A Phase 3, Randomized Study of Adjuvant Immunotherapy With Nivolumab Combined With Ipilimumab Versus Nivolumab Monotherapy After Complete Resection of Stage IIIb/c/d or Stage IV Melanoma
Phase: PHASE3
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CA209915
IND Number:
104,225
EUDRACT Number
2016-003729-41
Date
20-Dec-2016
Revised Date
11-Mar-2019
Clinical Protocol CA209915
A Phase 3, Randomized Study of Adjuvant Immunotherapy with Nivolumab Combined with 
Ipilimumab Versus Nivolumab Monotherapy after Complete Resection of Stage IIIb/c/d or Stage 
IV Melanoma 
(CheckMate 915: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 915)
Revised Protocol Number: 03
Incorporates Administrative Letters 04 and 05
Study Director / Medical Monitor
Elena Grigoryeva, MD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
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organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (e.g., amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, e.g., a Contract Research 
Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Date: 11-Mar-2019
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 03
11-Mar-2019
Incorporates administrative letters 04, and 05. Updates to this 
protocol include, additional medical monitor, continued 
treatment for malignant melanoma in situ, modification of the 
statistical design to evaluate RFS after a sufficient period of 
minimum follow-up, evaluation of the surrogate endpoint 
Progression-Free Survival 2 (PFS2), and assessment of quality 
of life for 4 years in survival follow up.
Administrative Letter 05
22-May-2018
The purpose of this letter is to advise of an additional Medical 
Monitor for the study, to clarify the criteria for treatment 
resumption and discontinuation, to add phosphate to laboratory 
test done during On-Treatment visits and clarify the laboratory 
assessments done during follow-up visits.
Administrative Letter 04
23-Feb-2018
This Administrative Letter is to clarify the study design 
regarding the age of adolescents and dosing of Nivolumab 
including the date of implementation of this design change.  In 
addition, this letter corrects inconsistencies and typographical 
errors.
Revised Protocol 02
12-Dec-2017
The purpose of this revised protocol is to modify the study 
design based on changes in the knowledge in the management 
of melanoma, and possible similarities in the pattern of efficacy 
by PD-L1 expression in adjuvant and metastatic settings. To 
understand the impact on sequencing of therapies the 
exploratory objective of evaluation of investigator-assessed 
outcomes on next-line therapies was added.
In addition, the protocol now clarifies the Schedule of 
Activities for participants during Arm C open label visits.
Also incorporates Administrative Letter 03
Administrative Letter 03
18-Aug-2017
This Administrative Letter is to clarify the study visits that will 
need to be completed by the subjects randomized to Arm C 
after they are un-blinded (per Amendment 6) and a decision is 
made to continue treatment with ipilimumab 10 mg/kg or to 
switch to nivolumab 480 mg every 4 weeks.
Also an inconsistency regarding the duration of the ipilimumab 
infusion will be clarified.
Revised Protocol 01
20-Jul-2017
Incorporates Amendment 06 and Administrative Letters 01 and 
02
Amendment 06
20-Jul-2017
This purpose of this amendment is: 
•
Remove treatment Arm C for Ipilimumab 10 mg/kg. 
•
Reduce infusion time for Ipilimumab from 90 minutes to 30 
minutes
•
Clarify the duration of post-treatment contraception
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Document
Date of Issue
Summary of Change
Administrative Letter 02
05-Apr-2017
This Administrative Letter clarifies the Inclusion Criteria for 
participants with prior anti-cancer therapy which is currently 
reflected only in the Exclusion Criteria, Prior/Concomitant 
Therapy.
Also inconsistencies about study procedures are clarified.
Administrative Letter 01
09-Mar-2017
This administrative letter clarifies the laboratory assessment for 
performing TSH with reflexive Free T4 and Free T3 if TSH is 
abnormal from D1Wk1 to D1Wk9. Also clarifies to perform 
thyroid panel, ACTH and Cortisol as indicated in the Schedule
of Assessments (Section 2) but not mentioned in the table of 
laboratory assessments in Section 9.4.4. Urinalysis assessment 
is not needed for this protocol and has been removed from the 
table of laboratory assessments indicated in Section 9.4.4. 
Original Protocol
20-Dec-2016
Not Applicable
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.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Title Page
Revised for additional Medical Monitor.
 
 
Section 2, Schedule of 
Activities, Table 2-2, On-
Treatment Assessments 
Week 1 - Week 9 
(CA209915) (Participants 
on Arm A or Arm B), 
Laboratory Tests
Phosphate was added to the list of 
laboratory assessments performed with 72 
hours prior to dosing.
Previously written:
Within 72hrs. 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, TSH (with reflexive FreeT4 and 
FreeT3 if TSH is abnormal) Albumin, 
ACTH, cortisol, amylase, and lipase as 
clinically indicated.
Changed to:
Within 72hrs. prior to dosing to include 
CBC w/differential, AST, ALT, ALP, 
T.Bili, BUN or serum urea level, 
creatinine, Ca, Phosphate, Mg, Na, K, 
Cl, LDH, Glucose, TSH (with reflexive 
FreeT4 and FreeT3 if TSH is abnormal) 
Albumin, ACTH, cortisol, amylase, and 
lipase as clinically indicated.
 
 
Section 2, Schedule of 
Activities, all tables 
excluding Table 2-1 and 
Table 2-8.
Regarding Outcome Research 
Assessments, added the following:
Adolescents should only complete the 
EQ-5D and not the EORTC QLQ-C30 or 
AI:GH.
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 2, Schedule of 
Activities, Table 2-10, 
Follow-up Procedural 
Outline, Adverse Events 
Assessment
Previously written:
Immune-mediated adverse reactions 
should be followed until stabilization. 
Nonimmunemediated adverse reactions 
should be followed until resolution or 
stabilization.
Changed to:
Record at each visit. Collect continuously 
throughout the treatment period and for a 
minimum of 100 days following 
discontinuation of dosing.
 
Section 2, Schedule of 
Activities, Table 2-10, 
Follow-up Procedural 
Outline, Laboratory Test: 
Notes
Previously written:
CBC w/ differential, chemistry panel, 
thyroid test for Follow-up Visit 1 (repeat 
at Visit 2 if toxicities are present)
Changed to:
CBC w/ differential, chemistry panel, 
thyroid test for Follow-up Visit 1 (repeat 
at Visit 2 if toxicities are present). Refer 
to Section 9.4.4 Clinical Safety 
laboratory Assessments for list of 
laboratory test.
 
Section 2, Schedule of 
Activities, Table 2-10, 
Follow-up Procedural 
Outline, Outcomes Research 
Assessment: Notes for 
EQ-5D-3L
Previously written:
Every 3 months (±14 days), maybe 
accomplished by visit or phone contact 
for up to 2 years after follow up visit 2
Changed to:
Every 3 months (±14 days), maybe 
accomplished by visit or phone contact 
for up to 4 years after follow up visit 2
 
 
Section 3.2, Background, 
under heading title 
Nivolumab + Ipilimumab 
Combination in Metastatic 
or Unresectable Melanoma 
A paragraph was added regarding the new 
secondary endpoint of PFS2.
 
Section 4, Objectives and 
Endpoints, Table 4-1, and 
Synopsis, Objectives and 
Endpoints
Secondary Objectives and Endpoints, and 
 Endpoints
were revised.
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 5.1, Overall Design, 
second dashed-bullet item, 
and Synopsis, Overall 
Design
Previously written:
For adolescents between 12 and 18 years 
of age the dosing of nivolumab is body 
weight based dosing as follows: Q2 week 
dosing - 3 mg/kg IV Q2 weeks up to a 
maximum of 240 mg; Q4 week dosing -
6 mg/kg Q4 weeks up to a maximum of 
480 mg. The change will be implemented 
upon IRT modification.
Changed to:
For adolescents between 12 to <18 years 
of age the dosing of nivolumab is body 
weight based dosing as follows: Q2 week 
dosing - 3 mg/kg IV Q2 weeks up to a 
maximum of 240 mg; Q4 week dosing - 6 
mg/kg Q4 weeks up to a maximum of 480 
mg. This will be applicable for 
participants enrolled after IRB approval 
of Revised Protocol 02 and will be 
implemented upon IRT modification.
 
 
 
Section 5.1, Overall Design, 
under Follow-up Phase, 
bullet 6
Previously written:
Participants 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
Changed to:
Participants will be followed for drug-
related toxicities according to the Section 
9. All toxicities will be documented for a 
minimum of 100 days after the last dose 
of study medication  
 
 
 
 
 
 
 
 
 
 
 
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 7.1, Treatments 
Administered, paragraph 1 
under Arm A (Nivolumab + 
Ipilimumab) Dosing; 
paragraph 1 under Arm B 
(Nivolumab) Dosing; 
paragraph 1, under For 
Participants who switch to 
Nivolumab 480 mg, Open-
label; and Table 7.1-1, 
Dosing Schedule for Study 
CA209915, footnote b; 
Synopsis, Treatment Arms 
and Duration
Previously written:
For adolescents between 12 and 18 years 
of age the dosing of nivolumab is body 
weight based dosing as follows: Q2 week 
dosing - 3 mg/kg IV Q2 weeks up to a 
maximum of 240 mg; Q4 week dosing -
6 mg/kg Q4 weeks up to a maximum of 
480 mg. The change will be implemented 
upon IRT modification.
Changed to:
For adolescents between 12 to <18 years 
of age the dosing of nivolumab is body 
weight based dosing as follows: Q2 week 
dosing - 3 mg/kg IV Q2 weeks up to a 
maximum of 240 mg; Q4 week dosing - 6 
mg/kg Q4 weeks up to a maximum of 480 
mg. This will be applicable for 
participants enrolled after IRB approval 
of Revised Protocol 02 and will be 
implemented upon IRT modification.
 
 
 
Section 7.2, Method of 
Treatment Assignment, first 
dash item under bullet 
regarding Participants will 
be stratified by; and 
Section 7.3, Blinding, last 
paragraph
Added text allowing that the statistician 
may be unblinded to the participant’s PD-
L1 status results.
 
 
 
Section 7.3, Blinding, 
paragraph 2
Added sentence to paragraph 2:
The actual task of unblinding can be 
delegated by the investigator to a 
designee assigned the task on the 
Delegation of Authority
 
Section 7.3, Blinding, last 
paragraph
Added text allowing that the statistician 
may be unblinded to the participant’s PD-
L1 status results.
 
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 7.4.3, Criteria to 
Resume Treatment
Previously written:
Participants with drug-related 
endocrinopathies adequately controlled 
with only physiologic hormone 
replacement may resume treatment after 
consultation with the BMS Medical 
Monitor. Adrenal insufficiency requires 
discontinuation regardless of control with 
hormone replacement.
Changed to:
Participants with drug-related 
endocrinopathies adequately controlled 
with only physiologic hormone 
replacement may resume treatment after 
consultation with the BMS Medical 
Monitor. Adrenal insufficiency ≥ Grade 
3 requires discontinuation regardless of 
control with hormone replacement.
 
Section 7.7.1, Prohibited 
and/or Restricted 
Treatments
Added sentence to bullet 4:
Use of marijuana and its derivatives for 
treatment of symptoms related to cancer 
or cancer treatment are permitted if 
obtained by medical prescription or if its 
use (even without a medical prescription) 
has been legalized locally
Added bullet 5: Any live/attenuated 
vaccine (eg, varicella, zoster, yellow 
fever, rotavirus, oral polio and measles, 
mumps, rubella (MMR)) during treatment 
and until 100 days post last dose.
 
Section 8.1, Discontinuation 
from Study Treatment
Bullet 3 under Treatment should be 
permanently discontinued for the 
following:
Myocarditis was added.
 
Section 8.1, Discontinuation 
from Study Treatment
Treatment should be permanently 
discontinued for the following:
Previously written:
Persistent Grade 2 or 3 immune-mediated 
adverse drug reactions that last 12 weeks 
or longer.
Changed to:
Persistent Grade 2 or 3 immune-mediated 
adverse drug reactions that last 12 weeks 
or longer with exception for Grade 2 
endocrinopathies.
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 9.2.1, Time Period
and Frequency for 
Collecting AE and SAE 
Information
Paragraph 5 
(eg, a follow-up skin biopsy ) was added
 
Section 9.2.2, Method of 
Detecting AEs and SAEs
Added sentence:
Every adverse event must be assessed by 
the investigator with regard to whether it 
is considered immune-mediated. For 
events which are potentially immune-
mediated, additional information will be 
collected on the participant’s case report 
form.
 
Section 9.3, Overdose
Changed to Appendix 5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 10.1, Sample Size 
Determination, 
Section 10.1.1.1, RFS in All 
Randomized Participants 
with PD-L1 Expression 
Level < 1%, 
Section 10.1.1.2, RFS in All 
Randomized Participants,
Section 10.1.2 Overall 
Survival; and Synopsis, 
Number of Participants
Section revised regarding RFS.
 
Section 10.3.1.1, Primary 
Endpoint Analysis, 
paragraph 1; Table 10.3.1.1-
1, Censoring Scheme for 
Primary Definition of RFS
Revised to include melanoma in situ.
 
 
 
 
 
 
 
 
 
 
Section 10.3.1.1, Primary 
Endpoint Analysis
Revisions were made to paragraphs 2, 3, 
and 4 regarding RFS testing strategy  and 
alpha adjustment
 
Section 10.3.1.2, Secondary 
Endpoint Analyses
Headings for “Overall Survival” and 
“Association between PD-L1 expression 
and RFS” were added in this section. 
Added section titled, Investigator-
Assessed Outcomes on Next-Line 
Therapies”.
 
 
 
 
 
 
 
 
 
 
  
Section 10.3.4, Interim 
Analyses and Hierarchical 
Testing
Revised section regarding RFS testing 
strategy.
 
Appendix 4, Study 
Governance Considerations
Revised language regarding a potential 
breach of the conditions and principles of 
Good Clinical Practice. Updated text 
regarding Study Treatment Records.
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Appendix 5, Adverse 
Events and Serious Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow Up and 
Reporting
Clarified text regarding: the definition of 
AE Events, events NOT meeting the AE 
definition, and the definition of SAEs.
 
 
 
 
Appendix 8, Revised 
Protocol Summary of 
Change History, Summary 
of Key Changes for Revised 
Protocol 02, Row 1, 
Column 3
 
 
 
 
 
 
 
 
All
Minor formatting and typographical 
corrections
 
 
 
 
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03 ......................... 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
 
 
 
 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
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6.3 Lifestyle Restrictions ........................................................................................ 
6.3.1 Meals and Dietary Restrictions ............................................................... 
6.3.2 Caffeine, Alcohol and Tobacco ................................................................ 
6.3.3 Activity ..................................................................................................... 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dose Modification ............................................................................................ 
7.4.1 Dose Delay Criteria ................................................................................. 
7.4.2 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ...... 
7.4.3 Criteria to Resume Treatment .................................................................. 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability/Bioequivalence ............................. 
7.6 Treatment Compliance ...................................................................................... 
 
