplastic nature 
must be confirmed either by cytology/histology or by lesion progression certified on the next 
CT/MRI examination.
Nonmeasurable Disease per RECIST 1.1:
Nonmeasurable lesions include all other lesions, including small lesions (longest diameter 
< 10 mm or pathological lymph nodes with ≥10 and < 15 mm short axis), as well as truly 
nonmeasurable lesions.  Lesions considered truly nonmeasurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement of 
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skin or lung, and abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques.
Note:
•
Cutaneous relapses occurring beyond the periphery of the previous surgical bed (ie, over 2 cm) 
are considered distant metastases.
•
Node relapses occurring beyond the anatomical compartment of the dissected basins are 
considered distant metastases.
•
Node relapses in nodal basins situated in a different anatomical compartment or beyond the 
previously dissected basin or in two nodal basins (even if contiguous; ie, 2 pelvic nodal basines, 
2 mediastinal nodal basins) are considered distant metastases.
5.4.2
Methods of measurements 
•
CT and MRI are an essential part of the work-up to establish recurrence. Conventional CT with 
IV contrast and MRI gadolinium should be performed with contiguous cuts of 10 mm or less 
slice thickness. Spiral CT should be performed using a 3- or 5-mm contiguous reconstruction 
algorithm; this specification applies to the tumors of the chest, abdomen and pelvis while head 
& neck tumors and those of the extremities usually require specific protocols. In each institute 
the same technique for CT/MRI should be used to characterize each new lesion.
−
For subjects allergic to contrast media, they may have a CT performed without contrast 
after discussion and agreement with the medical monitor
•
PET alone will not be considered for the disease assessment. Complementary CT and/or MRI 
or biopsy must be performed in such cases.
•
Cytology and/or histology are mandatory to confirm recurrence in solitary or in doubtful 
lesions, cutaneous, subcutaneous or lymph node lesions. Histological or cytological evidence 
of recurrence should be attempted in all cases except for brain metastases when safe and 
clinically feasible.  An example when obtaining a biopsy to confirm recurrence may not be 
safe and clinically feasible is brain metastases.
•
Clinically detected new lesions:
−
Superficial cutaneous lesions: the neoplastic nature must be confirmed by
cytology/histology.
−
Deep subcutaneous lesions and lymph node lesions should be documented by ultrasound 
and histological/cytological evidence should be attempted. In absence of pathology report, 
lesion recurrence will be documented with a CT scan/MRI.
•
Tumor markers or auto-antibodies alone cannot be used to assess recurrence.
5.4.3
Date of Recurrence
The first date when recurrence was observed is taken into account regardless the method of 
assessment. Therefore recurrence will be declared for any lesion when:
•
Only imaging was performed and recurrence confirmed
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•
Only pathology was done and malignancy confirmed (in solitary or in doubtful lesions, 
cutaneous, subcutaneous or lymph node lesions)
•
Both pathology and imaging were done and recurrence/malignancy confirmed. In this case, the 
date of whichever examination comes first is considered the date of recurrence.
Pathology reports of biopsies confirming recurrence should be sent to a central vendor.
Note: for documentation, the date of recurrence is the date that the pathology and/or imaging 
confirms recurrence--not the date that the information was communicated to the subject.
 
 
 
 
 
 
 
 
 
 
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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 melanoma clinical studies. It is a 30-item instrument that has 
gained wide acceptance in oncology clinical studies. The EORTC QLQ-C30 comprises 
5 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 1 (Not at all) to 4 (Very much). The overall health 
status/quality of life responses are 7-point Likert scales. 
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All PRO instruments will be administered during on-study, and follow-up phases as outlined in 
Table 5.1-2, Table 5.1-3, Table 5.1-4, Table 5.1-5, Table 5.1-6, and Table 5.1-7, respectively, to 
all randomized 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 asked as outlined in Tables of Section 5.1 during 
screening, on-study, and follow-up phases, respectively.
As of Revised Protocol 06, collection of EQ-5D-3L is not required during extended survival 
follow-up. Additional sample collection is unlikely to change interpretation of biomarker 
data that have already been analyzed.
 