 
 
 
7.8 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Rechallenge .............................................................................................. 
8.1.2 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Definitions ................................................................................................ 
9.1.2 Methods of measurements ........................................................................ 
9.1.3 Date of Recurrence .................................................................................. 
9.1.4 Imaging Assessment for the Study............................................................ 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
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9.4.2 Vital signs................................................................................................. 
9.4.3 Electrocardiograms ................................................................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
9.4.5 Suicidal Risk Monitoring ......................................................................... 
9.4.6 Imaging Safety Assessment ...................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.1.1 RFS ......................................................................................................... 
10.1.1.1 RFS in All Randomized Participants with PD-L1 Expression Level 
< 1% ..................................................................................................... 
10.1.1.2 RFS in All Randomized Participants ............................................ 
10.1.2 Overall Survival ..................................................................................... 
10.1.2.1 OS in All Randomized Participants with PD-L1 Expression Level 
< 1% ..................................................................................................... 
10.1.2.2 OS in All Randomized Participants .............................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.1.1 Primary Endpoint Analysis ........................................................... 
10.3.1.2 Secondary Endpoint Analyses ....................................................... 
10.3.2 Safety Analyses....................................................................................... 
 
 
 
 
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10.3.4 Interim Analyses and Hierarchical Testing ........................................... 
 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 AJCC MELANOMA STAGING .......................................................... 
APPENDIX 2 PERFORMANCE STATUS SCALES ................................................. 
APPENDIX 3 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 4 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 5 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 7 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
 
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1
SYNOPSIS
Protocol title: A Phase 3, Randomized Study of Adjuvant Immunotherapy with Nivolumab 
Combined with Ipilimumab Versus Nivolumab Monotherapy after Complete Resection of Stage 
IIIb/c/d or Stage IV Melanoma (CheckMate 915: CHECKpoint pathway and nivoluMAb clinical 
Trial Evaluation 915)
Study Phase: 3
 
 
 
 
 
 
Study Population:
1) Males and Females, at least 12 years of age, except where local regulations and/or institutional 
policies do not allow for participants <18 years of age (pediatric population) to participate. For 
those sites, the eligible participant population is ≥18 years of age.
Inclusion Criteria
a) All participants must be either stage IIIb/c/d or Stage IV AJCC (AJCC Cancer Staging, 8th 
edition; see also Appendix 1) and have histologically confirmed melanoma that is 
completely surgically resected in order to be eligible. All melanomas, except ocular/uveal 
melanoma, regardless of primary site of disease will be allowed; mucosal melanomas are 
eligible. Participants must have been surgically rendered free of disease with negative 
margins on resected specimens.
When T is....
And N is.....
And M is....
The pathological stage is...
T0
N1b, N1c
M0
IIIB
T0
N2b, N2c, 
N3b, N3c
M0
IIIC
T1a/b-T2a
N1b/c or 
N2b
M0
IIIB
T2b/T3a
N1a-N2b
M0
IIIB
T1a-T3a
N2c or 
N3a/b/c
M0
IIIC
T3b/T4a
Any N ≥N1
M0
IIIC
T4b
N1a-N2c
M0
IIIC
T4b
N3a/b/c
M0
IIID
Ant T, Tis
Any N
M1
IV
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i)
If stage III melanoma (whether Stage IIIb or IIIc or IIId) the participants should have 
clinical or radiographic evidence of regional metastases, either in the regional lymph 
nodes or locoregional metastases manifesting as satellite or in-transit metastases, or 
microsatellites discovered at the time of microscopic evaluation of the primary tumor 
diagnostic biopsy. Participants must have pathological evidence of regional metastases, 
regional lymph node and/or microsatellite/satellite/in-transit metastases, and no distant 
metastasis. The pathology report for stage IIIb, IIIc, and IIId must be reviewed, signed 
and dated by the investigator; this process will be confirmed during the IRT 
randomization call.
ii) If stage IV melanoma, the pathology report confirming negative margins must be 
reviewed, dated, and signed by the investigator prior to randomization.
iii) For CNS lesion(s), documentation indicating that there has been complete resection of 
CNS lesion(s) will suffice as confirmation of negative margins
b) 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
c) Complete resection must be performed within 12 weeks prior to randomization 
d) All participants 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 or MRI scans of the chest, abdomen, pelvis and all known sites of resected 
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). Participants with 
equivocal lymph nodes ≥10 mm and <15 mm in a short axis may be eligible if confirmation 
with histology/cytology is available. If risk of biopsy is too high or biopsy is not feasible, 
two sequential CT or MRI scans should be available and showing no progressive and 
measureable disease or PET/CT demonstrating no FDG uptake. The second scan should 
occur at least 4 weeks after the initial scan. Lymph nodes ≥15 mm in a short axis are 
defined as pathological.
e) The complete set of baseline images must be available before randomization
f)
ECOG performance status score of 0 or 1 (Appendix 2)
g) Tumor tissue from the resected site of disease must be provided for biomarker analyses
(preferably collected within 12 weeks of assessment time). In order to be randomized, a 
participant must have quantifiable PD-L1 expression (< 1% or 1%-< 5% or ≥5% tumor 
cell membrane staining) or be classified as PD-L1 indeterminate. 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.
h) Participants must not have received anti-cancer therapy (for example but not limited to 
systemic, local, radiation, radiopharmaceuticals) for their melanoma except: 
i)
Surgery for the melanoma lesion(s)
ii) Adjuvant radiation therapy (RT) after neurosurgical resection for central nervous 
system (CNS) lesions
iii) Prior adjuvant interferon if completed ≥ 6 months prior to randomization
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i)
Prior treated central nervous system (CNS) metastases must be without MRI evidence of 
recurrence for at least 4 weeks after treatment. Participants 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.
i)
The 4-week period of stability is measured after the completion of the neurologic 
interventions, ie, surgery and/or radiation
j)
In addition to neurosurgery to treat CNS metastases, adjuvant radiation after resection of 
CNS metastases is allowed. Immunosuppressive doses of systemic steroids (doses 
>10 mg/day mg/day prednisone or equivalent) must be discontinued at least 14 days before 
study drug administration.
k) Prior surgery that required anesthesia must be completed at least 4 weeks before drug 
administration. Surgery requiring local/epidural anesthesia must be completed at least 
72 hours before study drug administration.
Exclusion Criteria
a) History of ocular/uveal melanoma
b) Weight ≤ 40 kg “Not applicable as per amendment 07”
c) Participants with active, known, or suspected autoimmune disease. Participants with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
d) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.
e) Participants 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, and adrenal replacement 
steroid doses > 10 mg daily prednisone or equivalent, are permitted in the absence of active 
autoimmune disease.
f)
Pregnant or nursing women
g) 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 
participants 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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h) 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
i)
Treatment with botanical preparations (eg herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to randomization/treatment.
Objectives and Endpoints:
Endpoints: This should be a high level description of the assessments.
Objective
Endpoint
Primary
•
To compare the efficacy, as measured by recurrence 
free survival (RFS), provided by nivolumab plus 
ipilimumab versus nivolumab monotherapy in 
participants with completely resected stage IIIb/c/d
or stage IV no evidence of disease (NED) 
melanoma 
(in all randomized participants with PD-L1 
expression level < 1%. and all randomized 
participants)
•
Recurrence-free survival, RFS
Secondary
•
To compare the overall survival provided by 
nivolumab plus ipilimumab versus nivolumab 
monotherapy
in participants with completely 
resected stage IIIb/c/d or stage IV NED melanoma 
(in all randomized participants with PD-L1 
expression level < 1%. and all randomized 
participants)
•
To evaluate the association between PD-L1 
expression and RFS
To evaluate investigator-assessed outcomes on next-line 
therapies
•
Overall survival (OS)
•
PD-L1 expression
•
Objective response rates (if applicable)
•
Duration of treatment on next-line therapies
•
PFS2 defined as time from randomization to second 
recurrence/objective disease progression, or death 
from any cause, whichever occurs first.
End-of-next-line-treatment: To be used for situations 
where PFS2 cannot be reliably determined. Event 
defined as end or discontinuation of next-line treatment, 
second objective disease progression, or death from any 
cause, whichever occurs first.
 
 
 
 
 
 
 
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Objective
Endpoint
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall Design:
This is a Phase 3, randomized, double blind study designed to compare nivolumab plus ipilimumab 
vs nivolumab monotherapy participants (≥12 years) with completely resected stage IIIb/c/d or 
stage IV no evidence of disease (NED) melanoma.
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Participants will be treated with one of the following:
•
Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year 
of study drug treatment) 
•
Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab 
placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on 
Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
−
The original study design included an ipilimumab monotherapy arm (Arm C). 
Randomization into Arm C was discontinued upon implementation of Amendment 06. 
Sites who have randomized participants to the ipilimumab arm will be unblinded to that 
information and the participants will be allowed to continue as open-label on either 
ipilimumab 10 mg/kg IV Q3 weeks for 4 doses, then Q12 weeks starting at Week 24 or 
switch to the nivolumab 480 mg IV Q4 weeks in 8 weeks after the last dose of ipilimumab. 
The change will be implemented upon IRT modification.
−
For adolescents between 12 to < 18 years of age the dosing of nivolumab is body weight 
based dosing as follows: Q2 week dosing - 3 mg/kg IV Q2 weeks up to a maximum of 240 
mg; Q4 week dosing - 6 mg/kg Q4 weeks up to a maximum of 480 mg. This will be 
applicable for participants enrolled after IRB approval of Revised Protocol 02 and will be 
implemented upon IRT modification.
Number of Participants: 
Approximately 2000 participants will be randomized in a 1:1 ratio to nivolumab plus ipilimumab 
versus nivolumab monotherapy and stratified by PD-L1 status (PD-L1 expression < 1% or 
indeterminate, 1%-<5%, ≥5% tumor cell surface expression) and American Joint Committee on 
Cancer (AJCC) stage IIIb vs stage IIIc/d vs stage IV (Appendix 1). Accrual will be stopped when 
approximately 600 participants with PD-L1 expression level < 1% will be randomized in a 1:1 
ratio to nivolumab plus ipilimumab and nivolumab respectively. The prevalence of participants 
with PD-L1 expression level < 1% is expected to be around 30% of all randomized participants.  
Therefore, it is estimated that approximately 2000 participants will be randomized in a 1:1 ratio to 
nivolumab plus ipilimumab and nivolumab respectively. No more than 1400 participants with 
PD-L1 expression level ≥1% will be randomized to nivolumab plus ipilimumab and nivolumab 
respectively In addition, there will be a number of participants that were already randomized to 
the ipilimumab arm under the original protocol.
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The sample size of the study is based on a comparison of the RFS distribution between participants 
randomized to nivolumab plus ipilimumab and participants randomized to nivolumab. RFS will 
be evaluated for treatment effect using the following testing strategy: RFS will be compared first 
in the all randomized participants with PD-L1 expression level < 1% subgroup with an alpha 
allocation of 0.03 (two-sided); and if significant, the alpha allocated to this subgroup will be 
recycled to the treatment comparison in the overall population (all randomized participants). Thus 
RFS will be compared in all randomized participants with an alpha allocation of 0.05 (two-sided). 
If the treatment comparison in all randomized participants with PD-L1 expression level < 1% is 
not significant, RFS will be compared in all randomized participants with an alpha allocation based 
on the method published by Spiessens and Debois1. This method takes into account the correlation 
between the test statistics for the overall and the subgroup analysis, and is essentially the same as 
the method used when dealing with interim analyses, ie, group sequential method. The alpha 
allocated to the overall analysis will be calculated based on the fraction of information in the 
subgroup, relative to the overall population, which is determined by the ratio of events observed 
in the two groups. For example, if 257 events are observed in the PD-L1 expression level < 1% 
subgroup, and 651 events are observed in the overall population (ie, about 40% of all events in the 
PD-L1<1% subgroup), the alpha allocated to the overall analysis is 0.0265.
The sample size is driven by the comparison of RFS between all randomized participants with 
PD-L1 expression level < 1% randomized to receive nivolumab plus ipilimumab vs nivolumab. 
Approximately 600 participants with PD-L1 expression level < 1% will be randomized in a 1:1 
ratio to nivolumab plus ipilimumab and nivolumab respectively. Approximately 257 RFS events 
in all randomized participants with PD-L1 expression level < 1% will provide approximately 90% 
power to detect an average hazard ratio (HR) of 0.65 with an alpha level of 0.03 (two-sided). In 
case the 257 RFS events would be reached at a timepoint earlier than 13 months of minimum 
follow-up (from the randomization of the last participant), analysis of RFS will be conducted when 
there would be a minimum follow up of 13 months (ie, at the time when 257  events are reached 
or a minimum follow-up of 13 months, whatever occurs later).
Approximately 2000 participants will be randomized in a 1:1 ratio to nivolumab plus ipilimumab 
and nivolumab respectively. Approximately 700 participants with PD-L1 expression level < 1% 
were randomized in a 1:1 ratio to nivolumab plus ipilimumab and nivolumab respectively. 
Approximately 651 RFS events in all randomized participants will provide approximately 90% 
power to detect an average hazard ratio (HR) of 0.76 with an alpha level of 0.0265 (two-sided).
The analysis of RFS in the all randomized participants with PD-L1 expression level < 1% subgroup 
will be performed at the time when 257 RFS events are observed in this subgroup or a minimum 
follow-up of 13 months is reached, whatever occurs later.
If the treatment comparison in the all randomized participants with PD-L1 expression level < 1% 
subgroup is significant, RFS will be compared in all randomized participants with an alpha 
allocation of 0.05. In this case, two analyses, an interim and a final, will be conducted in all 
randomized participants. The interim analysis will take place at the same time as the RFS analysis 
for the PD-L1 expression level < 1% subgroup. The final analysis will take place when 560 RFS 
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events are observed in the overall population. 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. 
If the treatment comparison in all randomized participants subjects with PD-L1 expression level 
< 1% subgroup is not significant, RFS will be compared in the overall population with an alpha 
allocation based on the method published by Spiessens and Debois.1 In this case, no interim 
analysis is planned. The final RFS analysis for the overall population will be conducted when 
approximately 651 RFS events are observed. 
In case the events come slower than projected, final analysis of RFS for the overall population will 
be conducted when the minimum follow up from randomization of the last participant reaches 30 
months.
Given actual accrual rates so far and estimated accrual rates of 157 participants per month for the 
coming months, it is estimated that accrual of 2000 participants (ie, 1000 participants in a 1:1 ratio 
in the nivolumab plus ipilimumab and nivolumab arms each) and the participants in the ipilimumab 
arm that has already taken place, will take approximately 17 months. Given actual accrual rates, 
accrual took approximately 13.5 months.
Treatment Arms and Duration:
In this protocol, investigational products are nivolumab and ipilimumab.
Table 1-1:
Study treatments for CA209915
Product Description/
Class / Dosage Form
Potency
IP/Non-IMP
Packaging / 
Appearance
Storage Conditions
BMS-936558
Nivolumab Solution for 
Injection
100 mg 
(10 mg/mL)
or
40 mg 
(10 mg/mL)
IP
10 mL per vial
(5 or 10 vials per 
carton)
or
4 mL/vial
(240 mg kits: 2-
100 mg vials and 
1-40 mg vial)
Store at 2○ - 8○ C
Protect from light 
and freezing
Ipilimumab Solution for 
Injection
200 mg
(5 mg/mL)
IP
40 mL/vial
(4 vials/carton)
Store at 2○ - 8○ C
Protect from light 
and freezing
Placebo
Placebo for Nivolumab or Ipilimumab will be considered as drug diluent alone, 
either Normal Saline or Dextrose 5%. Preparation of placebo, blinding and 
labeling will be outlined in the CA209915 pharmacy manual.
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Arm A (Nivolumab + Ipilimumab) Dosing:
Participants randomized to Arm A will receive treatment with nivolumab at a dose of 240 mg as a 
30-minute infusion on Day 1 every 2 weeks plus ipilimumab 1 mg/kg as a 30-minute infusion
every 6 weeks until progression, unacceptable toxicity, withdrawal of consent, or the study ends, 
whichever occurs first with a maximum of 1 year total duration of study medication. For 
adolescents between 12 to < 18 years of age, use the body weight-based dosing for nivolumab of 
3 mg/kg Q2W up to a maximum of 240 mg. This will be applicable for participants enrolled after 
IRB approval of Revised Protocol 02 and will be implemented upon IRT modification. Participants 
should begin study treatment within 3 calendar days of randomization.
Arm B (Nivolumab) Dosing:
Participants should receive nivolumab at a dose of 480 mg as a 30-minute infusion on Day 1 of 
each treatment cycle every 4 weeks until progression, unacceptable toxicity, withdrawal of 
consent, or the study ends, whichever occurs first with a maximum of 1-year total duration of study 
medication. For adolescents between 12 to < 18 years of age, use the body weight-based dosing 
for nivolumab 6 mg/kg Q4W up to a maximum of 480 mg. This will be applicable for participants 
enrolled after IRB approval of Revised Protocol 02 and will be implemented upon IRT 
modification. Participants should begin study treatment within 3 calendar days of randomization. 
In order to maintain the blind, nivolumab placebo will be administered on D1WK3, D1WK7, 
D1WK11, D1WK15, D1WK19, D1WK23, D1WK27, D1WK31, D1WK35, D1WK39, D1WK43 
and D1WK47. Ipilimumab placebo will be administered on D1WK1, D1WK7, D1WK13, 
D1WK19, D1WK25, D1WK31, D1WK37, D1WK43, and D1WK49. (See Table 7.1-1 in the 
protocol)
For participants who have been randomized to Arm C: (Ipilimumab) before the 
implementation of Amendment:
Sites who have randomized participants to the ipilimumab arm will be unblinded to that 
information and the participants will be allowed to continue as open-label on either ipilimumab
10 mg/kg or switch to nivolumab 480 mg. The change will be implemented upon IRT 
modification. 
For participants who continued on Ipilimumab 10 mg/kg. 
Open-label.
Participants should continue receiving ipilimumab at a dose of 10 mg/kg as a 90-minute IV 
infusion, on Day 1 of each treatment cycle every 3 weeks for 4 doses, then every 12 weeks 
beginning at Week 24, until progression, unacceptable toxicity, withdrawal of consent, or the study 
ends, whichever occurs first with a maximum of 1-year total duration of study medication. 
Participants should begin study treatment within 3 calendar days of randomization. (See Table 2-8)
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For Participants who switched to Nivolumab 480 mg. 
Open-label.
The first dose of nivolumab 480 mg should occur 8 weeks after the last dose of ipilimumab
10 mg/kg. Participants should receive nivolumab at a dose of 480 mg as a 30 minute IV infusion 
of each treatment cycle every 4 weeks until progression, unacceptable toxicity, withdrawal of 
consent, or the study ends, whichever occurs first with a maximum of 1-year total duration of study 
medication starting from first dose of ipilimumab 10 mg/kg. (See Table 2-9) For adolescents 
between 12 to < 18 years of age, use the body weight-based dosing for nivolumab 6 mg/kg Q4W 
up to a maximum of 480 mg. The change will be implemented upon IRT modification.
Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to
re-calculate subsequent doses if the participant weight is within 10% of the weight used to calculate 
the previous dose. All doses should be rounded up or to the nearest milligram per institutional 
standard.
Dose reductions or dose escalations are not permitted. All dose modification rules apply to all arms 
given the blinded nature of this study.
Dose delay criteria apply for all drug-related adverse events regardless of whether or not the event 
is attributed to nivolumab, ipilimumab, or both. All study drugs must be delayed until treatment 
can resume. Dose delay criteria also apply to the placebo version of each agent, given the blinded 
nature of this study.
Study drug (nivolumab, ipilimumab and placebo version of each agent) administration should be 
delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see section 8)
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
A Data Monitoring Committee (DMC) will be established to provide oversight of safety and 
efficacy considerations in protocol CA209915. Additionally, the DMC will provide advice to the 
sponsor regarding actions the committee deems necessary for the continuing protection of 
participants enrolled in the study. The DMC will be charged with assessing such actions in light 
of an acceptable benefit/risk profile for nivolumab in combination with ipilimumab, 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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Details of the DMC responsibilities and procedures will be specified in the DMC charter.
 
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2
SCHEDULE OF ACTIVITIES
Participants originally assigned to Arm C (ipilimumab 10 mg/kg) who switch to nivolumab after 
the implementation of Amendment 6 after receiving ipilimumab 10 mg/kg and completing an 
8 week washout should receive nivolumab 480 mg every 4 weeks, and procedures should be 
performed at the same visit when dosing occurs as follows: 
−
All Safety Assessments (Targeted Physical Examination, Vital Signs, Weight and 
Performance Status, Adverse Events Assessments, Review of Concomitant Medications, 
Laboratory Tests, Pregnancy Tests) except Immunogenicity should be performed
−
 
−
Tumor surveillance assessment schedule (Efficacy Assessments) is remaining unchanged, 
and the timing should continue to be done from the first dose of study treatment in the study.
−
 
 
 
−
IRT will dispense study treatment (open-label)
−
Table 2-8 provides the schedule of activities for the participants originally assigned to Arm C 
(ipilimumab 10 mg/kg) who continue on ipilimumab.
Table 2-9 provides the schedule of activities described above for participants originally assigned 
to Arm C (ipilimumab 10 mg/kg) who switch to nivolumab 480 mg.
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Table 2-1:
Screening Procedural Outline (CA209915)
Procedure
Screening Visit (Before
Day 1, prior to
Randomization)
Notes
EligibilityAssessments
Informed Consent
X
Must be obtained prior to performing any screening procedures. If re-enrolled, the 
participant must be re-consented and assigned a new participant number from IRT.
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.
Tumor Tissue Samples
X
Sufficient tumor tissue from the resected site of the disease (a block or a minimum
of 15 slides) must be available and sent to a central laboratory for biomarker
analysis.
PD-L1 status will be assessed prior to randomization (PD-L1 expression < 1% or 
indeterminate, 1%-<5%, ≥5% tumor cell surface expression) (see Section 9.8.1)
Safety Assessments
Physical Examination
X
Includingheight and weight, within 14 days prior to randomization
Vital Signs
X
Including blood pressure (BP), heart rate (HR), temperature; obtain at the screening 
visit and within 72 hours prior to first dose
Performance Status (ECOG)
X
Within 14 days prior to randomization
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization
Serious Adverse Events
X
Serious Adverse Events from time of consent. See Section 9.2.1.
Electrocardiogram(ECG)
X
Within 14 days prior to randomization
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Table 2-1:
Screening Procedural Outline (CA209915)
Procedure
Screening Visit (Before
Day 1, prior to
Randomization)
Notes
LaboratoryTests
X
Must be completed with 14 days prior to randomization
•
CBC w/ differential
•
Chemistry panel including AST, ALT, ALP, T. Bili, blood urea nitrogen (BUN) 
or serum urea level, creatinine, creatinine clearance (Screening only),
phosphate, Ca, Na, K, CL, LDH, and glucose
•
Thyroid panel including TSH, free T4, free T3
•
Hep B/C (HBVsAG, HCV antibody, or HCV RNA)
•
Albumin at screening and as clinically indicated after screening visit
PregnancyTest
X
WOCBP only. Serum or urine to be done at screening visit and 
repeated within 24 hours prior to first dose of study therapy.
Efficacyassessment
Tumor surveillanceassessments
X
Performed within 28 days prior to randomization; see Section 9.1.4
Other
Interactive Response Technology 
(IRT)
X
For participant number assignment at the time informed consent is obtained
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Table 2-2:
On-Treatment Assessments Week 1 - Week 9 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 1
Day 1
Week 3
Day 1
Week 5
Day 1
Week 7
Day 1
Week 9
Notes
Safety Assessments
Targeted Physical
Examination
X
X
X
X
X
To be performed within 72 hours prior to dosing
Vital Signs
X
X
X
X
X
Including BP, HR, temperature
Weight and performance
status
X
X
X
X
X
Within 72 hours prior to dosing
Adverse Events
Assessment
Continuously
Review of concomitant
X
X
X
X
X
LaboratoryTests
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, Phosphate, Mg, Na,
K, Cl, LDH, Glucose, TSH (with reflexive Free T4
and Free T3 only if TSH is abnormal)
Note: Week 1 Laboratory tests do not need to be
repeated if performed within 14 days prior to first dose
Albumin, ACTH, cortisol, amylase, and lipase as 
clinically indicated.
PregnancyTest
X
X
X
Within 24 hours prior to the initial administration of
study drug, then every 4 weeks ± 1 week. Serum or
Urine
Immunogenicityblood
sample
X
X
X
Details regarding specific sample timing are specified 
in Table 9.5.2-1
 
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Table 2-2:
On-Treatment Assessments Week 1 - Week 9 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 1
Day 1
Week 3
Day 1
Week 5
Day 1
Week 7
Day 1
Week 9
Notes
  
 
 
 
 
X
X
  
X
X
  
 
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-2:
On-Treatment Assessments Week 1 - Week 9 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 1
Day 1
Week 3
Day 1
Week 5
Day 1
Week 7
Day 1
Week 9
Notes
Biopsy of affected
  
 
Efficacy Assessments
Tumor 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 participants and until distant recurrence for stage III
participants)
See Section 9.1.4
Study Drug
IRT Randomize
X
Tumor tissue submitted to central lab must be logged 
as received and PDL1 results must be documented by 
the central lab in IRT prior to randomization. Allow 
approximately 10 business days to be processed from 
the date of receipt.
IRT Dispense Study
Treatment (Active drug
or placebo - blinded)
X
X
X
X
X
First dose to be administered within 3 calendar days of
randomization. Subsequent doses may be administered
within 3 days before or after the scheduled date if
necessary.
Full details of the dosing schedule are 
provided in Table 7.1-1
 
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Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-2:
On-Treatment Assessments Week 1 - Week 9 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 1
Day 1
Week 3
Day 1
Week 5
Day 1
Week 7
Day 1
Week 9
Notes
X
X
X
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments Week 10 - Week 19 (CA209915) (Participants on Arm A or Arm B)
Procedure
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
Within 72 hours prior to dosing
Vital Signs
X
X
X
X
X
Including BP, HR, temperature
Weight and performance status
X
X
X
X
X
Within 72 hours prior to dosing
Adverse Events Assessment
Continuously
X
X
X
LaboratoryTests
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, Phosphate, Mg, 
Na, K, Cl, LDH, Glucose, TSH (with reflexive 
Free T4 and Free T3 if TSH is abnormal)
Albumin, ACTH, cortisol, amylase, and lipase as 
clinically indicated
PregnancyTest
X
X
Every 4 weeks ± 1 week. 
Serum or Urine
Immunogenicityblood sample
X
Details regarding specific sample timing are 
specified in Table 9.5.2-1
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments Week 10 - Week 19 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 11
Day 1
Week 13
Day 1
Week 15
Day 1
Week 17
Day 1
Week 19
Notes
 
 
 
 
 
 
 
 
 
 
 
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Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments Week 10 - Week 19 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 11
Day 1
Week 13
Day 1
Week 15
Day 1
Week 17
Day 1
Week 19
Notes
 
 
 
 
 
EfficacyAssessments
Tumor 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 participants; until distant recurrence for stage
III participants)
See Section 9.1.4
Study Drug
IRT Dispense Study Treatment
(Active drug or placebo -
blinded)
X
X
X
X
X
Subsequent doses may be administered within 3
days before or after the scheduled date if
necessary.
Full details of dosing schedule are provided in 
Table 7.1-1
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments Week 10 - Week 19 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 11
Day 1
Week 13
Day 1
Week 15
Day 1
Week 17
Day 1
Week 19
Notes
 
X
X
X
ing
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Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-4:
On-Treatment Assessments Week 21 - Week 29 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 21
Day 1
Week 23
Day 1
Week 25
Day 1
Week 27
Day 1
Week 29
Notes
Safety Assessments
Targeted Physical Examination
X
X
X
X
X
Within 72 hours prior to dosing
Vital Signs
X
X
X
X
X
Including BP, HR, Temperature
Weight and performance status
X
X
X
X
X
Within 72 hours prior to dosing
Adverse Events Assessment
Continuously
LaboratoryTests
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, Phosphate, Mg,
Na, K, Cl, LDH, Glucose, TSH (with reflexive
Free T4 and Free T3 if TSH is abnormal)
Albumin, ACTH, cortisol, amylase, and lipase as 
clinically indicated
PregnancyTest
X
X
X
Every 4 weeks ± 1 week. Serum or Urine
Immunogenicityblood sample
X
Details regarding specific sample timing are 
specified in Table 9.5.2-1
 
 
 
 
 
 
 
 
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-4:
On-Treatment Assessments Week 21 - Week 29 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 21
Day 1
Week 23
Day 1
Week 25
Day 1
Week 27
Day 1
Week 29
Notes
 
 
 
  
 
 
 
 
 
 
  
 
EfficacyAssessments
Tumor SurveillanceAssessments
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 participants and until distant
recurrence for stage III participants)
See Section 9.1.4
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-4:
On-Treatment Assessments Week 21 - Week 29 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 21
Day 1
Week 23
Day 1
Week 25
Day 1
Week 27
Day 1
Week 29
Notes
Study Drug
IRT Dispense Study Treatment (Active
drug or placebo - blinded)
X
X
X
X
X
Subsequent doses may be administered within 3
days before or after the scheduled date if
necessary
Full details of dosing schedule are provided in 
Table 7.1-1
 
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-5:
On-Treatment Assessments Week 31 - Week 37 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1 Week
31
Day 1
Week 33
Day 1
Week 35
Day 1
Week 37
Notes
Safety Assessments
Targeted Physical Examination
X
X
X
X
Within 72 hours prior to dosing
Vital Signs
X
X
X
X
Including BP, HR, temperature
Weight and performance status
X
X
X
X
Within 72 hours prior to dosing
Adverse Events Assessment
Continuously
LaboratoryTests
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, Phosphate, Mg,
Na, K, Cl, LDH, Glucose, TSH (with reflexive
Free T4 and Free T3 if TSH is abnormal)
Albumin, ACTH, cortisol, amylase, and lipase as 
clinically indicated
PregnancyTest
X
X
Every 4 weeks ± 1 week. Serum or Urine
Immunogenicityblood sample
X
Details regarding specific sample timing are 
specified in Table 9.5.2-1
 
 
 
 
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-5:
On-Treatment Assessments Week 31 - Week 37 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1 Week
31
Day 1
Week 33
Day 1
Week 35
Day 1
Week 37
Notes
 