 
 
 
  
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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. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
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hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
−
elective surgery, planned prior to signing consent
−
admissions as per protocol for a planned medical/surgical procedure
−
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).
−
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s or the legal representative’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. Subjects who are 
randomized and never treated with study drug, must have SAEs 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). 
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The investigator should report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours 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. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, the 
original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE (not only those deemed to be treatment-related) information 
should begin at initiation of study drug and continue until 100 days from the last dose of study 
drug. Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
withholding or discontinuation of study drug and for those present at the end of study treatment as 
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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. Every adverse event must be assessed by the 
investigator with regards to whether it is considered immune mediated. For events which are 
potentially immune mediated, additional information will be collected on the subject’s case report 
form.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug omitted or 
discontinued 
•
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).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half 
lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
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Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
•
AT (ALT or AST) elevation > 3 times ULN
AND
•
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
•
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A Data Monitoring Committee (DMC) will be established to provide oversight of safety and 
efficacy considerations in protocol CA209238. Additionally, the DMC will provide advice to the 
sponsor regarding actions the committee deems necessary for the continuing protection of subjects 
enrolled in the study. The DMC will be charged with assessing such actions in light of an 
acceptable benefit/risk profile for nivolumab and ipilimumab. The DMC will act in an advisory 
capacity to BMS and will monitor subject safety and evaluate the available efficacy data for the 
study. The oncology therapeutic area of BMS has primary responsibility for design and conduct 
of the study. 
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When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
The final DMC meeting occurred on 28-Apr-2020. 
8
STATISTICAL CONSIDERATIONS
As of Revised Protocol 06, all planned analyses were conducted based on the 48-month minimum 
follow-up database lock, which occurred in Jan-2020. No additional formal efficacy analyses will 
be conducted for newly collected efficacy data. Exploratory analysis on these new efficacy data 
will be conducted using similar analyses described in the Clinical Study Report (CSR) Statistical 
Analysis Plan (SAP) for the 48-month minimum follow-up database lock. Exploratory analyses 
will be performed, eg, every other year, though the analysis schedule might be adjusted based on 
the additional number of events accumulated.
8.1
Sample Size Determination
The sample size is calculated to compare RFS between subjects randomized to receive nivolumab 
vs ipilimumab. RFS will be evaluated for a treatment effect at an overall alpha level of 0.05 (two-
sided) with approximately 85% power. The number of events and power were calculated assuming 
a delayed treatment effect and cure fraction. 
Approximately 900 subjects have been randomized to the two treatment arms in a 1:1 ratio. Based 
on current accrual and revised piece-wise accrual rate assumptions, accrual duration was 7.5 
months. Taking into account the actual AJCC disease stage distribution, slower event rate, higher 
cure rates, and some early drop-out, the original planned 507 events might not be reached by the 
final RFS analysis (ie, after all subjects have a minimum of 36 months of follow-up). 
Approximately 450 RFS events are anticipated at the final RFS analysis, ensuring at least 85% 
power to detect a hazard ratio of 0.75 (critical hazard ratio of 0.83) with an overall type I error of 
0.05 (two-sided). Sample size calculations for this study design were done using EAST 6 (v 6.3.1) 
and R.
An interim analysis of RFS will take place after all subjects have a minimum of 18 months of 
follow-up. Approximately 350 RFS events are anticipated at this analysis. The stopping boundary 
at the interim analysis will be derived based on the exact number of RFS events at interim using 
Lan-DeMets alpha spending function with O’Brien-Fleming boundaries. With an interim RFS 
analysis at 350 RFS events (about 78% information fraction), the critical hazard ratio would be 
0.78 and the type I error would be 0.022 (two-sided). The type I error to be used for final RFS 
analysis would be 0.043 (two-sided). 
8.2
Populations for Analyses
•
All enrolled subjects: All subjects who signed an informed consent form and were registered 
into the IVRS.
•
All randomized subjects: All subjects who were randomized to any treatment arm in the study. 
•
All treated subjects: All subjects who received any study drug nivolumab or ipilimumab
including placebo doses.
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•
 