 
 
  
 
EfficacyAssessments
Tumor 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 participants and until
distant recurrence for stage III participants)
See Section 9.1.4
Study Drug
IRT Dispense Study Treatment (Active
drug or placebo - blinded)
X
X
X
X
Subsequent doses may be administered within 3
days before or after the scheduled date if
necessary
 
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-6:
On-Treatment Assessments Week 39 - Week 47 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 39
Day 1
Week 41
Day 1
Week 43
Day 1
Week 45
Day 1
Week 47
Notes
Safety Assessments
Targeted Physical Examination
X
X
X
X
X
Within 72 hours prior to dosing
Vital Signs
X
X
X
X
X
Including BP, HR, temperature
Weight and performance status
X
X
X
X
X
Within 72 hours prior to dosing
Adverse Events Assessment
Continuously
LaboratoryTests
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, Phosphate, Mg,
Na, K, Cl, LDH, Glucose, TSH (with reflexive
Free T4 and Free T3 if TSH is abnormal)
Albumin, ACTH, cortisol, amylase, and lipase as 
clinically indicated
PregnancyTest
X
X
Every 4 weeks ± 1 week. Serum or Urine
Immunogenicityblood sample
Details regarding specific sample timing are 
specified in Table 9.5.2-1
 
 
 
 
 
 
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Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-6:
On-Treatment Assessments Week 39 - Week 47 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 39
Day 1
Week 41
Day 1
Week 43
Day 1
Week 45
Day 1
Week 47
Notes
 
 
 
 
EfficacyAssessments
Tumor 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 participants and until distant recurrence for
stage III participants)
See Section 9.1.4
Study Drug
IRT Dispense Study Treatment
(Active drug or placebo - blinded)
X
X
X
X
X
Subsequent doses may be administered within 3
days before or after the scheduled date if necessary
 
Revised Protocol No.: 03
Date: 11-Mar-2019
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CA209915
BMS-936558
nivolumab
Table 2-7:
On-Treatment Assessments Week 48 - Week 49 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 49
Notes
Safety Assessments
Targeted Physical Examination
X
Within 72 hours prior to dosing
Vital Signs
X
Including BP, HR, temperature
Weight and performance status
X
Within 72 hours prior to dosing
Adverse Events Assessment
Continuously 
LaboratoryTests
X
Within 72 hrs. prior to dosing to include CBC w/differential, AST, ALT,
ALP, T. Bili, BUN or serum urea level, creatinine, Ca, Phosphate, Mg, Na, K,
Cl, LDH, Glucose, TSH (with reflexive Free T4 and Free T3 if TSH is 
abnormal)
Albumin, ACTH, cortisol, amylase, and lipase as clinically indicated
PregnancyTest
X
Every 4 weeks ± 1 week. Serum or Urine
Immunogenicityblood sample
Details regarding specific sample timing are specified in Table 9.5.2-1
 
 
 
 
 
 
 
 
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-7:
On-Treatment Assessments Week 48 - Week 49 (CA209915) (Participants on Arm A or Arm B)
Procedure
Day 1
Week 49
Notes
EfficacyAssessments
Tumor 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 participants
and until distant recurrence for
stage III participants)
See Section 9.1.4
Study Drug
IRT Dispense Study Treatment (Active drug
or placebo - blinded)
X
Subsequent doses may be administered within 3 days before or after the
scheduled date if necessary
 
Revised Protocol No.: 03
Date: 11-Mar-2019
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CA209915
BMS-936558
nivolumab
Table 2-8:
Arm C Open Label for Participants who continue on Ipilimumab 10 mg/kg
Procedure
At Dosing Visit
Notes
Safety Assessments
Targeted Physical Examination
X
To be performed within 72 hours prior to dosing
Vital Signs
X
Including BP, HR, temperature
Weight and performance status
X
Within 72 hours prior to dosing
Adverse Events Assessment
X
Laboratory Tests
X
Within 72 hrs. prior to dosing to include CBC w/differential, AST, ALT, ALP, T. Bili, BUN or 
serum urea level, creatinine, Ca, Phosphate, Mg, Na, K, Cl, LDH, Glucose, TSH (with reflexive 
Free T4 and Free T3 only if TSH is abnormal)
Albumin, ACTH, cortisol, amylase, and lipase as clinically indicated.
Pregnancy Test
X
Serum or Urine. Pregnancy test not required at week 13.
Efficacy Assessments
Tumor Surveillance Assessments
See comment
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 participants and until distant 
recurrence for stage III participants) See Section 9.1.4
Study Drug
IRT Dispense Study Treatment
X
IRT will dispense study treatment (open-label)
Doses may be administered within 3 days before or after the scheduled date if necessary
On treatment visits at week 1, 4, 7, 10, 13, 24, 36 and 48 should take place. (There is no dosing at Week 13, only safety assessments.) These participants will have 
these visits only.
These participants will also have laboratory tests and pregnancy test at each of these visits (pregnancy test is not required at Week 13 for these subjects as no study 
medication is administered at this visit).
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CA209915
BMS-936558
nivolumab
Table 2-9:
Arm C Open Label for Participants who switch to Nivolumab 480 mg Q4W
Procedure
At Dosing Visit 
(Q4W)
Notes
Safety Assessments
Targeted Physical Examination
X
To be performed within 72 hours prior to dosing
Vital Signs
X
Including BP, HR, temperature
Weight and performance status
X
Within 72 hours prior to dosing
Adverse Events Assessment
X
Laboratory Tests
X
Within 72 hrs. prior to dosing to include CBC w/differential, AST, ALT, ALP, T. Bili, BUN or 
serum urea level, creatinine, Ca, Phosphate, Mg, Na, K, Cl, LDH, Glucose, TSH (with reflexive 
Free T4 and Free T3 only if TSH is abnormal)
Albumin, ACTH, cortisol, amylase, and lipase as clinically indicated.
Pregnancy Test
X
Within 24 hours prior to the initial administration of study drug, then every 4 weeks ± 1 week. 
Serum or Urine
Immunogenicity blood sample
Not required
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-9:
Arm C Open Label for Participants who switch to Nivolumab 480 mg Q4W
Procedure
At Dosing Visit 
(Q4W)
Notes
 
 
 
 
 
Efficacy Assessments
Tumor Surveillance Assessments
See comment
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 participants and until distant 
recurrence for stage III participants) See Section 9.1.4
Study Drug
IRT Dispense Study Treatment
X
IRT will dispense study treatment (open-label)
Doses may be administered within 3 days before or after the scheduled date if necessary
Revised Protocol No.: 03
Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-9:
Arm C Open Label for Participants who switch to Nivolumab 480 mg Q4W
Procedure
At Dosing Visit 
(Q4W)
Notes
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CA209915
BMS-936558
nivolumab
Table 2-10:
Follow-Up Procedural Outline (CA209915)
Procedure
Follow-up,
Visits 1 and 2a
Survival,
Follow up Visitsb
Notes
Safety Assessments
Targeted Physical Examination
X
Adverse Events Assessment
X
X
Record at each visit. Collect continuously throughout the treatment 
period and for a minimum of 100 days following discontinuation of 
dosing.
LaboratoryTests
X
CBC w/ differential, chemistry panel, thyroid test for Follow-up 
Visit 1 (repeat at Visit 2 if toxicities are present). Refer to 
Section 9.4.4 Clinical Safety Laboratory Assessments for list of 
laboratory test.
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.
PregnancyTest
X
Serum or urine
Immunogenicityblood sample
Xf
Details regarding specific sample timing are 
specified in Table 9.5.2-1
 
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Date: 11-Mar-2019
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-10:
Follow-Up Procedural Outline (CA209915)
Procedure
Follow-up,
Visits 1 and 2a
Survival,
Follow up Visitsb
Notes
EfficacyAssessments
Tumor SurveillanceAssessment 
Every 12 weeks (± 7 days) < 12 monthd
Every 12 weeks (± 14 days) > 12 months
through 36 monthsd,
Every 6 months (± 4 weeks) > 36 months
through and up to Year 5d,
Until local, regional, or distant recurrence
(whichever comes first) for stage IV
participants and until distant recurrence for
stage III participants.
All time points are relative to the first dose
of study treatment.
See Section 9.1.4
Note: If a participant starts systemic therapy for melanoma
recurrence after study drug discontinuation, follow-up scans should
be discontinued. If a participant starts systemic therapy for a new
non-melanoma tumor after study drug discontinuation, follow-up
scans can be done as per standard of care.
Survival Status
Survival status
X
X
Every 3 months (± 14 days), maybe accomplished by visit or phone
contact, to include subsequent anti-cancer therapye
 
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Clinical Protocol
CA209915
BMS-936558
nivolumab
Table 2-10:
Follow-Up Procedural Outline (CA209915)
Procedure
Follow-up,
Visits 1 and 2a
Survival,
Follow up Visitsb
Notes
 
a Follow-up visit 1 (FU1) = 30 days (± 7 days) from the last dose or coincide with the date of discontinuation (± 7 days) 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; subsequent survival FU visits every 3 months (± 14 days)
c
d Every 12 weeks (± 7 days) through 12 months for participants who discontinued early from treatment (relative to the first dose of study drug); 
Every 12 weeks (± 14 days) if > 12 months through 36 months (relative to the first dose of study drug)
Every 6 months (± 4 weeks) if > 36 months through and up to Year 5 (relative to the first dose of study drug).
e Phone contacts during the survival follow-up visits are only allowed at time periods between surveillance assessment visits.
f
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
• To compare the efficacy, as measured by recurrence-free survival 
(RFS), provided by nivolumab plus ipilimumab versus nivolumab 
monotherapy in participants with completely resected stage IIIb/c/d
or stage IV no evidence of disease (NED) melanoma 
(in all randomized participants with PD-L1 expression level < 1%. 
and all randomized participants)
• Recurrence-free survival, RFS
Secondary
• To compare the overall survival provided by nivolumab plus 
ipilimumab versus nivolumab monotherapy in participants with 
completely resected stage IIIb/c/d or stage IV NED melanoma
(in all randomized participants with PD-L1 expression level < 1%. 
and all randomized participants)
• Overall survival (OS)
• To evaluate the association between PD-L1 expression and RFS
• PD-L1 expression
• Objective 
response 
rates 
(if 
applicable)
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CA209915
BMS-936558
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
• Duration of treatment on next-line 
therapies
• PFS2 defined as time from 
randomization to second 
recurrence/objective disease 
progression, or death from any 
cause, whichever occurs first.
• To evaluate investigator-assessed outcomes on next-line therapies
• End-of-next-line-treatment: To be 
used for situations where PFS2 
cannot be reliably determined. 
Event defined as end or 
discontinuation of next-line 
treatment, second objective 
disease progression, or death from 
any cause, whichever occurs first.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BMS-936558
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5
STUDY DESIGN
5.1
Overall Design
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
This is a Phase 3, randomized, double-blind study of nivolumab plus ipilimumab vs nivolumab 
monotherapy in participants (≥12 years) with completely resected stage IIIb/c/d or stage IV no 
evidence of disease (NED) melanoma.
Participants will be treated with one of the following:
•
Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of 
study drug treatment) 
•
Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab 
placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on 
Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
−
The original study design included an ipilimumab monotherapy arm (Arm C). 
Randomization into Arm C was discontinued upon implementation of Amendment 06. 
Sites who have randomized patients to the ipilimumab arm will be unblinded to that 
information and the patients will be allowed to continue as open-label on either ipilimumab
10 mg/kg IV Q3 weeks for 4 doses, then Q12 weeks starting at Week 24 or switch to the 
nivolumab 480 mg IV Q4 weeks in 8 weeks after the last dose of ipilimumab. The change 
will be implemented upon IRT modification.
−
For adolescents between 12 to < 18 years of age the dosing of nivolumab is body weight 
based dosing as follows: Q2 week dosing - 3 mg/kg IV Q2 weeks up to a maximum of 240 
mg; Q4 week dosing - 6 mg/kg Q4 weeks up to a maximum of 480 mg. This will be 
applicable for participants enrolled after IRB approval of Revised Protocol 02 and will be 
implemented upon IRT modification.
Approximately 2000 participants will be randomized in a 1:1 ratio to nivolumab plus ipilimumab 
versus nivolumab monotherpy and stratified by PD-L1 status (PD-L1 expression < 1% or 
indeterminate, 1% - < 5%, ≥5% tumor cell surface expression) and American Joint Committee on 
Cancer (AJCC) stage IIIb vs stage IIIc/d vs stage IV (Appendix 1). Accrual will be stopped when 
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BMS-936558
nivolumab
approximately 600 participants with PD-L1 expression level < 1% will be randomized in a 1:1 
ratio to nivolumab plus ipilimumab and nivolumab respectively. The prevalence of participants 
with PD-L1 expression level < 1% is expected to be around 30% of all randomized participants.  
Therefore, it is estimated that approximately 2000 participants will be randomized in a 1:1 ratio to 
nivolumab plus ipilimumab and nivolumab respectively. No more than 1400 participants with PD-
L1 expression level ≥1% will be randomized to nivolumab plus ipilimumab and nivolumab 
respectively. In addition, there will be a number of participants that were already randomized to 
the ipilimumab arm under the original protocol.
All participants will be treated until recurrence of disease, unacceptable toxicity, or participant 
withdrawal of consent with a maximum of 1 year of 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 9. 
Screening Phase:
•
Begins by establishing the participant’s initial eligibility and signing of the informed consent 
form (ICF)
•
Participant is enrolled using the IRT
•
Participant is assessed for complete study eligibility within the required timeframe found in
Table 2-1
•
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 participant 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
Treatment Phase:
•
Following confirmation of the participant’s eligibility, the randomization call to the IRT can 
be made. The participant is randomly assigned to receive either nivolumab plus ipilimumab, 
nivolumab monotherapy.
•
Within 3 calendar days from randomization the participant 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
•
 
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•
Treated participants will be evaluated for recurrence every 12 weeks ± 7 days. No central 
imaging assessments are planned. Scans will be submitted to central vendor for collect and 
hold, once the participant has been randomized and throughout the study period.
•
 