 
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary endpoint is RFS. The primary endpoint of RFS will be programmatically determined 
based on the disease recurrence date provided by the investigator and is defined as the time 
between the date of randomization and the date of first recurrence (local, regional or distant 
metastasis), new primary melanoma, or death (whatever the cause), whichever occurs first. (Note: 
a subject who dies without reported recurrence will be considered to have recurred on the date of 
death.) For subjects who remain alive and whose disease has not recurred, RFS will be censored 
on the date of last evaluable disease assessment. For those subjects who remained alive and had 
no recorded post-randomization tumor assessment, RFS will be censored on the day of 
randomization. Censoring rules for the primary analysis of RFS are presented in Table 8.3.1-1.
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Table 8.3.1-1:
Censoring Scheme for Primary Definition of RFS
Situation
Date of Event or Censoring
Outcome
Recurrence (local, regional, distant, new primary 
melanoma)
Date of first recurrence
Event
Death without recurrence
Date of death
Event
Disease at baseline
Date of randomization
Event
No baseline disease assessment
Date of randomization
Censored
No on-study disease assessments and no death
Date of randomization
Censored
No recurrence and no death
Date of last evaluable disease 
assessment
Censored
New anticancer therapy, tumor-directed 
radiotherapy, or tumor-directed surgery received 
without recurrence reported prior to or on the 
same day of disease assessment
Date of last evaluable disease 
assessment prior to or on the same 
date of initiation of subsequent 
therapy
Censored
Second non-melanoma primary cancer reported 
prior or on the same day of disease assessment
Date of last evaluable disease 
assessment prior to or on the same 
date of diagnosis of second non-
melanoma primary cancer
Censored
RFS, recurrence-free survival
As of Revised Protocol 06, since no study-specified surveillance assessments are to be collected 
beyond Year 5, the censoring rules for defining RFS will be different from the primary definition 
above. RFS will be defined as the time between the date of randomization and the date of first 
recurrence (local, regional, or distant metastasis), new primary melanoma, or death (whatever the 
cause), whichever occurs first. (Note: A subject who dies without reported recurrence will be 
considered to have recurred on the date of death.) For subjects who remain alive and whose disease 
has not recurred, RFS will be censored on the last date the subject was known to be alive. 
Censoring rules for the exploratory analysis of RFS are presented in Table 8.3.1-2.
Table 8.3.1-2:
Censoring Scheme for Definition of RFS
Situation
Date of Event or Censoring
Outcome
Recurrence (local, regional, distant, new primary 
melanoma)
Date of first recurrence
Event
Death without recurrence
Date of death
Event
Disease at baseline
Date of randomization
Event
No baseline disease assessment 
Date of randomization
Censored
No on-study disease assessments and no death
Date of randomization
Censored
No recurrence and no death
Date last known to be alive
Censored
New anticancer therapy, tumor-directed 
radiotherapy, or tumor-directed surgery received 
Date of initiation of subsequent 
therapy
Censored
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Table 8.3.1-2:
Censoring Scheme for Definition of RFS
Situation
Date of Event or Censoring
Outcome
without recurrence reported prior to or on the 
same day of disease assessment
Second non-melanoma primary cancer reported 
prior or on the same day of disease assessment
Date of diagnosis of second non-
melanoma primary cancer
Censored
RFS, recurrence-free survival
8.3.2
Secondary Endpoint(s)
The first secondary endpoint (OS) is defined as the time between the date of randomization and 
the date of death. For subjects without documentation of death, OS will be censored on the last 
date the subject was known to be alive. 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 second secondary endpoint (to assess the safety and tolerability of nivolumab and ipilimumab) 
will be measured by the incidence of adverse events, serious adverse events, deaths, and laboratory 
abnormalities.
The third secondary endpoint (to evaluate PD-L1 expression as a predictive biomarker) will be 
measured by the endpoint RFS based on PD-L1 expression level.
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 in all randomized subjects.  
 
 
 
 
 
 
 
 
 
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment arm as randomized 
using descriptive statistics for all randomized subjects.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Endpoint Methods
The primary RFS analyses will be conducted using a two-sided log-rank test stratified by PD-L1 
status and Stage at screening in randomized subjects. The hazard ratio and corresponding 
two-sided (1-adjusted α)% CI will be estimated using a Cox proportional hazards model, with 
treatment group as a single covariate, stratified by the above factors. RFS curves, RFS medians 
with 95% CIs, and RFS rates at 6, 12, 18, 24 and 36 months with 95% CIs will be estimated using 
Kaplan-Meier methodology.
8.4.2.2
Secondary Endpoint Methods
The secondary OS analysis will be conducted using a two-sided log-rank test stratified by PD-L1 
status and Stage at screening in randomized subjects. The hazard ratio and corresponding 
two-sided (1-adjusted α)% CI will be estimated using a Cox proportional hazards model, with 
treatment arm as a single covariate, stratified by the above factors. OS curves, OS medians with 
95% CIs and OS rates at 12 and 24 months with 95% CIs will be estimated using Kaplan-Meier 
methodology. 
To evaluate PD-L1 expression as a predictive biomarker, a Cox proportional hazards model will 
be used to test the interaction between PD-L1 expression (positive vs negative) and treatment arm 
for the RFS endpoint. Additionally, RFS will be analyzed within each PD-L1 expression subgroup 
(positive and negative) including log-rank tests and hazard ratios with corresponding confidence 
intervals. RFS curves and medians will be estimated using Kaplan-Meier methodology. These 
analyses will be descriptive and not adjusted for multiplicity. Other exploratory analyses, such as 
associations between PD-L1 expression and other efficacy endpoints and evaluations of different 
thresholds for PD-L1 positivity, will also be planned in the SAP.
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.0 by treatment group. All on-study AEs, treatment-related 
AEs, SAEs, and treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v 4.0 
criteria by system organ class and preferred term. On-study lab parameters including hematology, 
chemistry, liver function, and renal function will be summarized using worst grade NCI CTCAE 
v 4.0 criteria.
 
 
 
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8.4.6
Outcomes Research Analyses
EORTC QLQ C-30
The analysis of EORTC QLQ C-30 will be performed in all randomized who have an assessment 
at baseline and at least one follow-up assessment.
All scales and single items are scored on a categorical scales 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 
status/quality of life and higher scores for a symptom scale representing higher level of symptoms.
EORTC QLQ C-30 global health status/QoL composite scale data and the remaining EORTC QLQ 
C-30 scale data will be summarized by timepoint using descriptive statistics for each treatment 
arm. Exploratory analyses may be performed to examine differences between the 2 arms.
 