•
This phase ends when the participant 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 
8.1.
Follow-up Phase:
•
Begins after 1 year of treatment or when the decision is made to discontinue a participant from 
study therapy
•
•
After completion of the first two follow -up visits, participants will be followed every 3 months 
for survival
•
Participants 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 participants and until distant recurrence for stage III participants)
•
Tumor surveillance assessments should occur every 12 weeks ± 7 days during the first year 
after randomization, every 12 weeks ±14 days from 12 months to 36 months after 
randomization.  From 36 months until Year 5 after the first dose of study treatment, 
assessments should be performed every 6 months (± 4 weeks). No central imaging assessments
are planned. Scans will be submitted to central vendor for collect and hold, once the participant
has been randomized and throughout the study period.
•
Participants will be followed for drug-related toxicities according to the Section 9. All 
toxicities will be documented for a minimum of 100 days after the last dose of study medication
•
5.1.1
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 CA209915. Additionally, the DMC will provide advice to the 
sponsor regarding actions the committee deems necessary for the continuing protection of 
participants enrolled in the study. The DMC will be charged with assessing such actions in light 
of an acceptable benefit/risk profile for nivolumab in combination with ipilimumab, nivolumab
and ipilimumab. The DMC will act in an advisory capacity to BMS and will monitor participant
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. 
Details of the DMC responsibilities and procedures will be specified in the DMC charter.
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5.2
Number of Participants
Approximately 2000 participants will be randomized in a 1:1 ratio to nivolumab plus ipilimumab 
versus nivolumab monotherapy (1000 vs 1000 participants) and stratified by PD-L1 status (PD-
L1 expression < 1% or indeterminate, 1% - < 5%, ≥5% tumor cell surface expression) and 
American Joint Committee on Cancer (AJCC) stage IIIb vs stage IIIc/d vs stage IV. In addition, 
there are a number of participants who have already been randomized to the ipilimumab arm under 
the original protocol. Accrual will be stopped when approximately 600 participants with PD-L1 
expression level < 1% will be randomized in a 1:1 ratio to nivolumab plus ipilimumab and 
nivolumab respectively. The prevalence of participants with PD-L1 expression level < 1% is 
expected to be around 30% of all randomized participants. Therefore, it is estimated that 
approximately 2000 participants will be randomized in a 1:1 ratio to nivolumab plus ipilimumab 
and nivolumab respectively. No more than 1400 participants with PD-L1 expression level ≥1% 
will be randomized to nivolumab plus ipilimumab and nivolumab respectively.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant entered. End of trial is 
defined as the last visit or scheduled procedure shown in the Schedule of Activities for the last 
participant. Study completion is defined as the final date on which data for the primary endpoint 
was or is expected to be collected, if this is not the same.
The total duration of the study from start of randomization to final analysis of OS is expected to 
be approximately 5 years. The study will end once survival follow-up has concluded.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
participant care
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, tumor biopsies, and other requirements of the study
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2) Type of Participant and Target Disease Characteristics
a) All participants must be either stage IIIb/c/d or stage IV AJCC (AJCC Cancer Staging, 
8th edition; see also Appendix 1) and have histologically confirmed melanoma that is 
completely surgically resected in order to be eligible. All melanomas, except ocular/uveal 
melanoma, regardless of primary site of disease will be allowed; mucosal melanomas are 
eligible. Participants must have been surgically rendered free of disease with negative 
margins on resected specimens.
When T is....
And N is.....
And M is....
The pathological stage is...
T0
N1b, N1c
M0
IIIB
T0
N2b, N2c, 
N3b, N3c
M0
IIIC
T1a/b-T2a
N1b/c or 
N2b
M0
IIIB
T2b/T3a
N1a-N2b
M0
IIIB
T1a-T3a
N2c or 
N3a/b/c
M0
IIIC
T3b/T4a
Any N ≥N1
M0
IIIC
T4b
N1a-N2c
M0
IIIC
T4b
N3a/b/c
M0
IIID
Ant T, Tis
Any N
M1
IV
i)
If stage III melanoma (whether stage IIIb or IIIc or IIId) the participants should have 
clinical or radiographic evidence of regional metastases, either in the regional lymph 
nodes or locoregional metastases manifesting as satellite or in-transit metastases, or 
microsatellites discovered at the time of microscopic evaluation of the primary tumor 
diagnostic biopsy. Participants must have pathological evidence of regional metastases, 
regional lymph node and/or microsatellite/satellite/in-transit metastases, and no distant 
metastasis. The pathology report for stage IIIb, IIIc, and IIId must be reviewed, signed 
and dated by the investigator; this process will be confirmed during the IRT 
randomization call.
ii) If stage IV melanoma, the pathology report confirming negative margins must be 
reviewed, dated, and signed by the investigator prior to randomization.
iii) For CNS lesion(s), documentation indicating that there has been complete resection of 
CNS lesion(s) will suffice as confirmation of negative margins
b) 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
c) Complete resection must be performed within 12 weeks prior to randomization 
d) All participants 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 or MRI scans of the chest, abdomen, pelvis, and all known sites of 
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resected 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). Participants 
with equivocal lymph nodes ≥10 mm and < 15 mm in a short axis may be eligible if 
confirmation with histology/cytology is available. If risk of biopsy is too high or biopsy is
not feasible, two sequential CT or MRI scans should be available and showing no 
progressive and measureable disease or PET/CT demonstrating no FDG uptake. The 
second scan should occur at least 4 weeks after the initial scan. Lymph nodes ≥15 mm in 
a short axis are defined as pathological.
e) The complete set of baseline images must be available before randomization
f)
ECOG performance status score of 0 or 1 (Appendix 2)
g) Tumor tissue from the resected site of disease must be provided for biomarker analyses
(preferably collected within 12 weeks of assessment time). In order to be randomized, a 
participant must have quantifiable PD-L1 expression (< 1% or 1% - < 5% or ≥5% tumor 
cell membrane staining) or be classified as PD-L1 indeterminate. If insufficient tumor 
tissue content is provided for analysis, acquisition of additional tumor tissue (block and/or 
slides) for the biomarker analysis is required.
h) Participants must not have received anti-cancer therapy (for example but not limited to 
systemic, local, radiation, radiopharmaceuticals) for their melanoma except:
i)
Surgery for the melanoma lesion(s) 
ii) Adjuvant radiation therapy (RT) after neurosurgical resection for central nervous 
system (CNS) lesions 
iii) Prior adjuvant interferon if completed ≥6 months prior to randomization
i)
Prior treated central nervous system (CNS) metastases must be without MRI evidence of 
recurrence for at least 4 weeks after treatment. Participants 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.
i)
The 4-week period of stability is measured after the completion of the neurologic 
interventions, ie, surgery and/or radiation
j)
In addition to neurosurgery to treat CNS metastases, adjuvant radiation after resection of 
CNS metastases 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.
k) Prior surgery that required anesthesia must be completed at least 4 weeks before drug 
administration. Surgery requiring local/epidural anesthesia must be completed at least 
72 hours before study drug administration.
3) Age and Reproductive Status
a) Males and Females, at least 12 years of age, except where local regulations and/or 
institutional policies do not allow for participants < 18 years of age (pediatric population) 
to participate. For those sites, the eligible participant population is ≥18 years of age.
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b) Women of childbearing potential (WOCBP, Appendix 3) must have a negative serum or 
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study treatment
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of study drug treatment and 5 months after the 
last dose of study treatment (ie, 30 days [duration of ovulatory cycle] plus the time required 
for the study drug to undergo approximately five half-lives).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment and 7 months after the last 
dose of study treatment {ie, 90 days (duration of sperm turnover) plus the time required for 
study drug to undergo approximately five half-lives}
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception (Appendix 3)
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) History of ocular/uveal melanoma
b) Weight ≤40 kg “Not applicable as per amendment 07”
c) Participants with active, known, or suspected autoimmune disease. Participants with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
d) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.  
e) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone or equivalent, are permitted in the absence of active 
autoimmune disease
f)
Pregnant or nursing women
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2) Prior/Concomitant Therapy
a) 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 
participants 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
b) 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
c) Treatment with botanical preparations (eg herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to randomization/treatment. Refer to Section 7.7.1 for prohibited therapies.
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100*103/μL
d) Hemoglobin < 9.0g/dL
e) Serum creatinine > 1.5 × ULN, unless creatinine clearance ≥40 mL/min (measured or 
calculated using Cockcroft-Gault formula)
f)
AST/ALT > 3.0 × ULN
g) Total bilirubin > 1.5 × ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 × ULN)
h) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative)
i)
Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). Note:  Testing for HIV must be performed 
at sites where mandated locally.
4) Allergies and Adverse Drug Reaction
a) History of Grade ≥3 allergy to human monoclonal antibodies
b) History of allergy or hypersensitivity to study drug components
c) As per Amendment 06, this criteria has been moved under “Medical Conditions” as 1d.
d) Excluding participants with serious or uncontrolled medical disorders
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5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included as a participant. Strict 
conditions apply and Bristol-Myers Squibb approval is required).
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) 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 participant before registration in the trial.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable; no lifestyle restrictions are required.
6.3.1
Meals and Dietary Restrictions
Not applicable
6.3.2
Caffeine, Alcohol and Tobacco
Not applicable
6.3.3
Activity
Not applicable
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant re-enrollment: this study permits the re-enrollment of a participant who has 
discontinued the study as a screen failure (ie, participant has not been randomized/has not been 
treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
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Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
In this protocol, investigational products are nivolumab and ipilimumab (Table 7-1).
Table 7-1:
Study treatments for CA209915
Product Description/
Class / Dosage Form
Potency
IP/Non-IMP
Packaging / 
Appearance
Storage 
Conditions
BMS-936558
Nivolumab Solution for 
Injection
100 mg 
(10 mg/mL)
or
40 mg 
(10 mg/mL)
IP
10 mL per vial
(5 or 10 vials per 
carton)
or
4 mL/vial
(240 mg kits: 
2-100 mg vials 
and 1-40 mg vial)
Store at 2○ - 8○ C
Protect from light 
and freezing
Ipilimumab Solution for 
Injection
200 mg
(5 mg/mL)
IP
40 mL/vial
(4 vials/carton)
Store at 2○ - 8○ C
Protect from light 
and freezing
Placebo
Placebo for Nivolumab or Ipilimumab will be considered as drug diluent alone, 
either Normal Saline or Dextrose 5%. Preparation of placebo, blinding and 
labeling will be outlined in the CA209915 pharmacy manual.
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7.1
Treatments Administered
Arm A (Nivolumab + Ipilimumab) Dosing:
Participants randomized to Arm A will receive treatment with nivolumab at a dose of 240 mg as a 
30-minute infusion on Day 1 every 2 weeks plus ipilimumab 1 mg/kg as a 30-minute infusion 
every 6 weeks until progression, unacceptable toxicity, withdrawal of consent, or the study ends, 
whichever occurs first with a maximum of 1 year total duration of study medication. For 
adolescents between 12 to < 18 years of age, use the body weight-based dosing for nivolumab of 
3 mg/kg Q2W up to a maximum of 240 mg. This will be applicable for participants enrolled after 
IRB approval of Revised Protocol 02 and will be implemented upon IRT modification. Participants 
should begin study treatment within 3 calendar days of randomization.
When study drugs (nivolumab and ipilimumab) are to be administered on the same day, nivolumab 
is to be administered first. Nivolumab infusion must be promptly followed by a saline flush to 
clear the line of nivolumab before starting the ipilimumab infusion. The second infusion will 
always be the ipilimumab study drug and will start after the infusion line has been flushed, filters 
changed and participant has been observed to ensure no infusion reaction has occurred. The time 
in between infusions is expected to be approximately 30-minutes but may be more or less 
depending on the situation.
Participants may be dosed with nivolumab no less than 12 days from the previous dose. There are 
no premedications recommended.
Participants should be carefully monitored for infusion reactions. If an acute infusion reaction is 
noted, participant should be managed according to Section 7.4.2.
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending 
on how well the participant tolerates the treatment. For more details, see Sections 7.4 (dose 
modification) and Section 8 (discontinuations).
Please refer to the current version of the Investigator Brochure and/or pharmacy manual for 
complete preparation, storage, and handling information for nivolumab and ipilimumab.
Arm B (Nivolumab) Dosing:
Participants should receive nivolumab at a dose of 480 mg as a 30 minute infusion on Day 1 of 
each treatment cycle every 4 weeks until progression, unacceptable toxicity, withdrawal of 
consent, or the study ends, whichever occurs first with a maximum of 1-year total duration of study 
medication. For adolescents between 12 to < 18 years of age, use the body weight-based dosing 
for nivolumab 6 mg/kg Q4W up to a maximum of 480 mg. This will be applicable for participants 
enrolled after IRB approval of Revised Protocol 02 and will be implemented upon IRT 
modification. Participants should begin study treatment within 3 calendar days of randomization. 
In order to maintain the blind, nivolumab placebo will be administered on D1WK3, D1WK7, 
D1WK11, D1WK15, D1WK19, D1WK23, D1WK27, D1WK31, D1WK35, D1WK39, D1WK43 
and D1WK47. Ipilimumab placebo will be administered on D1WK1, D1WK7, D1WK13, 
D1WK19, D1WK25, D1WK31, D1WK37, D1WK43, and D1WK49. (See Table 7.1-1)
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For participants who have been randomized to Arm C: (Ipilimumab) before the 
implementation of Amendment 06:
Sites that have randomized participants to the ipilimumab arm will be unblinded to that 
information and the participants will be allowed to continue as open-label on either ipilimumab 10
mg/kg or switch to nivolumab 480 mg. The change will be implemented upon IRT modification
For participants who continue on Ipilimumab 10 mg/kg:
Open label
Participants should continue receiving ipilimumab at a dose of 10 mg/kg as a 90-minute IV 
infusion, on Day 1 of each treatment cycle every 3 weeks for 4 doses, then every 12 weeks 
beginning at Week 24, until progression, unacceptable toxicity, withdrawal of consent, or the study 
ends, whichever occurs first with a maximum of 1-year total duration of study medication. 
Participants should begin study treatment within 3 calendar days of randomization. (See Table 2-
8)
For Participants who switch to Nivolumab 480 mg. 
Open-label.
The first dose of nivolumab 480 mg should occur 8 weeks +/- 3 days after the last dose of 
ipilimumab 10 mg/kg. Participants should receive nivolumab at a dose of 480 mg as a 30 minute 
IV infusion in each treatment cycle every 4 weeks until progression, unacceptable toxicity, 
withdrawal of consent, or the study ends, whichever occurs first, with a maximum of 1-year total 
duration of study medication starting from first dose of ipilimumab 10 mg/kg. (See Table 2-9) For 
adolescents between 12 to < 18 years of age, use the body weight-based dosing for nivolumab 6 
mg/kg Q4W up to a maximum of 480 mg. The change will be implemented upon IRT modification. 
Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to 
re-calculate subsequent doses if the participant weight is within 10% of the weight used to calculate
the previous dose. All doses should be rounded up or to the nearest milligram per institutional 
standard.
Table 7.1-1 outlines the dosing schedule for Arms A and B in this study.
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Table 7.1-1:
Dosing Schedule for Study CA209915a,b
D1, W1
D1, W3
D1, W5
D1, W7
D1, W9
Arm Ac
Nivo 240 mg
Ipi 1 mg/kg
Nivo 240 mg
Nivo 240 mg
Nivo 240 mg
Ipi 1 mg/kg
Nivo 240 mg
Arm Bd
Nivo 480 mg
Placebo- ipi
Placebo - nivo
Nivo 480 mg
Placebo - nivo
Placebo - ipi
Nivo 480 mg
D1, W11
D1, W13
D1, W15
D1, W17
D1, W19
Arm A
Nivo 240 mg
Nivo 240 mg
Ipi 1 mg/kg
Nivo 240 mg
Nivo 240 mg
Nivo 240 mg
Ipi 1 mg/kg
Arm B
Placebo - nivo
Nivo 480 mg
Placebo - ipi
Placebo - nivo
Nivo 480 mg
Placebo - nivo
Placebo - ipi
D1, W21
D1, W23
D1, W25
D1, W27
D1, W29
Arm A
Nivo 240 mg
Nivo 240 mg
Nivo 240 mg
Ipi 1 mg/kg
Nivo 240 mg
Nivo 240 mg
Arm B
Nivo 480 mg
Placebo - nivo
Nivo 480 mg
Placebo - ipi