 
8.5
Interim Analyses and Hierarchical Testing
An interim analysis of RFS will be conducted after all subjects have a minimum of 18 months of 
follow-up. Approximately 350 RFS events are anticipated at this analysis. The stopping boundaries 
at the interim and final analyses will be derived based on the exact number of RFS events using 
Lan-DeMets alpha spending function with O’Brien-Fleming boundaries. No interim analysis of 
OS will be performed at this time
If RFS is significant, the trial will continue and OS will be tested hierarchically. One formal OS 
interim analysis will be conducted at the time of the final RFS analysis. This formal comparison 
of OS will allow for early stopping for superiority. The stopping boundaries at the interim and 
final analyses will be derived based on the exact number of deaths using Lan-DeMets alpha 
spending function with O’Brien-Fleming boundaries. 
The final OS analysis will take place after all subjects have a minimum of 48 months of follow-up, 
which will take place approximately 55.5 months from the start of the study. At the time of the 
final OS analysis, 302 events are expected ensuring approximately 88% overall power to detect a 
hazard ratio of 0.70. Details of the OS modeling will be presented in the SAP.
In addition to the formal planned interim analysis for OS, the DMC will have access to periodic 
unblinded interim reports of efficacy and safety to allow a risk/benefit assessment. Details will be 
included in the DMC charter.
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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.
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. 
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9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (inventoried and dispensed) is maintained at the study site. 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
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•
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.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator and 
who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review and 
approval/signature is completed electronically through the BMS electronic data capture tool. The 
investigator must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the CSR. 
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For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
Subject recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Other criteria (as determined by the study team).
The data collected during this study are confidential and proprietary to 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.
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 (eg, 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 or less effective 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
AJCC 
American Joint Committee on Cancer
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransaminases
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
HCG
human chorionic gonadotrophin
BMS
Bristol Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
CBC
complete blood count
CI
confidence interval
CL
clearance
cm
centimeter
Cmax
maximum observed concentration
CMV
cytomegalovirus
CNS
central nervous system
CR
Complete response 
CRF
Case Report Form, paper or electronic
CSR
clinical study report
CT
computed tomography
CTA 
Clinical trial agreement 
CTCAE
common terminology criteria for adverse events
CTLA-4
cytotoxic T lymphocyte associated antigen-4
DILI
drug-induced liver injury
dL
deciliter
DLT
dose limiting toxicity
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Term
Definition
DMC
data monitoring committee
DMFS 
distant metastases-free survival
ECOG
Eastern Cooperative Oncology Group 
eCRF
Electronic Case Report Form
EFS
Event-free survival
ELISA
enzyme-linked immunosorbent assay
EOI
end of infusion
EORTC
European Organization for Research and Treatment of Cancer
EDC
Electronic Data Capture
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate or hazard ratio
HRQoL
Health Related Quality of Life 
HRT
hormone replacement therapy
IB
Investigator Brochure 
irAE
immune-related adverse event
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IFN
Interferon 
IHC
immunohistochemistry
IMP
investigational medicinal product
IP
Investigational product 
IRB
Institutional Review Board
ITSM
immunoreceptor tyrosine-based switch motif
IU
International Unit
IV
intravenous
IVRS
Interactive Voice Response System
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Term
Definition
kg
kilogram
L
liter
LDH
lactate dehydrogenase
LFT
liver function test 
MDSC
Myeloid derived suppressor cells 
mg
milligram
mL
milliliter
MLR
mixed lymphocyte reaction
MRI
Magnetic resonance imaging 
MTD
maximum tolerated dose
MU
million units
μg
microgram
N
number of subjects or observations
N/A
not applicable
NSCLC
non-small cell lung cancer
NED
no evidence of disease
ng
nanogram
NIMP
non-investigational medicinal products 
Obs.
Observation
ORR
Objective response rate 
OS
overall survival
PBMC
peripheral blood mononuclear cells
PD-1
programmed death receptor-1
PFS
Progression free survival
PK
pharmacokinetics
PPK
Population pharmacokinetic 
PR
Partial response 
PRO
Patient Reported Outcome
QoL
Quality of Life 
QLQ-C30
Quality of Life Questionnaire-Core
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Term
Definition
RCC
renal cell carcinoma
RFS
recurrence free survival
RT
radiation therapy 
TCR
T-cell receptor
SAE
serious adverse event
SAP
Statistical Analysis Plan
SNP
single nucleotide polymorphism
T-HALF
Half life
Tmax
time of maximum observed concentration
ULN
upper limit of normal
US
United States
VAS
visual analog rating scale 
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
WBC
white blood cell
WOCBP
women of childbearing potential
WPAI:GH
Work Productivity and Activity Impairment : General Health
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