Placebo - nivo
Nivo 480 mg
D1, W31
D1, W33
D1, W35
D1, W37
D1, W39
Arm A
Nivo 240 mg
Ipi 1 mg/kg
Nivo 240 mg
Nivo 240 mg
Nivo 240 mg
Ipi 1 mg/kg
Nivo 240 mg
Arm B
Placebo - nivo
Placebo - ipi
Nivo 480 mg
Placebo - nivo
Nivo 480 mg
Placebo - ipi
Placebo - nivo
D1, W41
D1, W43
D1, W45
D1, W47
D1, W49
Arm A
Nivo 240 mg
Nivo 240 mg
Ipi 1 mg/kg
Nivo 240 mg
Nivo 240 mg
Nivo 240 mg
Ipi 1 mg/kg
Arm B
Nivo 480 mg
Placebo - nivo
Placebo - ipi
Nivo 480 mg
Placebo - nivo
Nivo 480 mg
Placebo - ipi
a Nivo = nivolumab, Ipi = ipilimumab
b For adolescents between 12 to < 18 years of age the dosing of nivolumab is body weight based dosing as follows 
Q2 week dosing - 3 mg/kg IV Q2 weeks up to a maximum of 240 mg; Q4 week dosing - 6 mg/kg Q4 weeks up to 
a maximum of 480 mg. This will be applicable for participants enrolled after IRB approval of Revised Protocol 02 
and will be implemented upon IRT modification.
c Arm A: Nivo 240 mg Q2W + Ipi 1 mg/kg Q6W 
d Arm B: Nivo 480 mg Q4W (nivo placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab 
placebo Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49)
7.2
Method of Treatment Assignment
After the participant’s initial eligibility is established and informed consent has been obtained, the 
participant must be enrolled into the study through IRT web to obtain the participant number. 
Every participant that signs the informed consent form must be assigned a participant number in 
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IRT. Specific instructions for using IRT will be provided to the investigational site in a separate 
document. The investigator or designee will register the participant for enrollment by following 
the enrollment procedures established by BMS. The following information is required for 
enrollment:
•
Date that informed consent was obtained
•
Date of birth
•
Gender at birth.
Once enrolled in IRT, enrolled participants that have met all eligibility criteria (including the 
required tumor tissue being received and processed and PD-L1 expression levels logged into the 
IRT by the central laboratory as well as the pathology report being approved by the investigator)
will be ready to be randomized through the IRT. The randomization call will be performed by the 
unblinded pharmacy site staff. The following information is required for participant 
randomization:
•
Participant number
•
Date of birth
•
Participants will be stratified by:
−
PD-L1 evaluable status (PD-L1 expression < 1% or indeterminate, 1% - <5%, ≥  5% tumor 
cell surface expression) is entered by the central laboratory into the IRT system and both 
the site and the BMS study team remain blinded to the result. The statistician may be 
unblinded to the participant’s PD-L1 status results in order to track the overall number of 
events in the primary population (subjects with PD-L1 < 1%).
−
AJCC Stage, 8th edition
♦stage IIIb
♦stage IIIc/d
♦stage IV
Participants will be treated with one of the following:
•
Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year
of treatment) 
•
Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of treatment) with nivo placebo on 
Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo Weeks 1, 7, 13, 
19, 25, 31, 37, 43, & 49
The original study design included an ipilimumab monotherapy arm (Arm C). Randomization into 
Arm C was discontinued upon implementation of Amendment 06. Sites that have randomized 
participants to the ipilimumab arm will be unblinded to that information and the participants will 
be allowed to continue as open-label on either ipilimumab 10 mg/kg IV Q3W for 4 doses, then 
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Q12W starting at Week 24 or switch to nivolumab 480 mg IV Q4W after 8 weeks +/- 3 days
washout after the last dose of ipilimumab. The change will be implemented upon IRT 
modification. See Table 2-8 and Table 2-9 for additional information.
The exact procedures for using the IRT will be detailed in the IRT manual.
7.3
Blinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of the 
investigational product is critical to the participant's management, the blind for that participant 
may be broken by the investigator. The participant’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, ie, that it will alter the participant'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 participant 
is receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The actual task of unblinding can be delegated by the investigator to a designee 
assigned the task on the Delegation of Authority. The Principal Investigator should only call in for 
emergency unblinding AFTER the decision to discontinue the participant has been made.
For this study, the method of unblinding for emergency purposes is IRT.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a participant for non-emergency purposes must be discussed with the 
Medical Monitor.
In case of an emergency, the investigator(s) has unrestricted access to randomization information 
via the Interactive Response Technology system (IRT) and is capable of breaking the blind through 
the IRT system without prior approval from sponsor. Following the unblinding the Investigator 
shall notify the medical monitor and/or study director.
Designated staff of BMS Research & Development may be unblinded prior to database lock to 
facilitate the bioanalytical analysis of pharmacokinetic samples and immunogenicity. A 
bioanalytical scientist in the Bioanalytical Sciences department of BMS Research & Development 
(or a designee in the external central bioanalytical laboratory) will be unblinded to the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples. The 
unblinded data will not impact the data integrity of the study. The pharmacist at the site and/or 
designate will be unblinded to the randomized treatment assignments in order to dispense treatment 
from bulk supplies, as needed. Except as noted above, other members of BMS Research and 
Development will remain blinded.
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To further minimize bias, the sponsor central study team and the investigative clinical site staff are 
blinded to results from PD-L1 analysis. Designated staff (ie, statistician) may be unblinded to the 
participant’s PD-L1 status results in order to track the overall number of events in the primary 
population (subjects with PD-L1 < 1%). The unblinded data will not impact the data integrity of 
the study.
7.4
Dose Modification
Dose reductions or dose escalations are not permitted. All dose modification rules apply to all arms 
given the blinded nature of this study.
7.4.1
Dose Delay Criteria
Dose delay criteria apply for all drug-related adverse events regardless of whether or not the event 
is attributed to nivolumab, ipilimumab, or both. All study drugs must be delayed until treatment 
can resume (Section 7.4.3).
Dose delay criteria also apply to the placebo version of each agent, given the blinded nature of this 
study. Study drug administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
o
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
o
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section 8)
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Participants who require delay of study drug administration should be re-evaluated weekly or more 
frequently if clinically indicated and resume dosing when re-treatment criteria are met.
7.4.2
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 participant 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 
participant with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor participant 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 participant closely. If symptoms recur then no further nivolumab 
or ipilimumab will be administered at that visit. Administer diphenhydramine 50 mg IV, and 
remain at bedside and monitor the participant until resolution of symptoms. The amount of study 
drug infused must be recorded on the electronic case report form (eCRF). 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 participant 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. Participant should be monitored until the investigator is 
comfortable that the symptoms will not recur. Nivolumab or ipilimumab will be permanently 
discontinued. Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor participant until recovery 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).
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7.4.3
Criteria to Resume Treatment
Participants may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity
•
For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor (or designee).
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor (or 
designee). Adrenal insufficiency ≥Grade 3 requires discontinuation regardless of control with 
hormone replacement.
If the criteria to resume treatment are met, the participant should restart treatment at the next 
scheduled time point per protocol. However, if the treatment is withheld past the window period 
of the next scheduled time point per protocol to ensure adequate recovery from the adverse event 
or tapering of immunosuppression, the next scheduled time point will be delayed until dosing 
resumes.
If treatment is withheld > 6 weeks from the last dose, the participant must be permanently 
discontinued from study therapy, except as specified in Section 8.
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
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documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 4.
Please refer to the current version of the Investigator Brochure and/or pharmacy manual for 
complete preparation, storage, and handling information for nivolumab and ipilimumab.
7.5.1
Retained Samples for Bioavailability/Bioequivalence
Not applicable.
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability. 
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
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 participants. 
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 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
participants 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 participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
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7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
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BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of nivolumab is 
terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
study objectives; c) the participant can obtain medication from a government sponsored or private 
health program. In all cases BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of this 
event. In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please contact the Sponsor or designee 
within 24 hours of awareness of the pregnancy. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study drug, a discussion between the investigator 
and the Sponsor or designee must occur. 
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
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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, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, myocarditis, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:
o
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
*In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently discontinued. 
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study drug(s), a discussion between the investigator and the BMS Medical Monitor/designee must 
occur.
•
Any Grade 3 non-hormonal immune-mediated adverse reaction that recurs on reintroduction 
of nivolumab or ipilimumab, or a requirement for 10 mg per day or greater of prednisone or 
prednisone equivalent for more than 12 weeks
•
Persistent Grade 2 or 3 immune-mediated adverse drug reactions that last 12 weeks or 
longer with exception for Grade 2 endocrinopathies.
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
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−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
•
Any event that leads to delay in dosing lasting >6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. 
Prior to re-initiating treatment in a participant with a dosing delay lasting >6 weeks, the BMS 
Medical Monitor (or designee) must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
should also continue every 6 weeks or more frequently if clinically indicated during such dosing 
delays.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued study drug dosing.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
8.1.1
Rechallenge
See Section 7.4.3.
8.1.2
Post Study Treatment Study Follow-up
In this study, recurrence-free survival and OS are key endpoints of the study. Post study follow-
up is of critical importance and is essential to preserving participant safety and the integrity of the 
study. Participants who discontinue study treatment must continue to be followed for collection of 
tumor surveillance assessments and survival follow-up data as required and in line with Section 5 
until death or the conclusion of the study.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window (see Table 2-10). At the time of this request, each participant will be 
contacted to determine their survival status unless the participant has withdrawn consent for all 
contacts or is lost to follow-up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
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participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and timing are summarized in the Schedule of Activities, Section 2. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
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•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
•
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 induced liver enzyme evaluations) will be monitored during the follow-up phase via on 
site/local labs until all study drug related toxicities resolve, return to baseline, or are deemed 
irreversible.
•
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, 
cough, and fever) consistent with possible pulmonary adverse events, the participant should be 
immediately evaluated to rule out pulmonary toxicity, according to the suspected pulmonary 
toxicity management algorithm in the BMS-936558 (nivolumab) Investigator Brochure.
•
Some of the assessments referred to in this section may not be captured as data in the eCRF. 
They are intended to be used as safety monitoring by the treating physician. Additional testing 
or assessments may be performed as clinically necessary or where required by institutional or 
local regulations.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 2.  Baseline disease 
assessments should be performed within 28 days prior to randomization utilizing CT or MRI.  This 
includes a CT or MRI scans of chest, abdomen, pelvis, and all known sites of resected disease in 
the setting of stage IIIb/c/d and stage IV, and brain MRI (brain CT allowable if MRI is 
contraindicated or if there is no known history of resected brain lesions). Participants will be 
evaluated for presence or continued lack of tumor until local, regional, or distant recurrence 
(whichever comes first) for stage IV participants and until distant recurrence for stage III 
participants 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 36 months after randomization, efficacy assessments should be every 12 weeks (±
14 days). From > 36 months until Year 5 after first dose of study treatment, efficacy assessments 
should be performed every 6 months (± 4 weeks).
If a participant starts systemic therapy for melanoma recurrence after study drug discontinuation, 
follow-up scans should be discontinued. If a participant starts systemic therapy for a new 
non-melanoma tumor after study drug discontinuation, follow-up scans can be done as per standard 
of care.
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9.1.1
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.
•
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 participants 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.
9.1.2
Methods of measurements 
•
Cross-sectional imaging
−
CT and MRI are an important part of the work-up to establish recurrence. Contrast 
enhanced CT and MRI are the preferred imaging modalities. See Section 9.1.4 for details.
−
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 
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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.
9.1.3
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
•
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 participant.
9.1.4
Imaging Assessment for the Study
Contrast enhanced CT or MRI scans of the chest, abdomen and pelvis and all other 
known/suspected sites of disease should be performed at all timepoints. 
•
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of 
the chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected 
sites of disease should be obtained. 
•
Should a participant have contraindication for both MRI and CT intravenous contrasts, a non-
contrast CT or non-contrast MRI of the chest, abdomen, pelvis, and other known/suspected 
sites of disease should be obtained. 
•
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition 
to contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, 
and other known/suspected sites of disease is acceptable.
At Screening, MRI (brain CT allowable if MRI is contraindicated) of the brain without and with 
contrast is required in participants with known history of brain metastases; Participants without 
known history of brain metastases should have head CT or MRI without and with contrast. On 
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treatment and follow-up, participants with a history of brain metastasis should have surveillance 
MRI approximately every 12 weeks, or sooner if clinically indicated; Participants without history 
of brain metastases should have MRI or CT if clinically indicated.
The same method of assessment used at Screening should be used for on-study timepoints. CT and 
MRI scans should be acquired with slice thickness of 5 mm or less with no intervening gap 
(contiguous). Every attempt should be made to image each participant using an identical 
acquisition protocol on the same scanner for all imaging timepoints. 
All participants must have disease-free status defined as no clinical or radiographic evidence of 
recurrence of disease documented by a complete physical examination and imaging studies within 
4 weeks prior to randomization. Participants with equivocal nodes ≥ 10 mm and < 15 mm in a
short axis may be eligible after if confirmation with histology/cytology is available. If risk of 
biopsy is too high or biopsy is not feasible, two sequential CT or MRI scans should be available 
and showing no signs of progressive and measurable disease or PET/CT demonstrating no FDG 
uptake. The second scan should occur at least 4 weeks after the initial scan. Lymph nodes ≥ 15 mm 
in a short axis are defined as pathological.
If recurrence is unequivocal (eg, multiple measurable lesions), confirmation with 
histology/cytology should be attempted but is not required.
If recurrence is equivocal, lymph node only, solitary lesion, confirmation with histology/cytology 
must be attempted. If risk of biopsy is too high or biopsy not feasible, either a follow-up CT or 
MRI scan showing progressive and measurable disease or PET/CT demonstrating unequivocal 
FDG uptake must confirm recurrence. Follow-up (confirmatory) scan should occur in 4-12 weeks 
after the initial scan. The date of initial scan showing recurrence will count as recurrence.
Imaging assessments will be submitted to a third party radiology vendor on an ongoing basis; 
participant management is not dependent on third-party review of tumor assessments.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 5.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting are specified in Appendix 5
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. 
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Immune-mediated adverse reactions 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 
IMARs 
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. In order to prospectively identify immune-mediated adverse 
reactions and to assist with the optimal management of such patients, please refer to the current 
version of the Investigator Brochure and the Adverse Event Management Algorithms for Immuno-
Oncology Agents (Appendix 6 to this protocol).
Information supporting the assessment will be collected on the participant’s case report form.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until the 
timepoints specified in the Schedule of Activities (Section 2). Nonserious AE information should 
also be collected from the start of a placebo lead-in period or other observational period intended 
to establish a baseline status for the participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants randomized to treatment and never treated with study 
drug, SAEs should be collected for 30 days from the date of randomization. If applicable, SAEs 
must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure, (eg, a follow-up skin biopsy).
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 5. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
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has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 5.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known adverse events, when appropriate for the program or protocol. Every adverse 
event must be assessed by the investigator with regard to whether it is considered immune-
mediated. For events which are potentially immune-mediated, additional information will be 
collected on the participant’s case report form.
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 5).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 5.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants randomized/assigned to treatment and never treated with 
study drug, SAEs should be collected for 30 days from the date of randomization.
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Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 5
In most cases, the study treatment will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24 
hours of awareness of the pregnancy.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
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9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Appendix 5 for reporting details).
Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times ULN
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Appendix 5, Safety).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities, Section 2.
Participants 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 2-10), 
toxicity assessments should be done in person. Once participants 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 participant’s status are 
acceptable. 
Adverse events and laboratory values will be graded according to the NCI CTCAE version 4.0.
Some of the 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.
9.4.1
Physical Examinations
Refer to Schedule of Activities.
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9.4.2
Vital signs
Refer to Schedule of Activities.
9.4.3
Electrocardiograms
Refer to Schedule of Activities.
9.4.4
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report. See the Schedule of 
Activities for specific assessments and time points.
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN)
Glucose
Amylase as clinically indicated 
Lipase as clinically indicated
Albumin at screening and as clinically indicated
Thyroid
Sodium
Potassium
Chloride
Calcium
Phosphate
Magnesium
Creatinine clearance (CLcr) - screening only
ACTH as clinically indicated 
Cortisol as clinically indicated
Serology
a) Serum for hepatitis C antibody, hepatitis B surface antigen, HIV-1 and -2 antibody 
(screening only) Note: Testing for HIV must be performed at sites where mandated 
locally.
Other Analyses
Pregnancy test (WOCBP only: as it is indicated on Section 2. Tables 2-1 to 2-8).
Follicle stimulating hormone (FSH) (screening only for women only) 
9.4.5
Suicidal Risk Monitoring
Not applicable
9.4.6
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
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10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination  
The sample size of the study is based on a comparison of the RFS distribution between participants 
randomized to nivolumab plus ipilimumab and participants randomized to nivolumab.  RFS will 
be evaluated for treatment effect using the following testing strategy: RFS will be compared first 
in the all randomized participants with PD-L1 expression level < 1% subgroup with an alpha 
allocation of 0.03 (two-sided); and if significant, the alpha allocated to this subgroup will be 
recycled to the treatment comparison in the overall population (all randomized participants). Thus
RFS will be compared in all randomized participants with an alpha allocation of 0.05 (two-sided). 
If the treatment comparison in all randomized participants with PD-L1 expression level < 1% is 
not significant, RFS will be compared in all randomized participants with an alpha allocation based 
on the method published by Spiessens and Debois53. This method takes into account the correlation 
between the test statistics for the overall and the subgroup analysis, and is essentially the same as 
the method used when dealing with interim analyses, ie, group sequential method. The alpha
allocated to the overall analysis will be calculated based on the fraction of information in the 
subgroup, relative to the overall population, which is determined by the ratio of events observed 
in the two groups. For example, if 257 events are observed in the PD-L1 expression level < 1%
subgroup, and 651 events are observed in the overall population (ie, about 40% of all events in the 
PD-L1<1% subgroup), the alpha allocated to the overall analysis is 0.0265.
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Simulation models incorporating aspects of immunotherapy like delayed separation (observed as 
late separation of survival curves between the experimental and SOC arms) and long term survival 
benefits (observed as a long-lasting plateau towards the tail of the survival curve) were developed 
for sample size estimation. Sample size calculations for this study design were done using EAST 
6 (v 6.3.1) and R.
The sample size is driven by the comparison of RFS between all randomized participants with PD-
L1 expression level < 1% randomized to receive nivolumab plus ipilimumab vs nivolumab. 
Approximately 600 participants with PD-L1 expression level < 1% will be randomized in a 
1:1 ratio to nivolumab plus ipilimumab and nivolumab respectively. Approximately 257 RFS 
events in all randomized participants with PD-L1 expression level < 1% will provide 
approximately 90% power to detect an average hazard ratio (HR) of 0.65 with an alpha level of 
0.03 (two-sided). In case the 257 RFS events would be reached at a timepoint earlier than 13 
months of minimum follow-up (from the randomization of the last participant), analysis of RFS 
will be conducted when there would be a minimum follow up of 13 months (ie, at the time when 
approximately 257 events are reached or a minimum follow-up of 13 months, whatever occurs 
later).
Accrual will be stopped when approximately 600 participants with PD-L1 expression level < 1% 
will be randomized in a 1:1 ratio to nivolumab plus ipilimumab and nivolumab respectively. The 
prevalence of participants with PD-L1 expression level < 1% is expected to be around 30% of all 
randomized participants. Therefore, it is estimated that approximately 2000 participants will be 
randomized in a 1:1 ratio to nivolumab plus ipilimumab and nivolumab respectively. No more than 
1400 participants with PD-L1 expression level ≥1% will be randomized to nivolumab plus 
ipilimumab and nivolumab respectively. Approximately 700 participants with PD-L1 expression 
level < 1% were randomized in a 1:1 ratio to nivolumab plus ipilimumab and nivolumab 
respectively. 
Approximately 651 RFS events in all randomized participants will provide approximately 90% 
power to detect an average hazard ratio (HR) of 0.76 with an alpha level of 0.0265 (two-sided).
The analysis of RFS in the all randomized participants with PD-L1 expression level < 1% subgroup 
will be performed at the time when approximately 257 RFS events are observed in this subgroup
or a minimum follow-up of 13 months is reached, whatever occurs later.
If the treatment comparison in the all randomized participants with PD-L1 expression level < 1% 
subgroup is significant, RFS will be compared in all randomized participants with an alpha 
allocation of 0.05. In this case, two analyses, an interim and a final, will be conducted in all 
randomized participants. The interim analysis will take place at the same time as the RFS analysis 
for the PD-L1 expression level < 1% subgroup. The final analysis will take place when
approximately 560 RFS events are observed in the overall population. 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. 
If the treatment comparison in all randomized participants with PD-L1 expression level < 1% 
subgroup is not significant, RFS will be compared in the overall population with an alpha 
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allocation based on the method published by Spiessens and Debois.53 In this case, no interim 
analysis is planned. The final RFS analysis for the overall population will be conducted when 
approximately 651 RFS events are observed (assuming allocated alpha is 0.0265). In case the 
events come slower than projected, final analysis of RFS for the overall population will be 
conducted when the minimum follow up from randomization of the last participant reaches 
30 months.
Given actual accrual rates so far and estimated accrual rates of 157 participants per month for the 
coming months, it is estimated that accrual of 2000 participants (ie, 1000 participants in a 1:1 ratio 
in the nivolumab plus ipilimumab and nivolumab arms each) and the participants in the ipilimumab 
arm that has already taken place, will take approximately 17 months. Given actual accrual rates, 
accrual took approximately 13.5 months.
Additional details on monitoring of events will be provided in the DMC charter.
10.1.1
RFS
The primary objective of the study is to compare RFS of nivolumab plus ipilimumab to nivolumab 
monotherapy in participants with completely resected stage IIIb/c/d or stage IV no evidence of 
disease (NED) melanoma. The number of events and power were calculated assuming a non-
proportional hazards model with a 3-month delayed treatment effect and a cure rate in each of the 
treatment arms.
10.1.1.1
RFS in All Randomized Participants with PD-L1 Expression Level < 1%  
For this comparison of RFS between nivolumab plus ipilimumab and nivolumab in all randomized 
participants with PD-L1 expression level < 1%, at least 257 RFS events would be required with 
PD-L1 expression level < 1% in the two respective treatment arms for a two-sided experiment-
wise alpha = 0.03 log-rank test, to show a statistically significant difference in RFS between the 
treatment arms with at least 90.0% power when the average hazard ratio (HR) of the nivolumab 
plus ipilimumab arm to the nivolumab arm is 0.65. A cure rate of 0.42 is assumed in the nivolumab 
treatment arm.  Under the assumptions for accrual and RFS distribution as per CA209238, 
Section 7.3 of the Clinical Study Report, nivolumab estimates and assumed HR as stated above, it 
would take approximately 29 months from the randomization of the first participant to observe the 
required number of RFS events. It is projected that an observed HR of 0.76 or less would result in 
a statistically significant improvement at the final analysis of RFS.
10.1.1.2
RFS in All Randomized Participants
For this comparison of RFS between nivolumab plus ipilimumab and nivolumab in all randomized 
participants, at least 651 RFS events would be required in the two respective treatment arms for a 
two-sided alpha = 0.0265 log-rank test, to show a statistically significant difference in RFS 
between the treatment arms with approximately 90% power when the average hazard ratio (HR) 
of the nivolumab plus ipilimumab arm to the nivolumab arm is 0.76. A cure rate of 0.49 is assumed 
in the nivolumab treatment arm. Under the assumptions for accrual and RFS distribution as per 
CA209238, Section 7.3 of the Clinical Study Report, nivolumab estimates and assumed HR as 
stated above, it would take approximately 44 months from the randomization of the first participant 
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to observe the required number of RFS events. It is projected that an observed HR of 0.84 or less 
would result in a statistically significant improvement at the final analysis of RFS.
For this comparison of RFS between nivolumab plus ipilimumab and nivolumab in all randomized 
participants, at least 560 RFS events would be required in the two respective treatment arms for a 
two-sided alpha = 0.05 log-rank test, to show a statistically significant difference in RFS between 
the treatment arms with approximately 90% power when the average hazard ratio (HR) of the 
nivolumab plus ipilimumab arm to the nivolumab arm is 0.76. A cure rate of 0.49 is assumed in 
the nivolumab treatment arm. Under the assumptions for accrual and RFS distribution as per 
CA209238, Section 7.3 of the Clinical Study Report, nivolumab estimates and assumed HR as
stated above, it would take approximately 30 months from the randomization of the first participant 
to observe the required number of RFS events. It is projected that an observed HR of 0.85 or less 
would result in a statistically significant improvement at the final analysis of RFS.
10.1.2
Overall Survival
The secondary objective of the study is to compare OS of nivolumab plus ipilimumab to nivolumab 
monotherapy in participants with completely resected stage IIIb/c/d or stage IV no evidence of 
disease (NED) melanoma. The number of events and power were calculated assuming a non-
proportional hazards model with a cure rate in each of the treatment arms.  
10.1.2.1
OS in All Randomized Participants with PD-L1 Expression Level < 1%
For this comparison of OS between nivolumab plus ipilimumab and nivolumab in all randomized 
participants with PD-L1 expression level <1%, at least 250 deaths would be required in the two 
respective treatment arms for a two-sided experiment-wise alpha = 0.05 adjusted log-rank test, to 
show a statistically significant difference in OS between the treatment arms with at least 80% 
power when the average hazard ratio (HR) of the nivolumab plus ipilimumab arm to the nivolumab 
arm is 0.70. It is projected that an observed HR of 0.78 or less would result in a statistically 
significant improvement at the final analysis of OS.
10.1.2.2
OS in All Randomized Participants 
For this comparison of OS between nivolumab plus ipilimumab and nivolumab in all randomized 
participants, at least 630 deaths would be required in the two respective treatment arms for a two-
sided experiment-wise alpha = 0.05 adjusted log-rank test, to show a statistically significant 
difference in OS between the treatment arms with at least 80% power when the average hazard 
ratio (HR) of the nivolumab plus ipilimumab arm to the nivolumab arm is 0.80. It is projected that 
an observed HR of 0.85 or less would result in a statistically significant improvement at the final 
analysis of OS.
For this comparison of OS between nivolumab plus ipilimumab and nivolumab in all randomized 
participants, at least 753 deaths would be required in the two respective treatment arms for a two-
sided experiment-wise alpha = 0.0265 adjusted log-rank test, to show a statistically significant 
difference in OS between the treatment arms with at least 80% power when the average hazard 
ratio (HR) of the nivolumab plus ipilimumab arm to the nivolumab arm is 0.80. It is projected that 
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an observed HR of 0.85 or less would result in a statistically significant improvement at the final 
analysis of OS.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All enrolled participants
All participants who signed an informed consent form and 
were registered into the IVRS.
All randomized participants
All participants who were randomized to any treatment arm 
in the study.
All randomized participants with 
PD-L1 expression level < 1%
All randomized participants with baseline tumor sample 
testing per IHC result < 1% membranous staining in tumor 
cell.
All treated participants
All participants who received at least one dose of study drug.
All treated participants with PD-
L1 expression level < 1%
All participants with baseline tumor sample testing per IHC 
result < 1% membranous staining in tumor cell who received 
at least one dose of study drug.
Immunogenicity evaluable 
participants:
-Nivolumab ADA evaluable 
participants
-Ipilimumab ADA evaluable 
participants
-All treated participants with baseline and at least 1 post 
baseline 
pre-infusion 
nivolumab 
immunogenicity 
assessment
-All treated participants with baseline and at least 1 post 
baseline 
pre-infusion 
ipilimumab 
immunogenicity 
assessment
 
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing and unused data. Below is a summary of planned statistical analyses of the primary and 
secondary endpoints. For participants in the ipilimumab arm, their data will be presented 
separately.
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A description of the participant population will be included in the statistical output reported, 
including subgroup of age, gender, and race.
10.3.1
Efficacy Analyses
10.3.1.1
Primary Endpoint Analysis
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 (including melanoma in situ), or death (whatever the cause), 
whichever occurs first. (Note: a participant who dies without reported recurrence will be 
considered to have recurred on the date of death.) For participants who remain alive and whose 
disease has not recurred, RFS will be censored on the date of last evaluable disease assessment. 
For those participants 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 10.3.1.1-1.
Table 10.3.1.1-1:
Censoring Scheme for Primary Definition of RFS
Situation
Date of Event or Censoring
Outcome
Recurrence (local, regional, distant, new primary 
melanoma (including melanoma in situ))
Date of first recurrence
Event
Death without recurrence
Date of death
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 distributions will be compared between treatment groups (nivolumab plus ipilimumab vs 
nivolumab) using a two-sided log-rank test stratified by AJCC stage at screening at a significance 
level of 3% (two-sided) in all randomized participants with PD-L1 expression level <1%.
RFS distributions will be compared, as described in Sections 10.1 and 10.3.4, between treatment 
groups (nivolumab plus ipilimumab vs nivolumab) using a two-sided log-rank test stratified by 
PD-L1 status and AJCC stage at screening in all randomized participants. 
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The hazard ratio and corresponding 100x (1-adjusted α)% confidence intervals (CIs) will be 
estimated using a Cox proportional hazards model, with treatment group as a single covariate, 
stratified by the above factors. 
RFS curves will be estimated using Kaplan-Meier (KM) product-limit methodology. Median RFS 
with two-sided 95% CIs using the log-log transformation will be computed. In addition, RFS rates 
at 6, 12, 24 and 36 months (and yearly after depending on follow-up) with two-sided 95% CIs 
using the log-log transformation will be computed.
The proportional hazards assumption will be assessed at the time of analysis and appropriate 
methods will be employed in case of non-proportional hazards.
10.3.1.2
Secondary Endpoint Analyses
Overall Survival
OS is defined as the time between the date of randomization and the date of death. For participants 
without documentation of death, OS will be censored on the last date the participant was known 
to be alive. OS will be followed continuously while participants are on the study drug and every 
3 months via in-person or phone contact after participants discontinue the study drug.
OS distributions will be compared in hierarchical testing order (order defined in Section 10.3.4) 
between treatment groups (nivolumab plus ipilimumab vs nivolumab) using a two-sided log-rank 
test stratified by AJCC stage at screening at the overall significance level of 5% (two-sided) in all 
randomized participants with PD-L1 expression level < 1%.
OS distributions will be compared in hierarchical testing order (order defined in Section 10.3.4) 
between treatment groups (nivolumab plus ipilimumab vs nivolumab) using a two-sided log-rank 
test stratified by PD-L1 status and AJCC stage at screening at the overall significance level of 5% 
(two-sided) in all randomized participants.
The hazard ratio and corresponding two-sided 100x (1-adjusted α)% CIs will be estimated using a 
Cox proportional hazards model, with treatment group as a single covariate, stratified by the above 
factors. 
OS curves will be estimated using Kaplan-Meier (KM) product-limit methodology. Median OS 
with two-sided 95% CIs using the log-log transformation will be computed.  In addition, OS rates 
at 6, 12, 24 and 36 months (and yearly after depending on follow-up) with two-sided 95% CIs 
using the log-log transformation will be computed.
Association between PD-L1 expression and RFS
The secondary objective (to evaluate the association between PD-L1 expression and RFS) will be 
measured by the endpoint RFS based on PD-L1 expression level.
Analyses of PD-L1 expression will include;
•
Examination of the distribution of PD-L1 expression using descriptive statistics and, 
cumulative distribution plots.
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•
Assessment of the potential association between PD-L1 expression using >= 1% expression 
level and RFS: forest plots of unstratified hazard ratios with 95% CIs for treatment effect on 
RFS by PD-L1 expression.
•
Assessment of the potential association between PD-L1 expression using >= 5% expression 
level and RFS: forest plots of unstratified hazard ratios with 95% CIs for treatment effect on 
RFS by PD-L1 expression.
Investigator-Assessed Outcomes on Next-Line Therapies 
PFS2 is defined as the time from randomization to second recurrence/objective disease 
progression, or death from any cause, whichever occurs first. 
In case PFS2 cannot be reliably determined, we will analyze the time from randomization to end 
or discontinuation of next-line treatment, second objective disease progression, or death from any 
cause, whichever occurs first. 
These endpoints will be analyzed using a two-sided log-rank test at the overall significance level 
of 5% (two-sided) in all randomized participants. The hazard ratio and corresponding 95% 
confidence intervals (CIs) will be estimated using a Cox proportional hazards model, with 
treatment group as a single covariate. No multiplicity adjustment will be applied. 
Objective response rates and duration of treatment on next-line therapies will be summarized.
10.3.2
Safety Analyses
Safety and tolerability of nivolumab combined with ipilimumab and nivolumab monotherapy will 
be measured by the incidence of adverse events, serious adverse events, deaths, and laboratory 
abnormalities.
Safety analyses will be performed in all treated participants with PD-L1 expression level <1% as 
well as in all treated participants. Descriptive statistics of safety will be presented using NCI 
CTCAE version 4.0 by treatment group (for the nivolumab combined with ipilimumab and 
nivolumab monotherapy arms). 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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10.3.4
Interim Analyses and Hierarchical Testing
RFS will be evaluated for treatment effect using the following testing strategy: RFS will be 
compared first in the all randomized participants with PD-L1 expression level < 1% subgroup with 
an alpha allocation of 0.03 (two-sided); and if significant, the alpha allocated to this subgroup will 
be recycled to the treatment comparison in the overall population (all randomized participants). 
Thus RFS will be compared in all randomized participants with an alpha allocation of 0.05 (two-
sided). If the treatment comparison in all randomized participants with PD-L1 expression level < 
1% is not significant, RFS will be compared in all randomized participants with an alpha allocation 
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based on the method published by Spiessens and Debois.53.This method takes into account the 
correlation between the test statistics for the overall and the subgroup analysis, and is essentially 
the same as the method used when dealing with interim analyses, ie, group sequential method.  The 
alpha allocated to the overall analysis will be calculated based on the fraction of information in the 
subgroup, relative to the overall population, which is determined by the ratio of events observed 
in the two groups. For example, if 257 events are observed in the PD-L1 expression level < 1% 
subgroup, and 651 events are observed in the overall population (ie, about 40% of all events in the 
PD-L1<1% subgroup), the alpha allocated to the overall analysis is 0.0265.
If the treatment comparison in the all randomized participants with PD-L1 expression level < 1% 
subgroup is significant, RFS will be compared in all randomized participants with an alpha 
allocation of 0.05. In this case, two analyses, an interim and a final, will be conducted in all 
randomized participants. The interim analysis will take place at the same time as the RFS analysis 
for the PD-L1 expression level < 1% subgroup. The final analysis will take place when 
approximately 560 RFS events are observed in the overall population. 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. 
If the treatment comparison in the all randomized participants  with PD-L1 expression level < 1% 
subgroup is not significant, RFS will be compared in the overall population with an alpha 
allocation based on the method published by Spiessens and Debois53.In this case, no interim 
analysis is planned. The final RFS analysis for the overall population will be conducted when 
approximately 651 RFS events are observed. (assuming allocated alpha is 0.0265). In case the 
events come slower than projected, final analysis for the overall population will be conducted 
when the minimum follow up from randomization of the last participant reaches 30 months. 
If both hypotheses for the RFS endpoint (for the PD-L1 < 1% subgroup and the overall population) 
are rejected, OS will be compared in all randomized participants with PD-L1 expression level < 
1% with an alpha allocation of 0.05 (two-sided); and if significant, then OS will be compared in 
all randomized participants with an alpha allocation of 0.05 (two-sided). One formal OS interim 
analysis will be conducted at the time that approximately 162 deaths (65% information fraction) 
have been reached among all randomized participants with PD-L1 expression level < 1%. 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. 
If the treatment comparison of RFS in the all randomized participants with PD-L1 expression level 
< 1% subgroup is not significant, but the treatment comparison of RFS in the all randomized 
participants population is significant (at alpha of 0.0265 or calculated), OS will be compared in all 
randomized participants at an alpha allocation of 0.0265 or calculated (two-sided).
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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12
APPENDICES
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APPENDIX 1
AJCC MELANOMA STAGING
[From AJCC Cancer Staging Manual, 8th Edition (pages 577 & 578)]
Definition of Primary Tumor (T)
T Category
Thickness
Ulceration Status
TX: primary tumor thickness cannot be 
assessed (e.g., diagnosis by curettage)
Not applicable
Not applicable
T0: no evidence of primary tumor (e.g., 
unknown primary or completely 
regressed melanoma)
Not applicable
Not applicable
Tis (melanoma in situ)
Not applicable
Not applicable
T1
≤1.0 mm
Unknown or unspecified
T1a
<0.8 mm
Without ulceration
T1b
<0.8 mm
With ulceration
0.8-1.0 mm
With or without 
ulceration
T2
>1.0-2.0 mm
Unknown or unspecified
T2a
>1.0-2.0 mm
Without ulceration
T2b
>1.0-2.0 mm
With ulceration
T3
>2.0-4.0 mm
Unknown or unspecified
T3a
>2.0-4.0 mm
Without ulceration
T3b
>2.0-4.0 mm
With ulceration
T4
>4.0 mm
Unknown or unspecified
T4a
>4.0 mm
Without ulceration
T4b
>4.0 mm
With ulceration
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Definition of Distant Metastasis (M)
M Category
Anatomic site
LDH level
M0
No evidence of distant metastasis
Not applicable
M1
Evidence of distant metastasis
See below
M1a
Distant metastasis to skin, soft tissue 
including muscle, and/or non-regional 
lymph node
Not recorded or unspecified
M1a(0)
Not elevated
M1a(1)
Elevated
M1b
Distant metastasis to lung with or 
without M1a sites of disease
Not recorded or unspecified
M1b(0)
Not elevated
M1b(1)
Elevated
M1c
Distant metastasis to non-CNS visceral 
sites with or without M1a or M1b sites 
of disease
Not recorded or unspecified
M1c(0)
Not elevated
M1c(1)
Elevated
M1d
Distant metastasis to CNS with or 
without M1a, M1b, or M1c sites of 
disease
Not recorded or unspecified
M1d(0)
Not elevated
M1d(1)
Elevated
Suffixes for M category: (0) LDH not elevated; (1) LDH elevated. No suffix is used if LDH is not 
recorded or is unspecified.
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Definition of Regional Lymph Node (N)
N 
Category
Number of tumor-involved regional 
lymph nodes
Presence of in-transit, 
satellite, or microsatellite 
metastases
NX
Regional nodes not assessed (e.g., SLN biopsy not 
performed, regional nodes previously removed for 
another reason)
Exception: pathological N category is not required for 
T1 melanomas, use cN
No
N0
No regional metastases detected
No
N1
One tumor-involved node or in-transit, satellite, and/or 
microsatellite metastases with no tumor-involved nodes
N1a
One clinically occult (i.e., detected by SLN biopsy)
No
N1b
One clinically detected
No
N1c
No regional lymph node disease
Yes
N2
Two or three tumor-involved nodes or in-transit, 
satellite, and/or microsatellite metastases with one 
tumor-involved node
N2a
Two or three clinically occult (i.e., detected by SLN 
biopsy)
No
N2b
Two or three, at least one of which was clinically 
detected
No
N2c
One clinically occult or clinically detected
Yes
N3
Four or more tumor-involved nodes or in-transit, 
satellite, or microsatellite metastases with two or more 
tumor-involved nodes, or any number of matted nodes 
with or without in-transit, satellite, and/or microsatellite 
metastases
N3a
Four or more clinically occult (i.e., detected by SLN 
biopsy)
No
N3b
Four or more, at least one of which was clinically 
detected, or presence any number of matted nodes
No
N3c
Two or more clinically occult or clinically detected, 
and/or presence any number of matted nodes
Yes
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AJCC Prognostic Stage Groups
Clinical (cTNM)
Clinical stage includes microstaging of the primary melanoma and clinical/radiologic/biopsy 
evaluation for metastases. By convention, clinical staging should be used after biopsy of the 
primary melanoma, with clinical assessment for regional and distant metastases. Note that 
pathological assessment of the primary melanoma is used for both clinical and pathological 
classification. Diagnostic biopsies to evaluate possible regional and/or distant metastasis also are 
included. Note there is only one stage group for clinical Stage III melanoma.
When T is....
And N is.....
And M is....
The clinical stage is...
Tis
N0
M0
0
T1a
N0
M0
IA
T1b
N0
M0
IB
T2a
N0
M0
IB
T2b
N0
M0
IIA
T3a
N0
M0
IIA
T3b
N0
M0
IIB
T4a
N0
M0
IIB
T4b
N0
M0
IIC
Any T, Tis
≥N1
M0
III
Any T
Any N
M1
IV
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PATHOLOGICAL (PTNM)
Pathological staging includes microstaging of the primary melanoma, including any additional 
staging information from the wide excision (surgical) specimen that constitutes primary tumor 
surgical treatment and pathological information about the regional lymph nodes after SLN 
biopsy or therapeutic lymph node dissection for clinically evident regional lymph node disease.
When T is....
And N is.....
And M is....
The pathological stage 
is...
Tis
N0
M0
0
T1a
N0
M0
IA
T1b
N0
M0
IA
T2a
N0
M0
IB
T2b
N0
M0
IIA
T3a
N0
M0
IIA
T3b
N0
M0
IIB
T4a
N0
M0
IIB
T4b
N0
M0
IIC
T0
N1b, N1c
M0
IIIB
T0
N2b, N2c, N3b or N3c
M0
IIIC
T1a/b-T2a
N1a-N2a
M0
IIIA
T1a/b-T2a
N1b/c or N2b
M0
IIIB
T2b/T3a
N1a-N2b
M0
IIIB
T1a-T3a
N2c or N3a/b/c
M0
IIIC
T3b/T4a
Any N >N1
M0
IIIC
T4b
N1a-N2c
M0
IIIC
T4b
N3a/b/c
M0
IIID
Ant T, Tis
Any N
M1
IV
Pathological Stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes 
to complete pathological staging; use cN information to assign their pathological stage.
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APPENDIX 2
PERFORMANCE STATUS SCALES
STATUS
SCALES
STATUS
KARNOFSKY
ZUBROD-
ECOG-WHO
Normal, no complaints
100
0
Normal activity
Able to carry on normal activities Minor signs 
or symptoms of disease
90
0
Normal activity with effort
80
1
Symptoms, but fully 
ambulatory
Cares for self. Unable to carry on normal 
activity or to do active work
70
1
Requires occasional assistance, but able to care 
for most of his needs
60
2
Symptomatic, but in 
bed < 50% of the day
Requires considerable assistance and frequent 
medical care
50
2
Disabled. Requires special care and assistance
40
3
Needs to be in bed 
> 50% of the day, but 
not bedridden
Severely disabled. Hospitalization indicated 
though death non imminent
30
3
Very sick. Hospitalization necessary. Active 
supportive treatment necessary
20
4
Unable to get out of 
bed
Moribund
10
4
Dead
0
5
Dead
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APPENDIX 3
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
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Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
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Unacceptable Methods of Contraception
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal(coitus interruptus)
•
Spermicide only
•
Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until the end of relevant 
systemic exposure defined as 7 months after the end of treatment in the male participant.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of treatment.
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 4
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A breach of 
the conditions and principles of Good Clinical Practice (GCP) (occurring in any country) in 
connection with that trial or the protocol related to the trial which is likely to affect to a significant 
degree the safety or physical or mental integrity of 1 or more subjects of the trial or the scientific 
value of the trial.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
•
IRB/IEC 
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given by subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language 
in which the participant is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the 
participant's legally acceptable representative and by the person who conducted the 
informed consent discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
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.
Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
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refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
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If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage 
area
•
amount currently in storage area
•
label identification number or batch 
number
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (e.g., lost, wasted) 
•
amount destroyed at study site, if 
applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence, if 
applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study treatment integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.   
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
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For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
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BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (e.g., 
cytotoxics or biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. 
The method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste 
disposal vendor must be documented.
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•
Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (e.g., among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
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APPENDIX 5
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose, as a verbatim term (as reported by the 
investigator), should not be reported as an AE/SAE unless it is an intentional overdose taken 
with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae and should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
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DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
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Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
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If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, the SAE report must be updated and submitted within 
24 hours to BMS (or designee) using the same procedure used for transmitting the initial 
SAE report.
All SAEs must be followed to resolution or stabilization.
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be 
reported to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the 
electronic data capture (EDC) system is unavailable/not functioning for 
transmission of the eCRF to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted 
via email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 7
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
β-HCG
beta-human chorionic gonadotrophin
BLQ
below limit of quantification 
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
minimum observed concentration
CNS
Central nervous system
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Term
Definition
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
DMC
Data monitoring committee
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
ESR
Expedited Safety Report
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
ie
id est (that is)
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Term
Definition
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
L
liter
LDH
lactate dehydrogenase
ln
natural logarithm
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
MMIS
malignant melanoma in situ
MMR
measles, mumps, rubella
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamics
PK
pharmacokinetics
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Term
Definition
QC
quality control
R2
coefficient of determination
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
t
temperature
T
time
T-HALF
Half life
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
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